Great Quotes about Homeopathy
/"There have been two great revelations in my life: The first was bepop, the second was homeopathy. "
----Dizzy Gillespie, great jazz musician
----Dizzy Gillespie, great jazz musician
Become a Certified Homeopath (CCH)
/FOR EDUCATED HOMEOPATHS: Prepare for your Homeopathic Certification with Access Natural Healing’s CCH Bootcamp Access Natural Healing’s Essential CCH Bootcamp Materials include: MATERIALS PACKAGE: 1. Materia Medica Study Cards 2. Study Calendar 3. Shopping List (you probably already have most of them) 4. Remedy List 5. First Weekly Course Materials emailed which include Materials for Study, Sample Quizzes, Assignments, etc… 6. Kick off Conference Call on Wednesday, January 12th at 6-7pm Pacific Time with Check-in, Weekly assignments, Q&A, etc… 7. RSVP to do conference calls in person at Access Natural Healing’s “Freedom Room” for those who live in the vicinity (up to 5 people). WEEKLY PACKAGES: 1. Seven More Weekly Course Materials Emailed To You 2. Seven More Conference Calls on Wednesdays, Jan. 12th, 19th, 26th, Feb 2nd, 9th, 16th, 23rd and March 2nd, 2011. 3. Post CCH Exam Optional Conference Call on Wednesday, March 9th at 6pm-7pm Pacific Standard Time (after your CCH Exam on March 5th, 2011). Why do the bootcamp for the CCH exam? I know that many of you are considering or have considered taking on this next step towards your professional development as a Homeopath. Then life throws other things at you, you get busy and it gets put on the backburner. I found from personal experience that making the Bootcamp commitment for myself that I actually was able to accomplish it. The studying process was important. It reminded me of the layers in certain remedies that I may not have used since studying them and it helped me see the deeper understanding that I have for the remedies that I’ve studied in school, used in practice, and then studied again! If you attend all the Access Natural Healing’s CCH Bootcamp Conference calls (8 in total), submit all the sample tests and homework (each week), and don't pass the exam you can choose to join any of Access Natural Healing’s upcoming CCH Bootcamps for Free. It's important you feel ready so if for any reason you decide not to take the test you can join the next group for no additional cost. Access Natural Healing’s CCH Bootcamp does not cover the CHC application process or fees, the proctoring requirements or the after exam ten case submissions. Although the conference calls will allow time for guidance and answers to any CCH application questions. Register now, LIMITED SPACE, by emailing info@accessnaturalhealing.com or calling 1-604-568-4663 (Pacific Standard Time in Vancouver, BC Canada) to get the DISCOUNTED rate of $469 if you sign up before November 30th, 2010. Regular amount is $529 after November 30th.
Homeopathic Remedy Support for Pre-Pardum conditions: A Series:
/ Nausea: One of the first indications that you might be pregnant! There are many homeopathic remedies to choose from for "Morning Sickness" or otherwise known as "hyperemesis gravidarum". Some very common choices are the remedies called 1. Ipecacuanha (Ipecac for short), 2. Nux Vomica which is sometimes called Colubrina or 3. Sepia which is made from the ink from a cuttlefish. 1. If you need the remedy Ipecacuanha, your version of nausea will be described as follows: This remedy is indicated for intense and constant nausea that is felt all day (not only in the morning) with retching, belching, and excessive salivation. You may feel worse from lying down, but also worse from motion. Even after you vomit, you still feel very nauseous. Hopefully, that is not your version of morning sickness. If so, luckily this remedy might help you. It can be found easily at most health food stores or natural pharmacies. You can also call any Homeopathic Centre (like Access Natural Healing) for the correct amount. 2. If you need the remedy Nux Vomica (aka Colubrina), this is what your description of morning sickness will sound like: Nausea, especially in the morning and after eating, especially if you are irritable, impatient, and chilly. You may retch a lot and have the urge to vomit, often without success. Your stomach feels sensitive and crampy, and you may be constipated. 3. OR if you should be taking the homeopathic remedy called Sepia, your Morning Sickness feels like this: Gnawing, intermittent nausea with an empty feeling in the stomach. It is especially indicated for you if you are feeling irritable, sad, worn out, and indifferent to your family. You feel worse in the morning before you eat, but are not improved by eating and may vomit afterward. Nausea can be worse when you are lying on your side. Odours of any kind may aggravate the symptoms. Food often tastes too salty. You may lose your taste for many foods, but may still crave vinegar and sour things. These homeopathic remedies will likely be easily found at any health food store or natural pharmacy. Look for one of the lower potencies (6C, 12C or 30C) and do not continue to take the remedies for more than one week continuously. If they are working you can stop taking them and only take them if the symptoms return. If they are not working, the remedies are not correctly chosen for you and will not work no matter how much of them you take, so stop taking them. Hope this leads you to some possibilities for helping your morning sickness or nausea during pregnancy and call a professionally trained Homeopath if it doesn't.
Use of Homeopathic Remedies during Epidemics
/Within three years of the Diphtheria outbreak in Broome County, NY from 1862 to 1864, there was a report of an 83.6% mortality rate amongst the conventional medical Doctors and a 16.4% mortality rate amongst the Homeopaths.
The use of homeopathy during the Influenza Pandemic of 1918
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The May 1921 edition of the Journal of the American Institute for Homeopathy had an article about the use of homeopathy during the Influenza Pandemic of 1918. Dr. T. A. McCann, from Dayton, Ohio reported that 24,000 cases of flu treated with conventional medicine had a mortality rate of 28.2%, while 26,000 cases of flu treated homeopathically had a mortality rate of 1.05%.
Alternative to Vaccines
/
What are my options? A personal quest.
By Elena Cecchetto DCH, CCH
Certified Homeopath
For a while I had been reading about homeopathy and knew that Homeopathic Remedies for Immunizations existed (Homeoprophylaxis). I knew that somehow you could use Homeopathic Remedies for the purpose of protection against targeted infectious diseases. I just didn’t know exactly how to do this. My fear of needles (specifically the vaccine dangers) sent me on this quest. So I called a few people to find out if they knew how. I called my friend’s cousin who had studied Homeopathy. I
called a few Homeopaths listed in the yellow pages (yes, back in the days of the yellow pages). I told them what I would like to do and asked if they knew how. I got a few different responses.
They all agreed that indeed it is entirely fitting for the system of medicine known as homoeopathy to be able to perform this function. But they just weren’t sure exactly how to do this. Keep in mind that I was investigating this many years ago. Now there are many Homeopaths internationally working with Homeopathic Remedies for Immunization.
Homeopathy has been well known for its incredible results during epidemics. In the era of the 1912 epidemic, the Homeopathic Remedy called Gelsemium had high success rates among the Homeopathic Doctors of the day. Yes, in the early 1900’s, in North America, Homeopaths were considered Doctors. Some excellent anecdotes and statistics that stick in my mind describing the use of Homeopathy for epidemics go something
like this:
1. One of the earliest tests of the homeopathic system was in the treatment of Typhus Fever (spread by lice) in an 1813 epidemic which followed the devastation of Napoleon’s army marching through Germany to attack Russia, followed by their retreat. When the epidemic came through Leipzig as the army pulled back from the east, Samuel Hahnemann, the founder of homeopathy, was able to treat 180 cases of Typhus, only losing two (1.11%). This was at a time when the conventional treatments were having a mortality rate of over 30%.
2. Within three years of the Diphtheria outbreak in Broome County, NY from 1862 to 1864, there was a report of an 83.6% mortality rate amongst the conventional medical Doctors and a 16.4% mortality rate amongst the Homeopaths.
3. The May 1921 edition of the Journal of the American Institute for Homeopathy had an article about the use of homeopathy during the Influenza Pandemic of 1918. Dr. T. A. McCann, from Dayton, Ohio reported that 24,000 cases of flu treated with conventional medicine had a mortality rate of 28.2%, while 26,000 cases of flu treated homeopathically had a mortality rate of 1.05%.
My quest wasn’t successful and I got the shots to go travelling. Luckily, I had no side effects that I know of, so far. Even better, I spent months reading the Homeopathic literature that I carted around with me and became completely enamored with the Philosophy of Homeopathy.
More than a decade later and I am finally one of the handful of Homeopaths in Vancouver with the level of education and accreditation that gives me the title of “Certified Classical Homeopath”. Even better, I have the opportunity to offer Homeopathic Remedies to help people be protected for specific infectious diseases. There are various protocols that can be used depending on the disease.
There is a great personal satisfaction that I get when I receive postcards from the travellers who have received excellent Homeopathic Care. Imagine going to India without experiencing any gastro-intestinal complaints! Amazing! Fun! That is how travel is meant to be. I am determined to be able to support people in attaining this kind of travel experience.
By Elena Cecchetto DCH, CCH
Certified Homeopath
For a while I had been reading about homeopathy and knew that Homeopathic Remedies for Immunizations existed (Homeoprophylaxis). I knew that somehow you could use Homeopathic Remedies for the purpose of protection against targeted infectious diseases. I just didn’t know exactly how to do this. My fear of needles (specifically the vaccine dangers) sent me on this quest. So I called a few people to find out if they knew how. I called my friend’s cousin who had studied Homeopathy. I
called a few Homeopaths listed in the yellow pages (yes, back in the days of the yellow pages). I told them what I would like to do and asked if they knew how. I got a few different responses.
They all agreed that indeed it is entirely fitting for the system of medicine known as homoeopathy to be able to perform this function. But they just weren’t sure exactly how to do this. Keep in mind that I was investigating this many years ago. Now there are many Homeopaths internationally working with Homeopathic Remedies for Immunization.
Homeopathy has been well known for its incredible results during epidemics. In the era of the 1912 epidemic, the Homeopathic Remedy called Gelsemium had high success rates among the Homeopathic Doctors of the day. Yes, in the early 1900’s, in North America, Homeopaths were considered Doctors. Some excellent anecdotes and statistics that stick in my mind describing the use of Homeopathy for epidemics go something
like this:
1. One of the earliest tests of the homeopathic system was in the treatment of Typhus Fever (spread by lice) in an 1813 epidemic which followed the devastation of Napoleon’s army marching through Germany to attack Russia, followed by their retreat. When the epidemic came through Leipzig as the army pulled back from the east, Samuel Hahnemann, the founder of homeopathy, was able to treat 180 cases of Typhus, only losing two (1.11%). This was at a time when the conventional treatments were having a mortality rate of over 30%.
2. Within three years of the Diphtheria outbreak in Broome County, NY from 1862 to 1864, there was a report of an 83.6% mortality rate amongst the conventional medical Doctors and a 16.4% mortality rate amongst the Homeopaths.
3. The May 1921 edition of the Journal of the American Institute for Homeopathy had an article about the use of homeopathy during the Influenza Pandemic of 1918. Dr. T. A. McCann, from Dayton, Ohio reported that 24,000 cases of flu treated with conventional medicine had a mortality rate of 28.2%, while 26,000 cases of flu treated homeopathically had a mortality rate of 1.05%.
My quest wasn’t successful and I got the shots to go travelling. Luckily, I had no side effects that I know of, so far. Even better, I spent months reading the Homeopathic literature that I carted around with me and became completely enamored with the Philosophy of Homeopathy.
More than a decade later and I am finally one of the handful of Homeopaths in Vancouver with the level of education and accreditation that gives me the title of “Certified Classical Homeopath”. Even better, I have the opportunity to offer Homeopathic Remedies to help people be protected for specific infectious diseases. There are various protocols that can be used depending on the disease.
There is a great personal satisfaction that I get when I receive postcards from the travellers who have received excellent Homeopathic Care. Imagine going to India without experiencing any gastro-intestinal complaints! Amazing! Fun! That is how travel is meant to be. I am determined to be able to support people in attaining this kind of travel experience.
A Randomized, Controlled Clinical Trial of the Homeopathic Medication TRAUMEEL in the Treatment of Chemotherapy-Induced Stomatitis in Children Und
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Menachem Oberbaum, M.D.1 Isaac Yaniv, M.D.2 Yael Ben-Gal, R.N.2 Jerry Stein, M.D.2
Nurit Ben-Zvi, R.N.2 Laurence S. Freedman, Ph.D.3 David Branski, M.D.4
1 The Institute of Research on Complementary Medicine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, Jerusa- lem, Israel.
2 Bone Marrow Transplantation Unit, The Schnei- der Children’s Medical Center of Israel, Rabin Med- ical Center, Petach Tikva, Sackler School of Med- icine, Tel-Aviv University, Israel.
3 Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University. Ramat- Gan, Israel.
4 Department of Pediatrics, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusa- lem, Israel.
Supported by a grant from the International Society of Homotoxicology, Baden-Baden, Germany.
The authors are grateful to Dr. Yoram Neumann from the Department of Pediatric Hematology On- cology at The Chaim Sheba Medical Center (Tel- Aviv, Israel) for his help in the planning and design of the first version of the study protocol. They also thank Nitzan Teva, R.N., for her initiative and enthusiastic work at the beginning of the study. Finally, the authors thank the nurses of the Bone Marrow Transplantation Unit at The Schneider Children’s Medical Center of Israel for their support and patience during this study.
Address for reprints: Menachem Oberbaum, M.D., The Institute of Research on Complementary Med- icine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel; Fax: 972-2- 6666975; E-mail: oberbaum@netvision.net.il
Received December 21, 2000; revision received March 27, 2001; accepted April 9, 2001.
BACKGROUND. Stomatitis is a common consequence of chemotherapy and a con- dition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL, in the management of chemotherapy- induced stomatitis in children undergoing bone marrow transplantation. METHODS. A randomized, placebo-controlled, double-blind clinical trial was con- ducted in 32 patients ages 3–25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a mini- mum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis.
RESULTS. A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P0.01). CONCLUSIONS. This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. Cancer 2001;92:684–90.
© 2001 American Cancer Society.
KEYWORDS: TRAUMEEL, stomatitis, mucositis, autologous, allogeneic, stem cell transplantation, bone marrow transplantation, randomized, placebo-controlled, ho- meopathy, complementary medicine.
Stomatitis occurs commonly as part of general inflammatory dam- age to the mucous membranes in patients receiving chemother- apy or radiation therapy to the oropharyngeal region. The overall incidence of reactive stomatitis is about 40%.1,2 However, it is partic- ularly common in patients receiving 5-fluorouracil (5-FU) treat- ment1–4 and is even more common in those undergoing radiation therapy for malignancies of the head and neck, in which approxi- mately 80% of patients are affected.2 In patients undergoing bone marrow transplantation (BMT), the incidence of stomatitis reaches 95%.1
The mechanism of development of stomatitis is primarily cytotoxic,1,5
© 2001 American Cancer Society
although neutropenia,1,6 periodontal pathology,1,7 poor oral hygiene,1,8 poor nutritional status,1 and infections also contribute to the condition. Morphologic character- istics can vary from slight erythema and edema of the oral mucosa to severe, focal, or widespread ulceration, bleeding and exudation.1,5 In addition to pain and dis- comfort, loss of the mechanical barrier together with the large surface of necrotic mucosa and neutropenia can lead to secondary local infections, sepsis, and even life- threatening systemic infections.1,6,9,10 Severe cases of stomatitis often necessitate the interruption of chemo- therapy treatment or dose reduction and may affect pa- tient compliance with further treatment.1 Compared with other chemotherapy-related toxicities, such as my- elosuppression, the incidence of mucositis and the sig- nificance of its toxicity is increasing. Consequently, oral mucositis is becoming the most common dose-limiting toxicity of chemotherapy.1,2
The current treatment of patients with stomatitis is essentially symptomatic. This includes stringent oral hygiene, avoiding irritating and abrasive foods, good oral and dental care, and the use of bland rinses, topical anesthetics, and systemic analgesics.11 Such treatments, however, are of limited value and have shown improvement only in patients with mild to moderate stomatitis.1,2,12
TRAUMEEL is a homeopathic-complex remedy that has been sold over the counter in pharmacies in Germany, Austria, and Switzerland for over 50 years. It contains extracts from the following plants and min- erals, all of them highly diluted (10��1–10��9 of the stem solution): Arnica montana, Calendula officinalis, Achillea millefolium, Matricaria chamomilla, Symphy- tum officinale, Atropa belladonna, Aconitum napellus, Bellis perennis, Hypericum perforatum, chinacea an- gustifolia, Echinacea purpurea, Hamamelis virginica, Mercurius solubilis, and Hepar sulfuris. Information from the manufacturer indicates that TRAUMEEL S is used normally to treat trauma, inflammation, and de- generative processes.
Informal experience in patients with chemother- apy-related stomatitis suggests that the condition may respond to treatment with TRAUMEEL S homeopath- ic-complex remedy. Based on this and subsequent positive results from a preliminary open study in 20 patients with stomatitis who were treated with TRAUMEEL S compared with 7 untreated, randomly selected patients,13 we decided to conduct the ran- domized, placebo-controlled, double-blind clinical trial reported here.
MATERIALS AND METHODS Patients Thirty-two consecutive patients who were admitted to Schneider Children’s Medical Center, ages 3–25 years,
suffering from malignant diseases and underwent BMT were enrolled. Patients had undergone alloge- neic or autologous stem cell transplantation.14 The study was approved by the ethical committee at the Rabin Medical Center, and informed, written consent was obtained from parents and/or guardians of all children prior to their enrolment in the study after a full explanation of the benefits, potential hazards, and procedures involved in the study to the patients and their parents and/or guardians.
Study Medication
For this study, both TRAUMEEL S and placebo were provided by the HEEL Company (Baden-Baden, Ger- many) in sterile, 2.2-mL ampoules. Solutions of TRAUMEEL S were prepared by diluting the active substance in saline, according to the German Homeo- pathic Pharmacopoeia (HAB). The placebo consisted only of saline. The active medication and placebo did not differ in color, taste, or odor.
TRAUMEEL S is manufactured according to the European Union Guidelines on Good Manufacturing Practice for Medicinal Products15 and in accordance with the HAB. The physical and microbiologic controls of the medications were according to the European Pharmacopoeia specifications.
Extensive safety data from a large survey of TRAUMEEL S showed adverse events in only 0.0035% of patients, despite its use in over 3.5 million patients (manufacturer’s own survey). Adverse effects reported were mostly skin reactions to the cream or local pru- ritus as a reaction to injection. However, because TRAUMEEL S contains dilutions of substances that may be regarded as toxic, we calculated the content of one of the most toxic substances, a mercury salt, in the medication. Assuming that a patient will have to be treated with TRAUMEEL S for 1 week, he or she will receive 35 ampoules. The mercury concentration of one ampoule is 0.5 ng/mL, giving a total amount of ingested mercury of approximately 17.5 ng per week. This compares favorably with the permitted mercury content of drinking water according to German law (0.001 mg/L).16 Thus, a 1-week treatment of TRAUMEEL S contains approximately 10��3 of the amount of mercury deemed permissible in 1 L of drinking water.
Study Procedures
Thirty-two patients received various conditioning reg- imens for 5–8 days followed by autologous (16 pa- tients) or allogeneic (16 patients) stem cell infusion on Day 0. Patients were randomized to receive either placebo or TRAUMEEL S on Day 2 of the study in addition to twice-daily mouth washes with chlorohex- imide, oral amphoterin B, and gentle tooth brushing
TRAUMEEL Treatment of Stomatitis/Oberbaum et al. 685
686 CANCER August 1, 2001 / Volume 92 / Number 3
TABLE 1 World Health Organization Grading System for Mucositis
Grade Status
0 No change 1 Soreness/erythema (painless) 2 Erythema (painful), ulcers; can eat solids 3 Ulcers; requires liquid diet only 4 Alimentation not possible
(institutional standard for mouth care). Packages of TRAUMEEL S and placebo were prepared by the HEEL Company and were identified by serial number only. The code showing the treatment corresponding to each serial number was kept by the company, the study coordinator (M.O.), and the statistician (L.S.F.). The code was not broken until the completion of the trial. Treatment was started on Day 2 after stem cell transplantation, so that treatment began before the first symptoms of stomatitis (e.g., dryness and/or sore- ness of the mouth) were observed. The peak incidence of mucositis is typically 5–7 days after transplantation. Fifteen evaluable patients received placebo, and 15 evaluable patients received TRAUMEEL S. Patients were instructed to rinse their mouths vigorously with the solution for a minimum of 30 seconds before swallowing. In addition, patients were directed to keep the liquid as long as possible on particularly trouble- some lesions in their mouth. This procedure was re- peated five times daily.
The World Health Organization (WHO) grading system for mucositis (Table 1) was used to evaluate stomatitis in each patient.17 In addition, a subjective scoring system was used in which either the patient or the parents were asked to judge the degree of oral pain and discomfort, dryness of mouth and tongue, dys- phagia, and ability to swallow. A five-grade system was used (Grade 0, no complaints; Grade 4, very severe complaints, unable even to swallow liquids). The time to worsening of stomatitis was evaluated as the time from randomization to the day when the mucositis score increased from that recorded at baseline. Pa- tients were evaluated at least once every 2 days. All evaluations were performed blind by the same ob- server (the study nurse). The trial continued until the patient symptomology had been scored as Grade 0 on 2 consecutive days or until a minimum of 14 days after the start of TRAUMEEL S or placebo treatment in patients in whom no symptoms developed.
The trial was carried out at the Bone Marrow Transplantation Unit, The Schneider Children’s Med- ical Center of Israel, Rabin Medical Center, Petach Tikva, Israel. All study forms were collected, stored, and transferred to computer for analysis by the study
coordinator (M.O.). Statistical analysis was performed at the Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University, Ramat-Gan, Israel (L.S.F.). The randomization code was prepared by the manufacturer (HEEL Company) and was re- vealed only on completion of the study. Neither the manufacturer, the study coordinator, nor the statisti- cian was involved in any aspect of the treatment of participating patients.
Statistical Analysis
All statistical analyses were done on an intent-to-treat basis unless indicated otherwise. That is, each patient was considered to be allocated randomly to a group regardless of the treatment actually received. The two main treatment comparisons, as specified in the pro- tocol, were of the area under the curve (AUC) for stomatitis symptoms, and the time to first worsening of stomatitis symptoms. Both are based on the WHO grading system.
The AUC is equivalent to the sum of the grade on each day from the start of TRAUMEEL S or placebo treatment. It therefore incorporates both severity and duration of symptoms. When grades were recorded every other day, we used linear interpolation to esti- mate the stomatitis score on those days when evalu- ation did not occur. Because the AUC score distribu- tion was not normal, statistical comparison was performed using the two-sample Wilcoxon rank-sum test.
Most patients (77%) started TRAUMEEL S or pla- cebo treatment before the onset of symptoms. In these patients, therefore, the time to worsening of symp- toms was the same as the time to the start of symp- toms. Consequently, the time to worsening differed from time to first development of symptoms in only 23% of patients (17% with Grade 1 symptoms and 6% with Grade 2 symptoms). The statistical comparison of this endpoint was performed using the log-rank test. All P values reported are two-sided.
RESULTS Patients A total of 32 patients were enrolled in this trial. How- ever, two patients (one in the TRAUMEEL S treatment group and the other in the placebo group) received a single dose of study drug but then refused further treatment, complaining of nausea. These patients were not evaluated subsequently for stomatitis and, thus, cannot be included in this analysis. Fifteen pa- tients each remained in the TRAUMEEL S group and the placebo group. The distribution of patient charac- teristics for each group is shown in Table 2. The groups were comparable with regard to age, gender, type of BMT, granulocyte-colony stimulating factor
TABLE 2 Patient Characteristics
Characteristic
Patients (no.) Age (yrs)
Mean (SD) Distribution
3–4 5–9 10–14 15–19 20–25
Gender (no. of men) (%) Diagnosis (%)
AML ALL CML Lymphoma Othera BMT (%) Allogeneic Autologous
GCSF GVHD prophylaxis (%)
CSA only CSA methotrexate CSA steroids None
TABLE 3 Stomatitis Area Under the Curve Scores and Time to First Worsening of Symptoms by Allocated Treatment
AML: acute myelogenous leukemia; ALL: acute lymphoblastic leukemia; CML: chronic myelogenous leukemia; BMT: bone marrow transplantation; GCSF: granulocyte-colony stimulating factor; GVHD: graft versus host disease; CSA: cyclosporin A; SD: standard deviation. a Other diagnoses in the TRAUMEEL group: one neuroblastoma, one aplastic anemia, one thalas- semia, one Ewing sarcoma, and one medulloblastoma. Other diagnoses in the placebo group: one neuroblastoma, one Wilms tumor, two aplastic anemia, one thalassemia, one Ewing sarcoma, and one Fanconi syndrome.
treatment and prophylaxis against graft versus host disease (GVHD). However, there were some differ- ences in the distribution of diseases between the groups: There were seven patients versus three pa- tients with acute myelogenous leukemia (AML) and zero patients versus three patients with lymphoma in the TRAUMEEL S and placebo groups, respectively. In addition, the three patients who underwent a higher risk BMT (haploidentical or cord blood) all were allo- cated randomly to the TRAUMEEL S treatment group. The use of concomitant medication, including analge- sic treatment, was comparable in both treatment groups.
There was doubt regarding the stomatitis score of Patient 12 as a result of an administrative error. Our policy in areas of doubt was to take the value less favorable to the TRAUMEEL S treatment group. In this instance, the choice was between an AUC score of either 38 or 0, and we used the score of 38. In addition, one patient who was allocated to the placebo group inadvertently received TRAUMEEL S. However, this
AUC: area under the curve. a Test for difference in AUC: Wilcoxon rank sum score, 167.5; expected score, 232.5 (P �� 0.01). b Test for difference in time to worsening: chi-square test, 13.4 with 1 degree of freedom (P �� 0.001). c The patient received TRAUMEEL S�� accidentally. d There was doubt regarding the AUC score and time to worsening. An alternative interpretation would be AUC, 0; time �� 19 days. e Means and medians of uncensored times only are shown.
patient was still considered part of the placebo treat- ment group, and it is interesting to note that this patient had the second lowest stomatitis AUC score in the placebo treatment group. This patient was in- cluded in the analysis according to the intent-to-treat principle and to guard against any bias in the study. Exclusion of this patient from the analysis would have increased the difference between the treatment groups (in favor of TRAUMEEL S). In view of the double-blind design and the intention-to-treat analy- sis used, it seems unlikely that these irregularities would have substantially affected the results of the study.
Efficacy
The stomatitis AUC scores, together with the times to first worsening, are summarized in Table 3. Stomatitis AUC scores range from 0 to 56. Five patients (33%) allocated to the TRAUMEEL S group did not develop stomatitis (AUC score, 0) compared with 1 patient (7%) from the placebo group. The mean AUC scores were 10.4 in the TRAUMEEL S group and 24.3 in the placebo group. This difference was statistically signif-
TRAUMEEL Placebo
15 15
10.1 (7.0) 3 5
TRAUMEEL
Patient AUCa
1 9 3 0 6 4 7 20 9 11 12d 38 13 0 15 0 17 0 19 17 22 0 23 17 25 3 28 5 30 26.5 Mean 10.4 Median 5.0
Placebo
6 2 3 1 8 (53)
3 (20) 1 (7) 1 (7) 3 (20) 7 (47)
8 (53) 7 (47) 4 (27)
1 (7) 3 (20) 3 (20) 8 (53)
9.7 (5.7)
3 3 3 1 9 (60)
7 (47) 2 (13) 1 (7) 0 (0) 5 (33)
7 (47) 8 (53) 4 (27)
2 (13) 4 (27) 1 (7) 8 (53)
worsening AUCa (days)b
27.5 4 16 4 16 2–3 36 1–2 4 6–7 56 4 14 2–3 20 2–3 31 10–11 21 3
0 ��6 26.5 5 45 4 35 10 16 4 24.3 4.3e 21.0 4.0e
TRAUMEEL S�� Treatment of Stomatitis/Oberbaum et al. 687
Time to worsening (days)b Patient
��8 2 ��18 4 ��9 5 4–5 8 3–5 10c 20 11 ��13 14 ��13 16 ��5 18 5 20 ��10 21 4–7 24 ��8 26 7 27 2–3 29 6.9e — 4.7e —
Time to
688 CANCER August 1, 2001 / Volume 92 / Number 3
icant (Wilcoxon rank-sum score, 167.5; expected score, 232.5; P �� 0.01) and suggests that TRAUMEEL S treatment reduced the severity and/or duration of sto- matitis compared with placebo.
In the group of 22 patients age �� 15 years, the mean AUC score for stomatitis was 11.0 in the TRAUMEEL S group and 25.9 in the placebo group. The Wilcoxon rank-sum test for the difference re- mained statistically significant (Wilcoxon rank-sum score, 93.0; expected score, 126.5; P �� 0.01). Thus, the difference remains only if younger patients are con- sidered.
Seven patients (47%) in the TRAUMEEL S treat- ment group and 14 patients (93%) in the placebo group experienced worsening of symptoms during treatment. The log-rank test indicated that there was a statistically significant difference (chi-square test, 13.4 with 1 degree of freedom; P �� 0.001) between the two groups in the time to worsening of symptoms. In those patients whose symptoms worsened, the median time to worsening was 4.7 days in the TRAUMEEL S group and 4.0 days in the placebo group. These results indi- cate that symptoms were much less likely to worsen in patients receiving TRAUMEEL S treatment than in those receiving placebo, but that, among those whose symptoms did worsen, there was little difference in the median time to worsening of stomatitis between the two treatment groups.
Subjective Symptom Score
The maximum symptom scores for dryness of mouth, oral pain, and eating difficulty over the first 7 days of TRAUMEEL S and placebo treatment are shown in Figure 1. These data were recorded at regular intervals over the 7-day treatment period. These results are very similar to the stomatitis AUC score results: Patients in the TRAUMEEL S group showed a clear reduction in severity of symptoms in all three categories, as indi- cated by changes in the symptom grading system, compared with the placebo group.
Safety and Tolerability
There was a high incidence of serious complications but with no significant difference between the groups, as expected in a group of patients undergoing BMT. GVHD occurred in three patients in the TRAUMEEL S group compared with six patients in the placebo group, sepsis occurred in three patients in the TRAUMEEL S group compared with eight patients in the placebo group, and gastrointestinal complications occurred in no patients in the TRAUMEEL S group compared with five patients in the placebo group. Four patients with venous-occlusive disease occurred in the TRAUMEEL S group compared with none in the placebo group, and pneumonitis occurred in four pa-
FIGURE 1. The maximum subjective score (0, no complaints; 4, very severe complaints/parenteral nutrition necessary) during the first 7 days of study treatment with TRAUMEEL (n �� 15 patients) or placebo (n �� 15 patients) for dryness of mouth (a), oral pain (b), and eating difficulty (c).
tients in the TRAUMEEL S group compared with none in the placebo group. Some patients developed more than one of these complications. There was no differ- ence in the incidence or duration of severe neutrope- nia between the two treatment groups.
There was no significant difference in the number of deaths between the TRAUMEEL S and placebo groups in a follow-up of 44 weeks. Only one death occurred during the study period (to Day 20).
DISCUSSION
Currently available treatments for chemotherapy-in- duced stomatitis are of limited efficacy in preventing or ameliorating it. The effect of local treatment is short lived, and the medications often have an unpleasant taste. Moreover, the risk of absorption limits the fre- quency with which some of these drugs may be used in small children and in the elderly. For these reasons, the potential benefits of treatment with TRAUMEEL S are of particular interest.
This study demonstrated a statistically significant and clinically relevant difference in efficacy between TRAUMEEL S and placebo in the treatment of stoma- titis in children undergoing stem cell transplantation. The strategy of analysis employed in this trial protects against any bias toward TRAUMEEL S. For example, a patient who developed stomatitis on the day that TRAUMEEL S was discontinued (Day 20) was classed as having stomatitis despite developing the condition after treatment was stopped. Patient 10, who acciden- tally received TRAUMEEL S instead of placebo, still was considered part of the placebo group and, in fact, had the second lowest stomatitis AUC score in this group. In addition, there was an excess of patients with lymphoma and a deficit of those with AML in the TRAUMEEL S group. Because it was observed that AML patients had, on average, slightly lower AUC scores compared with other patients in this trial (data not shown), any resulting bias would not benefit the TRAUMEEL S group. Finally, the three transplant pa- tients who were at the highest risk were allocated randomly to the TRAUMEEL S group. These patients subsequently died, two of them within 3 months of BMT. This may account for the somewhat higher number of deaths among patients in the TRAUMEEL S group. Because the AUC scores for these three patients were 0, 17, and 38, there is no evidence that these higher risk transplantation patients had less severe stomatitis.
Initial observations of treatment with TRAUMEEL S suggest that it is almost free from adverse effects. In addition to the patients in this trial, TRAUMEEL S has been given to over 80 patients receiving chemotherapy on an outpatient basis at the Schneider Children’s Medical Center. With the exception of one patient in the trial who stopped treatment on the first day and two other children who complained of nausea, no other acute adverse effects have been reported.
The mechanism of action of TRAUMEEL S re- mains unknown. It also is unclear whether only one of its components is biologically active or whether the effects are due to the action of several components. The marked effects seen in this study were achieved using a solution of TRAUMEEL S containing ingredi-
ents in very low concentrations. Some of the ingredi- ents of TRAUMEEL S are regarded by homeopaths as remedies with anti-inflammatory properties (Bella- donna, Aconitum, Mercurius, Hepar, and Chamo- milla) or mucoprotective properties (Calendula and Hamamelis). Arnica is one of the main remedies used in homeopathic treatment of trauma. Arnica, Calen- dula, Hamamelis, and Milefolium are believed to have antihemorrhagic properties. Echinacea angustifolia and Echinacea purpurea are thought to be immunos- timulatory. Hypericum has been used in patients with neural injury. This suggests that several components may play a role in the mechanism of action of TRAUMEEL S. Indeed, the observation that such a strong response is associated with such small quanti- ties of the different remedies in TRAUMEEL S suggests that a synergistic effect may be involved. However, further research is needed to identify which compo- nent(s) are the active compound(s).
The effect of orally administered TRAUMEEL S seems to be isolated to the oral mucosa. Patients with mucositis of other areas of the alimentary tract, for example, esophagitis, enteritis, or proctitis as assessed by subjective complaint (diarrhea and rectal or esoph- ageal pain), did not respond to the TRAUMEEL S administered orally in our trial. Furthermore, there was no difference between the two groups in the me- dian number of days with severe neutropenia. This supports the hypothesis that the effect of this homeo- pathic drug is a local one.
The localized effect of TRAUMEEL S also is im- portant for another reason, which has relevance to the general problem of complementary medicine in the treatment of patients with malignant disease. If com- plementary medical treatment in reality has no bio- logic effect, then at least it will do no harm. However, if it does have a biologic effect, and given our lack of understanding of the mechanisms of action of TRAUMEEL S and homeopathic medicine in general, concerns may be raised about deleterious systemic effects, for example, increasing the resistance of the malignant cells to chemotherapy. Because the effect of TRAUMEEL S appears to be only local, this concern becomes less relevant.
In conclusion, this double-blind, controlled study showed that TRAUMEEL S significantly reduces the severity and duration of chemotherapy-induced sto- matitis in children undergoing BMT. TRAUMEEL S appears capable, at least in part, of ameliorating a problem that not only causes considerable suffering to patients but often limits the possibilities of aggressive treatment with chemotherapy. Because there are few effective, conventional treatments for patients with chemotherapy-induced stomatitis currently available, the significance of treatment with TRAUMEEL S be-
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comes apparent. An effective treatment for stomatitis would allow more aggressive chemotherapy treat- ments, particularly in children, and, consequently, would be likely to improve the success rates of many chemotherapy programs. Our study population is small and includes patients with a variety of diagnoses who received several different forms of conditioning regimens. Confirmation of our results in a larger trial in patients receiving BMT or other intensive chemo- therapy protocols is needed. Therefore, we are plan- ning to extend our investigations to a large-scale, mul- ticenter study to evaluate the efficacy and safety of TRAUMEEL S in the treatment of adults who are at risk for chemotherapy-induced stomatitis.
REFERENCES
1. Wilkes RW. Prevention and treatment of oral mucositis fol- lowing cancer chemotherapy. Semin Oncol 1998;25:538 –51. 2. Sonis ST, Eiler EP, Epstein EB, Le Veque FG, Liggett WH Jr., Mulagha MT, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced
by radiation or chemotherapy. Cancer 1999;85:2103–13. 3. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athman LM, Therneau TM, et al. Inhibition of 5-fluoro-uracil-in- duced mucositis by oral cryotherapy. J Clin Oncol 1991;9:
449 –52. 4. Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iversen RK,
Finck G, et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluoroura- cil-realted stomatitis. Cancer 1993;72:2234 – 8.
5. Peterson DE, Schubert MM. Oral toxicity. In: Perry MC, editor. The chemotherapy source book, 1st edition. Balti- more: Williams & Wilkins, 1991:508 –30.
6. Pizzo PA. Granulocytopenia and cancer therapy: past prob- lems, current solutions, future challenges. Cancer 1984;54: 2649 – 61.
7. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infections in patients with acute nonlympho- cytic leukemia: prevalence of acute exacerbations. Arch In- tern Med 1982;142:551–5.
8. Levine RS. Saliva 1—the nature of saliva. Dent Update 1989; 4:102– 6.
9. De Conno F, Ripamonti C, Sbanatto A, Ventafridda V. Oral complications in patients with advanced cancer. J Palliat Care 1989;5:7–15.
10. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328(18): 1323–33.
11. Miascowski C. Management of mucositis during therapy. NCR Monogr 1990;9:95–8.
12. Peterson DE. Pretreatment strategies for infection preven- tion in chemotherapy patients. NCR Monogr 1990;9:61–71.
13. Oberbaum M. Experimental treatment of chemotherapy- induced stomatitis, using a homeopathic-complex remedy: a preliminary study. Biomed Ther 1998;16:261–5.
14. Lloyd ME. Oral medicine concerns the BMT patient. In: Buchsel P, Whedon M, editors. Bone marrow transplanta- tion administrative and clinical strategies, 1st edition. Bos- ton: Jones and Bartlett Publishers, 1995:257–281.
15. Auterhoff G. Manufacture of investigational medicinal prod- ucts. European Commission, Directorate-General III, Indus- try: Consumer goods industries, III/E/3: Pharmaceuticals. Pharm Ind 59, 1997;2:121– 4.
16. Verordnung u ̈ ber Trinkwasser und u ̈ ber Wasser fu ̈ r Lebens- mittelbetriebe (Trinkwasserverordnung) vol 5.12.1990. Bundesgesetztblatt Jahrgang 66:Teil 1.
17. World Health Organization. Handbook for reporting results of cancer treatment (offset publication 48). Geneva: World Health Organization, 1979:15–22.
Nurit Ben-Zvi, R.N.2 Laurence S. Freedman, Ph.D.3 David Branski, M.D.4
1 The Institute of Research on Complementary Medicine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, Jerusa- lem, Israel.
2 Bone Marrow Transplantation Unit, The Schnei- der Children’s Medical Center of Israel, Rabin Med- ical Center, Petach Tikva, Sackler School of Med- icine, Tel-Aviv University, Israel.
3 Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University. Ramat- Gan, Israel.
4 Department of Pediatrics, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusa- lem, Israel.
Supported by a grant from the International Society of Homotoxicology, Baden-Baden, Germany.
The authors are grateful to Dr. Yoram Neumann from the Department of Pediatric Hematology On- cology at The Chaim Sheba Medical Center (Tel- Aviv, Israel) for his help in the planning and design of the first version of the study protocol. They also thank Nitzan Teva, R.N., for her initiative and enthusiastic work at the beginning of the study. Finally, the authors thank the nurses of the Bone Marrow Transplantation Unit at The Schneider Children’s Medical Center of Israel for their support and patience during this study.
Address for reprints: Menachem Oberbaum, M.D., The Institute of Research on Complementary Med- icine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel; Fax: 972-2- 6666975; E-mail: oberbaum@netvision.net.il
Received December 21, 2000; revision received March 27, 2001; accepted April 9, 2001.
BACKGROUND. Stomatitis is a common consequence of chemotherapy and a con- dition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL, in the management of chemotherapy- induced stomatitis in children undergoing bone marrow transplantation. METHODS. A randomized, placebo-controlled, double-blind clinical trial was con- ducted in 32 patients ages 3–25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a mini- mum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis.
RESULTS. A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P0.01). CONCLUSIONS. This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. Cancer 2001;92:684–90.
© 2001 American Cancer Society.
KEYWORDS: TRAUMEEL, stomatitis, mucositis, autologous, allogeneic, stem cell transplantation, bone marrow transplantation, randomized, placebo-controlled, ho- meopathy, complementary medicine.
Stomatitis occurs commonly as part of general inflammatory dam- age to the mucous membranes in patients receiving chemother- apy or radiation therapy to the oropharyngeal region. The overall incidence of reactive stomatitis is about 40%.1,2 However, it is partic- ularly common in patients receiving 5-fluorouracil (5-FU) treat- ment1–4 and is even more common in those undergoing radiation therapy for malignancies of the head and neck, in which approxi- mately 80% of patients are affected.2 In patients undergoing bone marrow transplantation (BMT), the incidence of stomatitis reaches 95%.1
The mechanism of development of stomatitis is primarily cytotoxic,1,5
© 2001 American Cancer Society
although neutropenia,1,6 periodontal pathology,1,7 poor oral hygiene,1,8 poor nutritional status,1 and infections also contribute to the condition. Morphologic character- istics can vary from slight erythema and edema of the oral mucosa to severe, focal, or widespread ulceration, bleeding and exudation.1,5 In addition to pain and dis- comfort, loss of the mechanical barrier together with the large surface of necrotic mucosa and neutropenia can lead to secondary local infections, sepsis, and even life- threatening systemic infections.1,6,9,10 Severe cases of stomatitis often necessitate the interruption of chemo- therapy treatment or dose reduction and may affect pa- tient compliance with further treatment.1 Compared with other chemotherapy-related toxicities, such as my- elosuppression, the incidence of mucositis and the sig- nificance of its toxicity is increasing. Consequently, oral mucositis is becoming the most common dose-limiting toxicity of chemotherapy.1,2
The current treatment of patients with stomatitis is essentially symptomatic. This includes stringent oral hygiene, avoiding irritating and abrasive foods, good oral and dental care, and the use of bland rinses, topical anesthetics, and systemic analgesics.11 Such treatments, however, are of limited value and have shown improvement only in patients with mild to moderate stomatitis.1,2,12
TRAUMEEL is a homeopathic-complex remedy that has been sold over the counter in pharmacies in Germany, Austria, and Switzerland for over 50 years. It contains extracts from the following plants and min- erals, all of them highly diluted (10��1–10��9 of the stem solution): Arnica montana, Calendula officinalis, Achillea millefolium, Matricaria chamomilla, Symphy- tum officinale, Atropa belladonna, Aconitum napellus, Bellis perennis, Hypericum perforatum, chinacea an- gustifolia, Echinacea purpurea, Hamamelis virginica, Mercurius solubilis, and Hepar sulfuris. Information from the manufacturer indicates that TRAUMEEL S is used normally to treat trauma, inflammation, and de- generative processes.
Informal experience in patients with chemother- apy-related stomatitis suggests that the condition may respond to treatment with TRAUMEEL S homeopath- ic-complex remedy. Based on this and subsequent positive results from a preliminary open study in 20 patients with stomatitis who were treated with TRAUMEEL S compared with 7 untreated, randomly selected patients,13 we decided to conduct the ran- domized, placebo-controlled, double-blind clinical trial reported here.
MATERIALS AND METHODS Patients Thirty-two consecutive patients who were admitted to Schneider Children’s Medical Center, ages 3–25 years,
suffering from malignant diseases and underwent BMT were enrolled. Patients had undergone alloge- neic or autologous stem cell transplantation.14 The study was approved by the ethical committee at the Rabin Medical Center, and informed, written consent was obtained from parents and/or guardians of all children prior to their enrolment in the study after a full explanation of the benefits, potential hazards, and procedures involved in the study to the patients and their parents and/or guardians.
Study Medication
For this study, both TRAUMEEL S and placebo were provided by the HEEL Company (Baden-Baden, Ger- many) in sterile, 2.2-mL ampoules. Solutions of TRAUMEEL S were prepared by diluting the active substance in saline, according to the German Homeo- pathic Pharmacopoeia (HAB). The placebo consisted only of saline. The active medication and placebo did not differ in color, taste, or odor.
TRAUMEEL S is manufactured according to the European Union Guidelines on Good Manufacturing Practice for Medicinal Products15 and in accordance with the HAB. The physical and microbiologic controls of the medications were according to the European Pharmacopoeia specifications.
Extensive safety data from a large survey of TRAUMEEL S showed adverse events in only 0.0035% of patients, despite its use in over 3.5 million patients (manufacturer’s own survey). Adverse effects reported were mostly skin reactions to the cream or local pru- ritus as a reaction to injection. However, because TRAUMEEL S contains dilutions of substances that may be regarded as toxic, we calculated the content of one of the most toxic substances, a mercury salt, in the medication. Assuming that a patient will have to be treated with TRAUMEEL S for 1 week, he or she will receive 35 ampoules. The mercury concentration of one ampoule is 0.5 ng/mL, giving a total amount of ingested mercury of approximately 17.5 ng per week. This compares favorably with the permitted mercury content of drinking water according to German law (0.001 mg/L).16 Thus, a 1-week treatment of TRAUMEEL S contains approximately 10��3 of the amount of mercury deemed permissible in 1 L of drinking water.
Study Procedures
Thirty-two patients received various conditioning reg- imens for 5–8 days followed by autologous (16 pa- tients) or allogeneic (16 patients) stem cell infusion on Day 0. Patients were randomized to receive either placebo or TRAUMEEL S on Day 2 of the study in addition to twice-daily mouth washes with chlorohex- imide, oral amphoterin B, and gentle tooth brushing
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TABLE 1 World Health Organization Grading System for Mucositis
Grade Status
0 No change 1 Soreness/erythema (painless) 2 Erythema (painful), ulcers; can eat solids 3 Ulcers; requires liquid diet only 4 Alimentation not possible
(institutional standard for mouth care). Packages of TRAUMEEL S and placebo were prepared by the HEEL Company and were identified by serial number only. The code showing the treatment corresponding to each serial number was kept by the company, the study coordinator (M.O.), and the statistician (L.S.F.). The code was not broken until the completion of the trial. Treatment was started on Day 2 after stem cell transplantation, so that treatment began before the first symptoms of stomatitis (e.g., dryness and/or sore- ness of the mouth) were observed. The peak incidence of mucositis is typically 5–7 days after transplantation. Fifteen evaluable patients received placebo, and 15 evaluable patients received TRAUMEEL S. Patients were instructed to rinse their mouths vigorously with the solution for a minimum of 30 seconds before swallowing. In addition, patients were directed to keep the liquid as long as possible on particularly trouble- some lesions in their mouth. This procedure was re- peated five times daily.
The World Health Organization (WHO) grading system for mucositis (Table 1) was used to evaluate stomatitis in each patient.17 In addition, a subjective scoring system was used in which either the patient or the parents were asked to judge the degree of oral pain and discomfort, dryness of mouth and tongue, dys- phagia, and ability to swallow. A five-grade system was used (Grade 0, no complaints; Grade 4, very severe complaints, unable even to swallow liquids). The time to worsening of stomatitis was evaluated as the time from randomization to the day when the mucositis score increased from that recorded at baseline. Pa- tients were evaluated at least once every 2 days. All evaluations were performed blind by the same ob- server (the study nurse). The trial continued until the patient symptomology had been scored as Grade 0 on 2 consecutive days or until a minimum of 14 days after the start of TRAUMEEL S or placebo treatment in patients in whom no symptoms developed.
The trial was carried out at the Bone Marrow Transplantation Unit, The Schneider Children’s Med- ical Center of Israel, Rabin Medical Center, Petach Tikva, Israel. All study forms were collected, stored, and transferred to computer for analysis by the study
coordinator (M.O.). Statistical analysis was performed at the Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University, Ramat-Gan, Israel (L.S.F.). The randomization code was prepared by the manufacturer (HEEL Company) and was re- vealed only on completion of the study. Neither the manufacturer, the study coordinator, nor the statisti- cian was involved in any aspect of the treatment of participating patients.
Statistical Analysis
All statistical analyses were done on an intent-to-treat basis unless indicated otherwise. That is, each patient was considered to be allocated randomly to a group regardless of the treatment actually received. The two main treatment comparisons, as specified in the pro- tocol, were of the area under the curve (AUC) for stomatitis symptoms, and the time to first worsening of stomatitis symptoms. Both are based on the WHO grading system.
The AUC is equivalent to the sum of the grade on each day from the start of TRAUMEEL S or placebo treatment. It therefore incorporates both severity and duration of symptoms. When grades were recorded every other day, we used linear interpolation to esti- mate the stomatitis score on those days when evalu- ation did not occur. Because the AUC score distribu- tion was not normal, statistical comparison was performed using the two-sample Wilcoxon rank-sum test.
Most patients (77%) started TRAUMEEL S or pla- cebo treatment before the onset of symptoms. In these patients, therefore, the time to worsening of symp- toms was the same as the time to the start of symp- toms. Consequently, the time to worsening differed from time to first development of symptoms in only 23% of patients (17% with Grade 1 symptoms and 6% with Grade 2 symptoms). The statistical comparison of this endpoint was performed using the log-rank test. All P values reported are two-sided.
RESULTS Patients A total of 32 patients were enrolled in this trial. How- ever, two patients (one in the TRAUMEEL S treatment group and the other in the placebo group) received a single dose of study drug but then refused further treatment, complaining of nausea. These patients were not evaluated subsequently for stomatitis and, thus, cannot be included in this analysis. Fifteen pa- tients each remained in the TRAUMEEL S group and the placebo group. The distribution of patient charac- teristics for each group is shown in Table 2. The groups were comparable with regard to age, gender, type of BMT, granulocyte-colony stimulating factor
TABLE 2 Patient Characteristics
Characteristic
Patients (no.) Age (yrs)
Mean (SD) Distribution
3–4 5–9 10–14 15–19 20–25
Gender (no. of men) (%) Diagnosis (%)
AML ALL CML Lymphoma Othera BMT (%) Allogeneic Autologous
GCSF GVHD prophylaxis (%)
CSA only CSA methotrexate CSA steroids None
TABLE 3 Stomatitis Area Under the Curve Scores and Time to First Worsening of Symptoms by Allocated Treatment
AML: acute myelogenous leukemia; ALL: acute lymphoblastic leukemia; CML: chronic myelogenous leukemia; BMT: bone marrow transplantation; GCSF: granulocyte-colony stimulating factor; GVHD: graft versus host disease; CSA: cyclosporin A; SD: standard deviation. a Other diagnoses in the TRAUMEEL group: one neuroblastoma, one aplastic anemia, one thalas- semia, one Ewing sarcoma, and one medulloblastoma. Other diagnoses in the placebo group: one neuroblastoma, one Wilms tumor, two aplastic anemia, one thalassemia, one Ewing sarcoma, and one Fanconi syndrome.
treatment and prophylaxis against graft versus host disease (GVHD). However, there were some differ- ences in the distribution of diseases between the groups: There were seven patients versus three pa- tients with acute myelogenous leukemia (AML) and zero patients versus three patients with lymphoma in the TRAUMEEL S and placebo groups, respectively. In addition, the three patients who underwent a higher risk BMT (haploidentical or cord blood) all were allo- cated randomly to the TRAUMEEL S treatment group. The use of concomitant medication, including analge- sic treatment, was comparable in both treatment groups.
There was doubt regarding the stomatitis score of Patient 12 as a result of an administrative error. Our policy in areas of doubt was to take the value less favorable to the TRAUMEEL S treatment group. In this instance, the choice was between an AUC score of either 38 or 0, and we used the score of 38. In addition, one patient who was allocated to the placebo group inadvertently received TRAUMEEL S. However, this
AUC: area under the curve. a Test for difference in AUC: Wilcoxon rank sum score, 167.5; expected score, 232.5 (P �� 0.01). b Test for difference in time to worsening: chi-square test, 13.4 with 1 degree of freedom (P �� 0.001). c The patient received TRAUMEEL S�� accidentally. d There was doubt regarding the AUC score and time to worsening. An alternative interpretation would be AUC, 0; time �� 19 days. e Means and medians of uncensored times only are shown.
patient was still considered part of the placebo treat- ment group, and it is interesting to note that this patient had the second lowest stomatitis AUC score in the placebo treatment group. This patient was in- cluded in the analysis according to the intent-to-treat principle and to guard against any bias in the study. Exclusion of this patient from the analysis would have increased the difference between the treatment groups (in favor of TRAUMEEL S). In view of the double-blind design and the intention-to-treat analy- sis used, it seems unlikely that these irregularities would have substantially affected the results of the study.
Efficacy
The stomatitis AUC scores, together with the times to first worsening, are summarized in Table 3. Stomatitis AUC scores range from 0 to 56. Five patients (33%) allocated to the TRAUMEEL S group did not develop stomatitis (AUC score, 0) compared with 1 patient (7%) from the placebo group. The mean AUC scores were 10.4 in the TRAUMEEL S group and 24.3 in the placebo group. This difference was statistically signif-
TRAUMEEL Placebo
15 15
10.1 (7.0) 3 5
TRAUMEEL
Patient AUCa
1 9 3 0 6 4 7 20 9 11 12d 38 13 0 15 0 17 0 19 17 22 0 23 17 25 3 28 5 30 26.5 Mean 10.4 Median 5.0
Placebo
6 2 3 1 8 (53)
3 (20) 1 (7) 1 (7) 3 (20) 7 (47)
8 (53) 7 (47) 4 (27)
1 (7) 3 (20) 3 (20) 8 (53)
9.7 (5.7)
3 3 3 1 9 (60)
7 (47) 2 (13) 1 (7) 0 (0) 5 (33)
7 (47) 8 (53) 4 (27)
2 (13) 4 (27) 1 (7) 8 (53)
worsening AUCa (days)b
27.5 4 16 4 16 2–3 36 1–2 4 6–7 56 4 14 2–3 20 2–3 31 10–11 21 3
0 ��6 26.5 5 45 4 35 10 16 4 24.3 4.3e 21.0 4.0e
TRAUMEEL S�� Treatment of Stomatitis/Oberbaum et al. 687
Time to worsening (days)b Patient
��8 2 ��18 4 ��9 5 4–5 8 3–5 10c 20 11 ��13 14 ��13 16 ��5 18 5 20 ��10 21 4–7 24 ��8 26 7 27 2–3 29 6.9e — 4.7e —
Time to
688 CANCER August 1, 2001 / Volume 92 / Number 3
icant (Wilcoxon rank-sum score, 167.5; expected score, 232.5; P �� 0.01) and suggests that TRAUMEEL S treatment reduced the severity and/or duration of sto- matitis compared with placebo.
In the group of 22 patients age �� 15 years, the mean AUC score for stomatitis was 11.0 in the TRAUMEEL S group and 25.9 in the placebo group. The Wilcoxon rank-sum test for the difference re- mained statistically significant (Wilcoxon rank-sum score, 93.0; expected score, 126.5; P �� 0.01). Thus, the difference remains only if younger patients are con- sidered.
Seven patients (47%) in the TRAUMEEL S treat- ment group and 14 patients (93%) in the placebo group experienced worsening of symptoms during treatment. The log-rank test indicated that there was a statistically significant difference (chi-square test, 13.4 with 1 degree of freedom; P �� 0.001) between the two groups in the time to worsening of symptoms. In those patients whose symptoms worsened, the median time to worsening was 4.7 days in the TRAUMEEL S group and 4.0 days in the placebo group. These results indi- cate that symptoms were much less likely to worsen in patients receiving TRAUMEEL S treatment than in those receiving placebo, but that, among those whose symptoms did worsen, there was little difference in the median time to worsening of stomatitis between the two treatment groups.
Subjective Symptom Score
The maximum symptom scores for dryness of mouth, oral pain, and eating difficulty over the first 7 days of TRAUMEEL S and placebo treatment are shown in Figure 1. These data were recorded at regular intervals over the 7-day treatment period. These results are very similar to the stomatitis AUC score results: Patients in the TRAUMEEL S group showed a clear reduction in severity of symptoms in all three categories, as indi- cated by changes in the symptom grading system, compared with the placebo group.
Safety and Tolerability
There was a high incidence of serious complications but with no significant difference between the groups, as expected in a group of patients undergoing BMT. GVHD occurred in three patients in the TRAUMEEL S group compared with six patients in the placebo group, sepsis occurred in three patients in the TRAUMEEL S group compared with eight patients in the placebo group, and gastrointestinal complications occurred in no patients in the TRAUMEEL S group compared with five patients in the placebo group. Four patients with venous-occlusive disease occurred in the TRAUMEEL S group compared with none in the placebo group, and pneumonitis occurred in four pa-
FIGURE 1. The maximum subjective score (0, no complaints; 4, very severe complaints/parenteral nutrition necessary) during the first 7 days of study treatment with TRAUMEEL (n �� 15 patients) or placebo (n �� 15 patients) for dryness of mouth (a), oral pain (b), and eating difficulty (c).
tients in the TRAUMEEL S group compared with none in the placebo group. Some patients developed more than one of these complications. There was no differ- ence in the incidence or duration of severe neutrope- nia between the two treatment groups.
There was no significant difference in the number of deaths between the TRAUMEEL S and placebo groups in a follow-up of 44 weeks. Only one death occurred during the study period (to Day 20).
DISCUSSION
Currently available treatments for chemotherapy-in- duced stomatitis are of limited efficacy in preventing or ameliorating it. The effect of local treatment is short lived, and the medications often have an unpleasant taste. Moreover, the risk of absorption limits the fre- quency with which some of these drugs may be used in small children and in the elderly. For these reasons, the potential benefits of treatment with TRAUMEEL S are of particular interest.
This study demonstrated a statistically significant and clinically relevant difference in efficacy between TRAUMEEL S and placebo in the treatment of stoma- titis in children undergoing stem cell transplantation. The strategy of analysis employed in this trial protects against any bias toward TRAUMEEL S. For example, a patient who developed stomatitis on the day that TRAUMEEL S was discontinued (Day 20) was classed as having stomatitis despite developing the condition after treatment was stopped. Patient 10, who acciden- tally received TRAUMEEL S instead of placebo, still was considered part of the placebo group and, in fact, had the second lowest stomatitis AUC score in this group. In addition, there was an excess of patients with lymphoma and a deficit of those with AML in the TRAUMEEL S group. Because it was observed that AML patients had, on average, slightly lower AUC scores compared with other patients in this trial (data not shown), any resulting bias would not benefit the TRAUMEEL S group. Finally, the three transplant pa- tients who were at the highest risk were allocated randomly to the TRAUMEEL S group. These patients subsequently died, two of them within 3 months of BMT. This may account for the somewhat higher number of deaths among patients in the TRAUMEEL S group. Because the AUC scores for these three patients were 0, 17, and 38, there is no evidence that these higher risk transplantation patients had less severe stomatitis.
Initial observations of treatment with TRAUMEEL S suggest that it is almost free from adverse effects. In addition to the patients in this trial, TRAUMEEL S has been given to over 80 patients receiving chemotherapy on an outpatient basis at the Schneider Children’s Medical Center. With the exception of one patient in the trial who stopped treatment on the first day and two other children who complained of nausea, no other acute adverse effects have been reported.
The mechanism of action of TRAUMEEL S re- mains unknown. It also is unclear whether only one of its components is biologically active or whether the effects are due to the action of several components. The marked effects seen in this study were achieved using a solution of TRAUMEEL S containing ingredi-
ents in very low concentrations. Some of the ingredi- ents of TRAUMEEL S are regarded by homeopaths as remedies with anti-inflammatory properties (Bella- donna, Aconitum, Mercurius, Hepar, and Chamo- milla) or mucoprotective properties (Calendula and Hamamelis). Arnica is one of the main remedies used in homeopathic treatment of trauma. Arnica, Calen- dula, Hamamelis, and Milefolium are believed to have antihemorrhagic properties. Echinacea angustifolia and Echinacea purpurea are thought to be immunos- timulatory. Hypericum has been used in patients with neural injury. This suggests that several components may play a role in the mechanism of action of TRAUMEEL S. Indeed, the observation that such a strong response is associated with such small quanti- ties of the different remedies in TRAUMEEL S suggests that a synergistic effect may be involved. However, further research is needed to identify which compo- nent(s) are the active compound(s).
The effect of orally administered TRAUMEEL S seems to be isolated to the oral mucosa. Patients with mucositis of other areas of the alimentary tract, for example, esophagitis, enteritis, or proctitis as assessed by subjective complaint (diarrhea and rectal or esoph- ageal pain), did not respond to the TRAUMEEL S administered orally in our trial. Furthermore, there was no difference between the two groups in the me- dian number of days with severe neutropenia. This supports the hypothesis that the effect of this homeo- pathic drug is a local one.
The localized effect of TRAUMEEL S also is im- portant for another reason, which has relevance to the general problem of complementary medicine in the treatment of patients with malignant disease. If com- plementary medical treatment in reality has no bio- logic effect, then at least it will do no harm. However, if it does have a biologic effect, and given our lack of understanding of the mechanisms of action of TRAUMEEL S and homeopathic medicine in general, concerns may be raised about deleterious systemic effects, for example, increasing the resistance of the malignant cells to chemotherapy. Because the effect of TRAUMEEL S appears to be only local, this concern becomes less relevant.
In conclusion, this double-blind, controlled study showed that TRAUMEEL S significantly reduces the severity and duration of chemotherapy-induced sto- matitis in children undergoing BMT. TRAUMEEL S appears capable, at least in part, of ameliorating a problem that not only causes considerable suffering to patients but often limits the possibilities of aggressive treatment with chemotherapy. Because there are few effective, conventional treatments for patients with chemotherapy-induced stomatitis currently available, the significance of treatment with TRAUMEEL S be-
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comes apparent. An effective treatment for stomatitis would allow more aggressive chemotherapy treat- ments, particularly in children, and, consequently, would be likely to improve the success rates of many chemotherapy programs. Our study population is small and includes patients with a variety of diagnoses who received several different forms of conditioning regimens. Confirmation of our results in a larger trial in patients receiving BMT or other intensive chemo- therapy protocols is needed. Therefore, we are plan- ning to extend our investigations to a large-scale, mul- ticenter study to evaluate the efficacy and safety of TRAUMEEL S in the treatment of adults who are at risk for chemotherapy-induced stomatitis.
REFERENCES
1. Wilkes RW. Prevention and treatment of oral mucositis fol- lowing cancer chemotherapy. Semin Oncol 1998;25:538 –51. 2. Sonis ST, Eiler EP, Epstein EB, Le Veque FG, Liggett WH Jr., Mulagha MT, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced
by radiation or chemotherapy. Cancer 1999;85:2103–13. 3. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athman LM, Therneau TM, et al. Inhibition of 5-fluoro-uracil-in- duced mucositis by oral cryotherapy. J Clin Oncol 1991;9:
449 –52. 4. Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iversen RK,
Finck G, et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluoroura- cil-realted stomatitis. Cancer 1993;72:2234 – 8.
5. Peterson DE, Schubert MM. Oral toxicity. In: Perry MC, editor. The chemotherapy source book, 1st edition. Balti- more: Williams & Wilkins, 1991:508 –30.
6. Pizzo PA. Granulocytopenia and cancer therapy: past prob- lems, current solutions, future challenges. Cancer 1984;54: 2649 – 61.
7. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infections in patients with acute nonlympho- cytic leukemia: prevalence of acute exacerbations. Arch In- tern Med 1982;142:551–5.
8. Levine RS. Saliva 1—the nature of saliva. Dent Update 1989; 4:102– 6.
9. De Conno F, Ripamonti C, Sbanatto A, Ventafridda V. Oral complications in patients with advanced cancer. J Palliat Care 1989;5:7–15.
10. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328(18): 1323–33.
11. Miascowski C. Management of mucositis during therapy. NCR Monogr 1990;9:95–8.
12. Peterson DE. Pretreatment strategies for infection preven- tion in chemotherapy patients. NCR Monogr 1990;9:61–71.
13. Oberbaum M. Experimental treatment of chemotherapy- induced stomatitis, using a homeopathic-complex remedy: a preliminary study. Biomed Ther 1998;16:261–5.
14. Lloyd ME. Oral medicine concerns the BMT patient. In: Buchsel P, Whedon M, editors. Bone marrow transplanta- tion administrative and clinical strategies, 1st edition. Bos- ton: Jones and Bartlett Publishers, 1995:257–281.
15. Auterhoff G. Manufacture of investigational medicinal prod- ucts. European Commission, Directorate-General III, Indus- try: Consumer goods industries, III/E/3: Pharmaceuticals. Pharm Ind 59, 1997;2:121– 4.
16. Verordnung u ̈ ber Trinkwasser und u ̈ ber Wasser fu ̈ r Lebens- mittelbetriebe (Trinkwasserverordnung) vol 5.12.1990. Bundesgesetztblatt Jahrgang 66:Teil 1.
17. World Health Organization. Handbook for reporting results of cancer treatment (offset publication 48). Geneva: World Health Organization, 1979:15–22.
A Randomized, Controlled Clinical Trial of the Homeopathic Medication TRAUMEEL in the Treatment of Chemotherapy-Induced Stomatitis in Children Undergoing Stem Cell Transplantation
/A Randomized, Controlled Clinical Trial of the Homeopathic Medication TRAUMEEL S in the Treatment of Chemotherapy-Induced Stomatitis in Children Undergoing Stem Cell Transplantation
Menachem Oberbaum, M.D.1 Isaac Yaniv, M.D.2 Yael Ben-Gal, R.N.2 Jerry Stein, M.D.2
Nurit Ben-Zvi, R.N.2 Laurence S. Freedman, Ph.D.3 David Branski, M.D.4
1 The Institute of Research on Complementary Medicine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, Jerusa- lem, Israel.
2 Bone Marrow Transplantation Unit, The Schnei- der Children’s Medical Center of Israel, Rabin Med- ical Center, Petach Tikva, Sackler School of Med- icine, Tel-Aviv University, Israel.
3 Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University. Ramat- Gan, Israel.
4 Department of Pediatrics, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusa- lem, Israel.
Supported by a grant from the International Society of Homotoxicology, Baden-Baden, Germany.
The authors are grateful to Dr. Yoram Neumann from the Department of Pediatric Hematology On- cology at The Chaim Sheba Medical Center (Tel- Aviv, Israel) for his help in the planning and design of the first version of the study protocol. They also thank Nitzan Teva, R.N., for her initiative and enthusiastic work at the beginning of the study. Finally, the authors thank the nurses of the Bone Marrow Transplantation Unit at The Schneider Children’s Medical Center of Israel for their support and patience during this study.
Address for reprints: Menachem Oberbaum, M.D., The Institute of Research on Complementary Med- icine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel; Fax: 972-2- 6666975; E-mail: oberbaum@netvision.net.il
Received December 21, 2000; revision received March 27, 2001; accepted April 9, 2001.
BACKGROUND. Stomatitis is a common consequence of chemotherapy and a con- dition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL S, in the management of chemotherapy- induced stomatitis in children undergoing bone marrow transplantation. METHODS. A randomized, placebo-controlled, double-blind clinical trial was con- ducted in 32 patients ages 3–25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a mini- mum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis.
RESULTS. A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P 0.01). CONCLUSIONS. This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. Cancer 2001;92:684–90.
© 2001 American Cancer Society.
KEYWORDS: TRAUMEEL S, stomatitis, mucositis, autologous, allogeneic, stem cell transplantation, bone marrow transplantation, randomized, placebo-controlled, ho- meopathy, complementary medicine.
Stomatitis occurs commonly as part of general inflammatory dam- age to the mucous membranes in patients receiving chemother- apy or radiation therapy to the oropharyngeal region. The overall incidence of reactive stomatitis is about 40%.1,2 However, it is partic- ularly common in patients receiving 5-fluorouracil (5-FU) treat- ment1–4 and is even more common in those undergoing radiation therapy for malignancies of the head and neck, in which approxi- mately 80% of patients are affected.2 In patients undergoing bone marrow transplantation (BMT), the incidence of stomatitis reaches 95%.1
The mechanism of development of stomatitis is primarily cytotoxic,1,5
© 2001 American Cancer Society
although neutropenia,1,6 periodontal pathology,1,7 poor oral hygiene,1,8 poor nutritional status,1 and infections also contribute to the condition. Morphologic character- istics can vary from slight erythema and edema of the oral mucosa to severe, focal, or widespread ulceration, bleeding and exudation.1,5 In addition to pain and dis- comfort, loss of the mechanical barrier together with the large surface of necrotic mucosa and neutropenia can lead to secondary local infections, sepsis, and even life- threatening systemic infections.1,6,9,10 Severe cases of stomatitis often necessitate the interruption of chemo- therapy treatment or dose reduction and may affect pa- tient compliance with further treatment.1 Compared with other chemotherapy-related toxicities, such as my- elosuppression, the incidence of mucositis and the sig- nificance of its toxicity is increasing. Consequently, oral mucositis is becoming the most common dose-limiting toxicity of chemotherapy.1,2
The current treatment of patients with stomatitis is essentially symptomatic. This includes stringent oral hygiene, avoiding irritating and abrasive foods, good oral and dental care, and the use of bland rinses, topical anesthetics, and systemic analgesics.11 Such treatments, however, are of limited value and have shown improvement only in patients with mild to moderate stomatitis.1,2,12
TRAUMEEL S is a homeopathic-complex remedy that has been sold over the counter in pharmacies in Germany, Austria, and Switzerland for over 50 years. It contains extracts from the following plants and min- erals, all of them highly diluted (101–109 of the stem solution): Arnica montana, Calendula officinalis, Achillea millefolium, Matricaria chamomilla, Symphy- tum officinale, Atropa belladonna, Aconitum napellus, Bellis perennis, Hypericum perforatum, chinacea an- gustifolia, Echinacea purpurea, Hamamelis virginica, Mercurius solubilis, and Hepar sulfuris. Information from the manufacturer indicates that TRAUMEEL S is used normally to treat trauma, inflammation, and de- generative processes.
Informal experience in patients with chemother- apy-related stomatitis suggests that the condition may respond to treatment with TRAUMEEL S homeopath- ic-complex remedy. Based on this and subsequent positive results from a preliminary open study in 20 patients with stomatitis who were treated with TRAUMEEL S compared with 7 untreated, randomly selected patients,13 we decided to conduct the ran- domized, placebo-controlled, double-blind clinical trial reported here.
MATERIALS AND METHODS Patients Thirty-two consecutive patients who were admitted to Schneider Children’s Medical Center, ages 3–25 years,
suffering from malignant diseases and underwent BMT were enrolled. Patients had undergone alloge- neic or autologous stem cell transplantation.14 The study was approved by the ethical committee at the Rabin Medical Center, and informed, written consent was obtained from parents and/or guardians of all children prior to their enrolment in the study after a full explanation of the benefits, potential hazards, and procedures involved in the study to the patients and their parents and/or guardians.
Study Medication
For this study, both TRAUMEEL S and placebo were provided by the HEEL Company (Baden-Baden, Ger- many) in sterile, 2.2-mL ampoules. Solutions of TRAUMEEL S were prepared by diluting the active substance in saline, according to the German Homeo- pathic Pharmacopoeia (HAB). The placebo consisted only of saline. The active medication and placebo did not differ in color, taste, or odor.
TRAUMEEL S is manufactured according to the European Union Guidelines on Good Manufacturing Practice for Medicinal Products15 and in accordance with the HAB. The physical and microbiologic controls of the medications were according to the European Pharmacopoeia specifications.
Extensive safety data from a large survey of TRAUMEEL S showed adverse events in only 0.0035% of patients, despite its use in over 3.5 million patients (manufacturer’s own survey). Adverse effects reported were mostly skin reactions to the cream or local pru- ritus as a reaction to injection. However, because TRAUMEEL S contains dilutions of substances that may be regarded as toxic, we calculated the content of one of the most toxic substances, a mercury salt, in the medication. Assuming that a patient will have to be treated with TRAUMEEL S for 1 week, he or she will receive 35 ampoules. The mercury concentration of one ampoule is 0.5 ng/mL, giving a total amount of ingested mercury of approximately 17.5 ng per week. This compares favorably with the permitted mercury content of drinking water according to German law (0.001 mg/L).16 Thus, a 1-week treatment of TRAUMEEL S contains approximately 103 of the amount of mercury deemed permissible in 1 L of drinking water.
Study Procedures
Thirty-two patients received various conditioning reg- imens for 5–8 days followed by autologous (16 pa- tients) or allogeneic (16 patients) stem cell infusion on Day 0. Patients were randomized to receive either placebo or TRAUMEEL S on Day 2 of the study in addition to twice-daily mouth washes with chlorohex- imide, oral amphoterin B, and gentle tooth brushing
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TABLE 1 World Health Organization Grading System for Mucositis
Grade Status
0 No change 1 Soreness/erythema (painless) 2 Erythema (painful), ulcers; can eat solids 3 Ulcers; requires liquid diet only 4 Alimentation not possible
(institutional standard for mouth care). Packages of TRAUMEEL S and placebo were prepared by the HEEL Company and were identified by serial number only. The code showing the treatment corresponding to each serial number was kept by the company, the study coordinator (M.O.), and the statistician (L.S.F.). The code was not broken until the completion of the trial. Treatment was started on Day 2 after stem cell transplantation, so that treatment began before the first symptoms of stomatitis (e.g., dryness and/or sore- ness of the mouth) were observed. The peak incidence of mucositis is typically 5–7 days after transplantation. Fifteen evaluable patients received placebo, and 15 evaluable patients received TRAUMEEL S. Patients were instructed to rinse their mouths vigorously with the solution for a minimum of 30 seconds before swallowing. In addition, patients were directed to keep the liquid as long as possible on particularly trouble- some lesions in their mouth. This procedure was re- peated five times daily.
The World Health Organization (WHO) grading system for mucositis (Table 1) was used to evaluate stomatitis in each patient.17 In addition, a subjective scoring system was used in which either the patient or the parents were asked to judge the degree of oral pain and discomfort, dryness of mouth and tongue, dys- phagia, and ability to swallow. A five-grade system was used (Grade 0, no complaints; Grade 4, very severe complaints, unable even to swallow liquids). The time to worsening of stomatitis was evaluated as the time from randomization to the day when the mucositis score increased from that recorded at baseline. Pa- tients were evaluated at least once every 2 days. All evaluations were performed blind by the same ob- server (the study nurse). The trial continued until the patient symptomology had been scored as Grade 0 on 2 consecutive days or until a minimum of 14 days after the start of TRAUMEEL S or placebo treatment in patients in whom no symptoms developed.
The trial was carried out at the Bone Marrow Transplantation Unit, The Schneider Children’s Med- ical Center of Israel, Rabin Medical Center, Petach Tikva, Israel. All study forms were collected, stored, and transferred to computer for analysis by the study
coordinator (M.O.). Statistical analysis was performed at the Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University, Ramat-Gan, Israel (L.S.F.). The randomization code was prepared by the manufacturer (HEEL Company) and was re- vealed only on completion of the study. Neither the manufacturer, the study coordinator, nor the statisti- cian was involved in any aspect of the treatment of participating patients.
Statistical Analysis
All statistical analyses were done on an intent-to-treat basis unless indicated otherwise. That is, each patient was considered to be allocated randomly to a group regardless of the treatment actually received. The two main treatment comparisons, as specified in the pro- tocol, were of the area under the curve (AUC) for stomatitis symptoms, and the time to first worsening of stomatitis symptoms. Both are based on the WHO grading system.
The AUC is equivalent to the sum of the grade on each day from the start of TRAUMEEL S or placebo treatment. It therefore incorporates both severity and duration of symptoms. When grades were recorded every other day, we used linear interpolation to esti- mate the stomatitis score on those days when evalu- ation did not occur. Because the AUC score distribu- tion was not normal, statistical comparison was performed using the two-sample Wilcoxon rank-sum test.
Most patients (77%) started TRAUMEEL S or pla- cebo treatment before the onset of symptoms. In these patients, therefore, the time to worsening of symp- toms was the same as the time to the start of symp- toms. Consequently, the time to worsening differed from time to first development of symptoms in only 23% of patients (17% with Grade 1 symptoms and 6% with Grade 2 symptoms). The statistical comparison of this endpoint was performed using the log-rank test. All P values reported are two-sided.
RESULTS Patients A total of 32 patients were enrolled in this trial. How- ever, two patients (one in the TRAUMEEL S treatment group and the other in the placebo group) received a single dose of study drug but then refused further treatment, complaining of nausea. These patients were not evaluated subsequently for stomatitis and, thus, cannot be included in this analysis. Fifteen pa- tients each remained in the TRAUMEEL S group and the placebo group. The distribution of patient charac- teristics for each group is shown in Table 2. The groups were comparable with regard to age, gender, type of BMT, granulocyte-colony stimulating factor
TABLE 2 Patient Characteristics
Characteristic
Patients (no.) Age (yrs)
Mean (SD) Distribution
3–4 5–9 10–14 15–19 20–25
Gender (no. of men) (%) Diagnosis (%)
AML ALL CML Lymphoma Othera BMT (%) Allogeneic Autologous
GCSF GVHD prophylaxis (%)
CSA only CSA methotrexate CSA steroids None
TABLE 3 Stomatitis Area Under the Curve Scores and Time to First Worsening of Symptoms by Allocated Treatment
AML: acute myelogenous leukemia; ALL: acute lymphoblastic leukemia; CML: chronic myelogenous leukemia; BMT: bone marrow transplantation; GCSF: granulocyte-colony stimulating factor; GVHD: graft versus host disease; CSA: cyclosporin A; SD: standard deviation. a Other diagnoses in the TRAUMEEL S group: one neuroblastoma, one aplastic anemia, one thalas- semia, one Ewing sarcoma, and one medulloblastoma. Other diagnoses in the placebo group: one neuroblastoma, one Wilms tumor, two aplastic anemia, one thalassemia, one Ewing sarcoma, and one Fanconi syndrome.
treatment and prophylaxis against graft versus host disease (GVHD). However, there were some differ- ences in the distribution of diseases between the groups: There were seven patients versus three pa- tients with acute myelogenous leukemia (AML) and zero patients versus three patients with lymphoma in the TRAUMEEL S and placebo groups, respectively. In addition, the three patients who underwent a higher risk BMT (haploidentical or cord blood) all were allo- cated randomly to the TRAUMEEL S treatment group. The use of concomitant medication, including analge- sic treatment, was comparable in both treatment groups.
There was doubt regarding the stomatitis score of Patient 12 as a result of an administrative error. Our policy in areas of doubt was to take the value less favorable to the TRAUMEEL S treatment group. In this instance, the choice was between an AUC score of either 38 or 0, and we used the score of 38. In addition, one patient who was allocated to the placebo group inadvertently received TRAUMEEL S. However, this
AUC: area under the curve. a Test for difference in AUC: Wilcoxon rank sum score, 167.5; expected score, 232.5 (P 0.01). b Test for difference in time to worsening: chi-square test, 13.4 with 1 degree of freedom (P 0.001). c The patient received TRAUMEEL S accidentally. d There was doubt regarding the AUC score and time to worsening. An alternative interpretation would be AUC, 0; time 19 days. e Means and medians of uncensored times only are shown.
patient was still considered part of the placebo treat- ment group, and it is interesting to note that this patient had the second lowest stomatitis AUC score in the placebo treatment group. This patient was in- cluded in the analysis according to the intent-to-treat principle and to guard against any bias in the study. Exclusion of this patient from the analysis would have increased the difference between the treatment groups (in favor of TRAUMEEL S). In view of the double-blind design and the intention-to-treat analy- sis used, it seems unlikely that these irregularities would have substantially affected the results of the study.
Efficacy
The stomatitis AUC scores, together with the times to first worsening, are summarized in Table 3. Stomatitis AUC scores range from 0 to 56. Five patients (33%) allocated to the TRAUMEEL S group did not develop stomatitis (AUC score, 0) compared with 1 patient (7%) from the placebo group. The mean AUC scores were 10.4 in the TRAUMEEL S group and 24.3 in the placebo group. This difference was statistically signif-
TRAUMEEL S Placebo
15 15
10.1 (7.0) 3 5
TRAUMEEL S
Patient AUCa
1 9 3 0 6 4 7 20 9 11 12d 38 13 0 15 0 17 0 19 17 22 0 23 17 25 3 28 5 30 26.5 Mean 10.4 Median 5.0
Placebo
6 2 3 1 8 (53)
3 (20) 1 (7) 1 (7) 3 (20) 7 (47)
8 (53) 7 (47) 4 (27)
1 (7) 3 (20) 3 (20) 8 (53)
9.7 (5.7)
3 3 3 1 9 (60)
7 (47) 2 (13) 1 (7) 0 (0) 5 (33)
7 (47) 8 (53) 4 (27)
2 (13) 4 (27) 1 (7) 8 (53)
worsening AUCa (days)b
27.5 4 16 4 16 2–3 36 1–2 4 6–7 56 4 14 2–3 20 2–3 31 10–11 21 3
0 6 26.5 5 45 4 35 10 16 4 24.3 4.3e 21.0 4.0e
TRAUMEEL S Treatment of Stomatitis/Oberbaum et al. 687
Time to worsening (days)b Patient
8 2 18 4 9 5 4–5 8 3–5 10c 20 11 13 14 13 16 5 18 5 20 10 21 4–7 24 8 26 7 27 2–3 29 6.9e — 4.7e —
Time to
688 CANCER August 1, 2001 / Volume 92 / Number 3
icant (Wilcoxon rank-sum score, 167.5; expected score, 232.5; P 0.01) and suggests that TRAUMEEL S treatment reduced the severity and/or duration of sto- matitis compared with placebo.
In the group of 22 patients age 15 years, the mean AUC score for stomatitis was 11.0 in the TRAUMEEL S group and 25.9 in the placebo group. The Wilcoxon rank-sum test for the difference re- mained statistically significant (Wilcoxon rank-sum score, 93.0; expected score, 126.5; P 0.01). Thus, the difference remains only if younger patients are con- sidered.
Seven patients (47%) in the TRAUMEEL S treat- ment group and 14 patients (93%) in the placebo group experienced worsening of symptoms during treatment. The log-rank test indicated that there was a statistically significant difference (chi-square test, 13.4 with 1 degree of freedom; P 0.001) between the two groups in the time to worsening of symptoms. In those patients whose symptoms worsened, the median time to worsening was 4.7 days in the TRAUMEEL S group and 4.0 days in the placebo group. These results indi- cate that symptoms were much less likely to worsen in patients receiving TRAUMEEL S treatment than in those receiving placebo, but that, among those whose symptoms did worsen, there was little difference in the median time to worsening of stomatitis between the two treatment groups.
Subjective Symptom Score
The maximum symptom scores for dryness of mouth, oral pain, and eating difficulty over the first 7 days of TRAUMEEL S and placebo treatment are shown in Figure 1. These data were recorded at regular intervals over the 7-day treatment period. These results are very similar to the stomatitis AUC score results: Patients in the TRAUMEEL S group showed a clear reduction in severity of symptoms in all three categories, as indi- cated by changes in the symptom grading system, compared with the placebo group.
Safety and Tolerability
There was a high incidence of serious complications but with no significant difference between the groups, as expected in a group of patients undergoing BMT. GVHD occurred in three patients in the TRAUMEEL S group compared with six patients in the placebo group, sepsis occurred in three patients in the TRAUMEEL S group compared with eight patients in the placebo group, and gastrointestinal complications occurred in no patients in the TRAUMEEL S group compared with five patients in the placebo group. Four patients with venous-occlusive disease occurred in the TRAUMEEL S group compared with none in the placebo group, and pneumonitis occurred in four pa-
FIGURE 1. The maximum subjective score (0, no complaints; 4, very severe complaints/parenteral nutrition necessary) during the first 7 days of study treatment with TRAUMEEL S (n 15 patients) or placebo (n 15 patients) for dryness of mouth (a), oral pain (b), and eating difficulty (c).
tients in the TRAUMEEL S group compared with none in the placebo group. Some patients developed more than one of these complications. There was no differ- ence in the incidence or duration of severe neutrope- nia between the two treatment groups.
There was no significant difference in the number of deaths between the TRAUMEEL S and placebo groups in a follow-up of 44 weeks. Only one death occurred during the study period (to Day 20).
DISCUSSION
Currently available treatments for chemotherapy-in- duced stomatitis are of limited efficacy in preventing or ameliorating it. The effect of local treatment is short lived, and the medications often have an unpleasant taste. Moreover, the risk of absorption limits the fre- quency with which some of these drugs may be used in small children and in the elderly. For these reasons, the potential benefits of treatment with TRAUMEEL S are of particular interest.
This study demonstrated a statistically significant and clinically relevant difference in efficacy between TRAUMEEL S and placebo in the treatment of stoma- titis in children undergoing stem cell transplantation. The strategy of analysis employed in this trial protects against any bias toward TRAUMEEL S. For example, a patient who developed stomatitis on the day that TRAUMEEL S was discontinued (Day 20) was classed as having stomatitis despite developing the condition after treatment was stopped. Patient 10, who acciden- tally received TRAUMEEL S instead of placebo, still was considered part of the placebo group and, in fact, had the second lowest stomatitis AUC score in this group. In addition, there was an excess of patients with lymphoma and a deficit of those with AML in the TRAUMEEL S group. Because it was observed that AML patients had, on average, slightly lower AUC scores compared with other patients in this trial (data not shown), any resulting bias would not benefit the TRAUMEEL S group. Finally, the three transplant pa- tients who were at the highest risk were allocated randomly to the TRAUMEEL S group. These patients subsequently died, two of them within 3 months of BMT. This may account for the somewhat higher number of deaths among patients in the TRAUMEEL S group. Because the AUC scores for these three patients were 0, 17, and 38, there is no evidence that these higher risk transplantation patients had less severe stomatitis.
Initial observations of treatment with TRAUMEEL S suggest that it is almost free from adverse effects. In addition to the patients in this trial, TRAUMEEL S has been given to over 80 patients receiving chemotherapy on an outpatient basis at the Schneider Children’s Medical Center. With the exception of one patient in the trial who stopped treatment on the first day and two other children who complained of nausea, no other acute adverse effects have been reported.
The mechanism of action of TRAUMEEL S re- mains unknown. It also is unclear whether only one of its components is biologically active or whether the effects are due to the action of several components. The marked effects seen in this study were achieved using a solution of TRAUMEEL S containing ingredi-
ents in very low concentrations. Some of the ingredi- ents of TRAUMEEL S are regarded by homeopaths as remedies with anti-inflammatory properties (Bella- donna, Aconitum, Mercurius, Hepar, and Chamo- milla) or mucoprotective properties (Calendula and Hamamelis). Arnica is one of the main remedies used in homeopathic treatment of trauma. Arnica, Calen- dula, Hamamelis, and Milefolium are believed to have antihemorrhagic properties. Echinacea angustifolia and Echinacea purpurea are thought to be immunos- timulatory. Hypericum has been used in patients with neural injury. This suggests that several components may play a role in the mechanism of action of TRAUMEEL S. Indeed, the observation that such a strong response is associated with such small quanti- ties of the different remedies in TRAUMEEL S suggests that a synergistic effect may be involved. However, further research is needed to identify which compo- nent(s) are the active compound(s).
The effect of orally administered TRAUMEEL S seems to be isolated to the oral mucosa. Patients with mucositis of other areas of the alimentary tract, for example, esophagitis, enteritis, or proctitis as assessed by subjective complaint (diarrhea and rectal or esoph- ageal pain), did not respond to the TRAUMEEL S administered orally in our trial. Furthermore, there was no difference between the two groups in the me- dian number of days with severe neutropenia. This supports the hypothesis that the effect of this homeo- pathic drug is a local one.
The localized effect of TRAUMEEL S also is im- portant for another reason, which has relevance to the general problem of complementary medicine in the treatment of patients with malignant disease. If com- plementary medical treatment in reality has no bio- logic effect, then at least it will do no harm. However, if it does have a biologic effect, and given our lack of understanding of the mechanisms of action of TRAUMEEL S and homeopathic medicine in general, concerns may be raised about deleterious systemic effects, for example, increasing the resistance of the malignant cells to chemotherapy. Because the effect of TRAUMEEL S appears to be only local, this concern becomes less relevant.
In conclusion, this double-blind, controlled study showed that TRAUMEEL S significantly reduces the severity and duration of chemotherapy-induced sto- matitis in children undergoing BMT. TRAUMEEL S appears capable, at least in part, of ameliorating a problem that not only causes considerable suffering to patients but often limits the possibilities of aggressive treatment with chemotherapy. Because there are few effective, conventional treatments for patients with chemotherapy-induced stomatitis currently available, the significance of treatment with TRAUMEEL S be-
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comes apparent. An effective treatment for stomatitis would allow more aggressive chemotherapy treat- ments, particularly in children, and, consequently, would be likely to improve the success rates of many chemotherapy programs. Our study population is small and includes patients with a variety of diagnoses who received several different forms of conditioning regimens. Confirmation of our results in a larger trial in patients receiving BMT or other intensive chemo- therapy protocols is needed. Therefore, we are plan- ning to extend our investigations to a large-scale, mul- ticenter study to evaluate the efficacy and safety of TRAUMEEL S in the treatment of adults who are at risk for chemotherapy-induced stomatitis.
REFERENCES
1. Wilkes RW. Prevention and treatment of oral mucositis fol- lowing cancer chemotherapy. Semin Oncol 1998;25:538 –51. 2. Sonis ST, Eiler EP, Epstein EB, Le Veque FG, Liggett WH Jr., Mulagha MT, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced
by radiation or chemotherapy. Cancer 1999;85:2103–13. 3. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athman LM, Therneau TM, et al. Inhibition of 5-fluoro-uracil-in- duced mucositis by oral cryotherapy. J Clin Oncol 1991;9:
449 –52. 4. Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iversen RK,
Finck G, et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluoroura- cil-realted stomatitis. Cancer 1993;72:2234 – 8.
5. Peterson DE, Schubert MM. Oral toxicity. In: Perry MC, editor. The chemotherapy source book, 1st edition. Balti- more: Williams & Wilkins, 1991:508 –30.
6. Pizzo PA. Granulocytopenia and cancer therapy: past prob- lems, current solutions, future challenges. Cancer 1984;54: 2649 – 61.
7. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infections in patients with acute nonlympho- cytic leukemia: prevalence of acute exacerbations. Arch In- tern Med 1982;142:551–5.
8. Levine RS. Saliva 1—the nature of saliva. Dent Update 1989; 4:102– 6.
9. De Conno F, Ripamonti C, Sbanatto A, Ventafridda V. Oral complications in patients with advanced cancer. J Palliat Care 1989;5:7–15.
10. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328(18): 1323–33.
11. Miascowski C. Management of mucositis during therapy. NCR Monogr 1990;9:95–8.
12. Peterson DE. Pretreatment strategies for infection preven- tion in chemotherapy patients. NCR Monogr 1990;9:61–71.
13. Oberbaum M. Experimental treatment of chemotherapy- induced stomatitis, using a homeopathic-complex remedy: a preliminary study. Biomed Ther 1998;16:261–5.
14. Lloyd ME. Oral medicine concerns the BMT patient. In: Buchsel P, Whedon M, editors. Bone marrow transplanta- tion administrative and clinical strategies, 1st edition. Bos- ton: Jones and Bartlett Publishers, 1995:257–281.
15. Auterhoff G. Manufacture of investigational medicinal prod- ucts. European Commission, Directorate-General III, Indus- try: Consumer goods industries, III/E/3: Pharmaceuticals. Pharm Ind 59, 1997;2:121– 4.
16. Verordnung u ̈ ber Trinkwasser und u ̈ ber Wasser fu ̈ r Lebens- mittelbetriebe (Trinkwasserverordnung) vol 5.12.1990. Bundesgesetztblatt Jahrgang 66:Teil 1.
17. World Health Organization. Handbook for reporting results of cancer treatment (offset publication 48). Geneva: World Health Organization, 1979:15–22.
Menachem Oberbaum, M.D.1 Isaac Yaniv, M.D.2 Yael Ben-Gal, R.N.2 Jerry Stein, M.D.2
Nurit Ben-Zvi, R.N.2 Laurence S. Freedman, Ph.D.3 David Branski, M.D.4
1 The Institute of Research on Complementary Medicine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, Jerusa- lem, Israel.
2 Bone Marrow Transplantation Unit, The Schnei- der Children’s Medical Center of Israel, Rabin Med- ical Center, Petach Tikva, Sackler School of Med- icine, Tel-Aviv University, Israel.
3 Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University. Ramat- Gan, Israel.
4 Department of Pediatrics, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusa- lem, Israel.
Supported by a grant from the International Society of Homotoxicology, Baden-Baden, Germany.
The authors are grateful to Dr. Yoram Neumann from the Department of Pediatric Hematology On- cology at The Chaim Sheba Medical Center (Tel- Aviv, Israel) for his help in the planning and design of the first version of the study protocol. They also thank Nitzan Teva, R.N., for her initiative and enthusiastic work at the beginning of the study. Finally, the authors thank the nurses of the Bone Marrow Transplantation Unit at The Schneider Children’s Medical Center of Israel for their support and patience during this study.
Address for reprints: Menachem Oberbaum, M.D., The Institute of Research on Complementary Med- icine, The Center of Integrated Complementary Medicine, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel; Fax: 972-2- 6666975; E-mail: oberbaum@netvision.net.il
Received December 21, 2000; revision received March 27, 2001; accepted April 9, 2001.
BACKGROUND. Stomatitis is a common consequence of chemotherapy and a con- dition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL S, in the management of chemotherapy- induced stomatitis in children undergoing bone marrow transplantation. METHODS. A randomized, placebo-controlled, double-blind clinical trial was con- ducted in 32 patients ages 3–25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a mini- mum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis.
RESULTS. A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P 0.01). CONCLUSIONS. This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. Cancer 2001;92:684–90.
© 2001 American Cancer Society.
KEYWORDS: TRAUMEEL S, stomatitis, mucositis, autologous, allogeneic, stem cell transplantation, bone marrow transplantation, randomized, placebo-controlled, ho- meopathy, complementary medicine.
Stomatitis occurs commonly as part of general inflammatory dam- age to the mucous membranes in patients receiving chemother- apy or radiation therapy to the oropharyngeal region. The overall incidence of reactive stomatitis is about 40%.1,2 However, it is partic- ularly common in patients receiving 5-fluorouracil (5-FU) treat- ment1–4 and is even more common in those undergoing radiation therapy for malignancies of the head and neck, in which approxi- mately 80% of patients are affected.2 In patients undergoing bone marrow transplantation (BMT), the incidence of stomatitis reaches 95%.1
The mechanism of development of stomatitis is primarily cytotoxic,1,5
© 2001 American Cancer Society
although neutropenia,1,6 periodontal pathology,1,7 poor oral hygiene,1,8 poor nutritional status,1 and infections also contribute to the condition. Morphologic character- istics can vary from slight erythema and edema of the oral mucosa to severe, focal, or widespread ulceration, bleeding and exudation.1,5 In addition to pain and dis- comfort, loss of the mechanical barrier together with the large surface of necrotic mucosa and neutropenia can lead to secondary local infections, sepsis, and even life- threatening systemic infections.1,6,9,10 Severe cases of stomatitis often necessitate the interruption of chemo- therapy treatment or dose reduction and may affect pa- tient compliance with further treatment.1 Compared with other chemotherapy-related toxicities, such as my- elosuppression, the incidence of mucositis and the sig- nificance of its toxicity is increasing. Consequently, oral mucositis is becoming the most common dose-limiting toxicity of chemotherapy.1,2
The current treatment of patients with stomatitis is essentially symptomatic. This includes stringent oral hygiene, avoiding irritating and abrasive foods, good oral and dental care, and the use of bland rinses, topical anesthetics, and systemic analgesics.11 Such treatments, however, are of limited value and have shown improvement only in patients with mild to moderate stomatitis.1,2,12
TRAUMEEL S is a homeopathic-complex remedy that has been sold over the counter in pharmacies in Germany, Austria, and Switzerland for over 50 years. It contains extracts from the following plants and min- erals, all of them highly diluted (101–109 of the stem solution): Arnica montana, Calendula officinalis, Achillea millefolium, Matricaria chamomilla, Symphy- tum officinale, Atropa belladonna, Aconitum napellus, Bellis perennis, Hypericum perforatum, chinacea an- gustifolia, Echinacea purpurea, Hamamelis virginica, Mercurius solubilis, and Hepar sulfuris. Information from the manufacturer indicates that TRAUMEEL S is used normally to treat trauma, inflammation, and de- generative processes.
Informal experience in patients with chemother- apy-related stomatitis suggests that the condition may respond to treatment with TRAUMEEL S homeopath- ic-complex remedy. Based on this and subsequent positive results from a preliminary open study in 20 patients with stomatitis who were treated with TRAUMEEL S compared with 7 untreated, randomly selected patients,13 we decided to conduct the ran- domized, placebo-controlled, double-blind clinical trial reported here.
MATERIALS AND METHODS Patients Thirty-two consecutive patients who were admitted to Schneider Children’s Medical Center, ages 3–25 years,
suffering from malignant diseases and underwent BMT were enrolled. Patients had undergone alloge- neic or autologous stem cell transplantation.14 The study was approved by the ethical committee at the Rabin Medical Center, and informed, written consent was obtained from parents and/or guardians of all children prior to their enrolment in the study after a full explanation of the benefits, potential hazards, and procedures involved in the study to the patients and their parents and/or guardians.
Study Medication
For this study, both TRAUMEEL S and placebo were provided by the HEEL Company (Baden-Baden, Ger- many) in sterile, 2.2-mL ampoules. Solutions of TRAUMEEL S were prepared by diluting the active substance in saline, according to the German Homeo- pathic Pharmacopoeia (HAB). The placebo consisted only of saline. The active medication and placebo did not differ in color, taste, or odor.
TRAUMEEL S is manufactured according to the European Union Guidelines on Good Manufacturing Practice for Medicinal Products15 and in accordance with the HAB. The physical and microbiologic controls of the medications were according to the European Pharmacopoeia specifications.
Extensive safety data from a large survey of TRAUMEEL S showed adverse events in only 0.0035% of patients, despite its use in over 3.5 million patients (manufacturer’s own survey). Adverse effects reported were mostly skin reactions to the cream or local pru- ritus as a reaction to injection. However, because TRAUMEEL S contains dilutions of substances that may be regarded as toxic, we calculated the content of one of the most toxic substances, a mercury salt, in the medication. Assuming that a patient will have to be treated with TRAUMEEL S for 1 week, he or she will receive 35 ampoules. The mercury concentration of one ampoule is 0.5 ng/mL, giving a total amount of ingested mercury of approximately 17.5 ng per week. This compares favorably with the permitted mercury content of drinking water according to German law (0.001 mg/L).16 Thus, a 1-week treatment of TRAUMEEL S contains approximately 103 of the amount of mercury deemed permissible in 1 L of drinking water.
Study Procedures
Thirty-two patients received various conditioning reg- imens for 5–8 days followed by autologous (16 pa- tients) or allogeneic (16 patients) stem cell infusion on Day 0. Patients were randomized to receive either placebo or TRAUMEEL S on Day 2 of the study in addition to twice-daily mouth washes with chlorohex- imide, oral amphoterin B, and gentle tooth brushing
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TABLE 1 World Health Organization Grading System for Mucositis
Grade Status
0 No change 1 Soreness/erythema (painless) 2 Erythema (painful), ulcers; can eat solids 3 Ulcers; requires liquid diet only 4 Alimentation not possible
(institutional standard for mouth care). Packages of TRAUMEEL S and placebo were prepared by the HEEL Company and were identified by serial number only. The code showing the treatment corresponding to each serial number was kept by the company, the study coordinator (M.O.), and the statistician (L.S.F.). The code was not broken until the completion of the trial. Treatment was started on Day 2 after stem cell transplantation, so that treatment began before the first symptoms of stomatitis (e.g., dryness and/or sore- ness of the mouth) were observed. The peak incidence of mucositis is typically 5–7 days after transplantation. Fifteen evaluable patients received placebo, and 15 evaluable patients received TRAUMEEL S. Patients were instructed to rinse their mouths vigorously with the solution for a minimum of 30 seconds before swallowing. In addition, patients were directed to keep the liquid as long as possible on particularly trouble- some lesions in their mouth. This procedure was re- peated five times daily.
The World Health Organization (WHO) grading system for mucositis (Table 1) was used to evaluate stomatitis in each patient.17 In addition, a subjective scoring system was used in which either the patient or the parents were asked to judge the degree of oral pain and discomfort, dryness of mouth and tongue, dys- phagia, and ability to swallow. A five-grade system was used (Grade 0, no complaints; Grade 4, very severe complaints, unable even to swallow liquids). The time to worsening of stomatitis was evaluated as the time from randomization to the day when the mucositis score increased from that recorded at baseline. Pa- tients were evaluated at least once every 2 days. All evaluations were performed blind by the same ob- server (the study nurse). The trial continued until the patient symptomology had been scored as Grade 0 on 2 consecutive days or until a minimum of 14 days after the start of TRAUMEEL S or placebo treatment in patients in whom no symptoms developed.
The trial was carried out at the Bone Marrow Transplantation Unit, The Schneider Children’s Med- ical Center of Israel, Rabin Medical Center, Petach Tikva, Israel. All study forms were collected, stored, and transferred to computer for analysis by the study
coordinator (M.O.). Statistical analysis was performed at the Department of Mathematics, Statistics, and Computer Sciences, Bar-Ilan University, Ramat-Gan, Israel (L.S.F.). The randomization code was prepared by the manufacturer (HEEL Company) and was re- vealed only on completion of the study. Neither the manufacturer, the study coordinator, nor the statisti- cian was involved in any aspect of the treatment of participating patients.
Statistical Analysis
All statistical analyses were done on an intent-to-treat basis unless indicated otherwise. That is, each patient was considered to be allocated randomly to a group regardless of the treatment actually received. The two main treatment comparisons, as specified in the pro- tocol, were of the area under the curve (AUC) for stomatitis symptoms, and the time to first worsening of stomatitis symptoms. Both are based on the WHO grading system.
The AUC is equivalent to the sum of the grade on each day from the start of TRAUMEEL S or placebo treatment. It therefore incorporates both severity and duration of symptoms. When grades were recorded every other day, we used linear interpolation to esti- mate the stomatitis score on those days when evalu- ation did not occur. Because the AUC score distribu- tion was not normal, statistical comparison was performed using the two-sample Wilcoxon rank-sum test.
Most patients (77%) started TRAUMEEL S or pla- cebo treatment before the onset of symptoms. In these patients, therefore, the time to worsening of symp- toms was the same as the time to the start of symp- toms. Consequently, the time to worsening differed from time to first development of symptoms in only 23% of patients (17% with Grade 1 symptoms and 6% with Grade 2 symptoms). The statistical comparison of this endpoint was performed using the log-rank test. All P values reported are two-sided.
RESULTS Patients A total of 32 patients were enrolled in this trial. How- ever, two patients (one in the TRAUMEEL S treatment group and the other in the placebo group) received a single dose of study drug but then refused further treatment, complaining of nausea. These patients were not evaluated subsequently for stomatitis and, thus, cannot be included in this analysis. Fifteen pa- tients each remained in the TRAUMEEL S group and the placebo group. The distribution of patient charac- teristics for each group is shown in Table 2. The groups were comparable with regard to age, gender, type of BMT, granulocyte-colony stimulating factor
TABLE 2 Patient Characteristics
Characteristic
Patients (no.) Age (yrs)
Mean (SD) Distribution
3–4 5–9 10–14 15–19 20–25
Gender (no. of men) (%) Diagnosis (%)
AML ALL CML Lymphoma Othera BMT (%) Allogeneic Autologous
GCSF GVHD prophylaxis (%)
CSA only CSA methotrexate CSA steroids None
TABLE 3 Stomatitis Area Under the Curve Scores and Time to First Worsening of Symptoms by Allocated Treatment
AML: acute myelogenous leukemia; ALL: acute lymphoblastic leukemia; CML: chronic myelogenous leukemia; BMT: bone marrow transplantation; GCSF: granulocyte-colony stimulating factor; GVHD: graft versus host disease; CSA: cyclosporin A; SD: standard deviation. a Other diagnoses in the TRAUMEEL S group: one neuroblastoma, one aplastic anemia, one thalas- semia, one Ewing sarcoma, and one medulloblastoma. Other diagnoses in the placebo group: one neuroblastoma, one Wilms tumor, two aplastic anemia, one thalassemia, one Ewing sarcoma, and one Fanconi syndrome.
treatment and prophylaxis against graft versus host disease (GVHD). However, there were some differ- ences in the distribution of diseases between the groups: There were seven patients versus three pa- tients with acute myelogenous leukemia (AML) and zero patients versus three patients with lymphoma in the TRAUMEEL S and placebo groups, respectively. In addition, the three patients who underwent a higher risk BMT (haploidentical or cord blood) all were allo- cated randomly to the TRAUMEEL S treatment group. The use of concomitant medication, including analge- sic treatment, was comparable in both treatment groups.
There was doubt regarding the stomatitis score of Patient 12 as a result of an administrative error. Our policy in areas of doubt was to take the value less favorable to the TRAUMEEL S treatment group. In this instance, the choice was between an AUC score of either 38 or 0, and we used the score of 38. In addition, one patient who was allocated to the placebo group inadvertently received TRAUMEEL S. However, this
AUC: area under the curve. a Test for difference in AUC: Wilcoxon rank sum score, 167.5; expected score, 232.5 (P 0.01). b Test for difference in time to worsening: chi-square test, 13.4 with 1 degree of freedom (P 0.001). c The patient received TRAUMEEL S accidentally. d There was doubt regarding the AUC score and time to worsening. An alternative interpretation would be AUC, 0; time 19 days. e Means and medians of uncensored times only are shown.
patient was still considered part of the placebo treat- ment group, and it is interesting to note that this patient had the second lowest stomatitis AUC score in the placebo treatment group. This patient was in- cluded in the analysis according to the intent-to-treat principle and to guard against any bias in the study. Exclusion of this patient from the analysis would have increased the difference between the treatment groups (in favor of TRAUMEEL S). In view of the double-blind design and the intention-to-treat analy- sis used, it seems unlikely that these irregularities would have substantially affected the results of the study.
Efficacy
The stomatitis AUC scores, together with the times to first worsening, are summarized in Table 3. Stomatitis AUC scores range from 0 to 56. Five patients (33%) allocated to the TRAUMEEL S group did not develop stomatitis (AUC score, 0) compared with 1 patient (7%) from the placebo group. The mean AUC scores were 10.4 in the TRAUMEEL S group and 24.3 in the placebo group. This difference was statistically signif-
TRAUMEEL S Placebo
15 15
10.1 (7.0) 3 5
TRAUMEEL S
Patient AUCa
1 9 3 0 6 4 7 20 9 11 12d 38 13 0 15 0 17 0 19 17 22 0 23 17 25 3 28 5 30 26.5 Mean 10.4 Median 5.0
Placebo
6 2 3 1 8 (53)
3 (20) 1 (7) 1 (7) 3 (20) 7 (47)
8 (53) 7 (47) 4 (27)
1 (7) 3 (20) 3 (20) 8 (53)
9.7 (5.7)
3 3 3 1 9 (60)
7 (47) 2 (13) 1 (7) 0 (0) 5 (33)
7 (47) 8 (53) 4 (27)
2 (13) 4 (27) 1 (7) 8 (53)
worsening AUCa (days)b
27.5 4 16 4 16 2–3 36 1–2 4 6–7 56 4 14 2–3 20 2–3 31 10–11 21 3
0 6 26.5 5 45 4 35 10 16 4 24.3 4.3e 21.0 4.0e
TRAUMEEL S Treatment of Stomatitis/Oberbaum et al. 687
Time to worsening (days)b Patient
8 2 18 4 9 5 4–5 8 3–5 10c 20 11 13 14 13 16 5 18 5 20 10 21 4–7 24 8 26 7 27 2–3 29 6.9e — 4.7e —
Time to
688 CANCER August 1, 2001 / Volume 92 / Number 3
icant (Wilcoxon rank-sum score, 167.5; expected score, 232.5; P 0.01) and suggests that TRAUMEEL S treatment reduced the severity and/or duration of sto- matitis compared with placebo.
In the group of 22 patients age 15 years, the mean AUC score for stomatitis was 11.0 in the TRAUMEEL S group and 25.9 in the placebo group. The Wilcoxon rank-sum test for the difference re- mained statistically significant (Wilcoxon rank-sum score, 93.0; expected score, 126.5; P 0.01). Thus, the difference remains only if younger patients are con- sidered.
Seven patients (47%) in the TRAUMEEL S treat- ment group and 14 patients (93%) in the placebo group experienced worsening of symptoms during treatment. The log-rank test indicated that there was a statistically significant difference (chi-square test, 13.4 with 1 degree of freedom; P 0.001) between the two groups in the time to worsening of symptoms. In those patients whose symptoms worsened, the median time to worsening was 4.7 days in the TRAUMEEL S group and 4.0 days in the placebo group. These results indi- cate that symptoms were much less likely to worsen in patients receiving TRAUMEEL S treatment than in those receiving placebo, but that, among those whose symptoms did worsen, there was little difference in the median time to worsening of stomatitis between the two treatment groups.
Subjective Symptom Score
The maximum symptom scores for dryness of mouth, oral pain, and eating difficulty over the first 7 days of TRAUMEEL S and placebo treatment are shown in Figure 1. These data were recorded at regular intervals over the 7-day treatment period. These results are very similar to the stomatitis AUC score results: Patients in the TRAUMEEL S group showed a clear reduction in severity of symptoms in all three categories, as indi- cated by changes in the symptom grading system, compared with the placebo group.
Safety and Tolerability
There was a high incidence of serious complications but with no significant difference between the groups, as expected in a group of patients undergoing BMT. GVHD occurred in three patients in the TRAUMEEL S group compared with six patients in the placebo group, sepsis occurred in three patients in the TRAUMEEL S group compared with eight patients in the placebo group, and gastrointestinal complications occurred in no patients in the TRAUMEEL S group compared with five patients in the placebo group. Four patients with venous-occlusive disease occurred in the TRAUMEEL S group compared with none in the placebo group, and pneumonitis occurred in four pa-
FIGURE 1. The maximum subjective score (0, no complaints; 4, very severe complaints/parenteral nutrition necessary) during the first 7 days of study treatment with TRAUMEEL S (n 15 patients) or placebo (n 15 patients) for dryness of mouth (a), oral pain (b), and eating difficulty (c).
tients in the TRAUMEEL S group compared with none in the placebo group. Some patients developed more than one of these complications. There was no differ- ence in the incidence or duration of severe neutrope- nia between the two treatment groups.
There was no significant difference in the number of deaths between the TRAUMEEL S and placebo groups in a follow-up of 44 weeks. Only one death occurred during the study period (to Day 20).
DISCUSSION
Currently available treatments for chemotherapy-in- duced stomatitis are of limited efficacy in preventing or ameliorating it. The effect of local treatment is short lived, and the medications often have an unpleasant taste. Moreover, the risk of absorption limits the fre- quency with which some of these drugs may be used in small children and in the elderly. For these reasons, the potential benefits of treatment with TRAUMEEL S are of particular interest.
This study demonstrated a statistically significant and clinically relevant difference in efficacy between TRAUMEEL S and placebo in the treatment of stoma- titis in children undergoing stem cell transplantation. The strategy of analysis employed in this trial protects against any bias toward TRAUMEEL S. For example, a patient who developed stomatitis on the day that TRAUMEEL S was discontinued (Day 20) was classed as having stomatitis despite developing the condition after treatment was stopped. Patient 10, who acciden- tally received TRAUMEEL S instead of placebo, still was considered part of the placebo group and, in fact, had the second lowest stomatitis AUC score in this group. In addition, there was an excess of patients with lymphoma and a deficit of those with AML in the TRAUMEEL S group. Because it was observed that AML patients had, on average, slightly lower AUC scores compared with other patients in this trial (data not shown), any resulting bias would not benefit the TRAUMEEL S group. Finally, the three transplant pa- tients who were at the highest risk were allocated randomly to the TRAUMEEL S group. These patients subsequently died, two of them within 3 months of BMT. This may account for the somewhat higher number of deaths among patients in the TRAUMEEL S group. Because the AUC scores for these three patients were 0, 17, and 38, there is no evidence that these higher risk transplantation patients had less severe stomatitis.
Initial observations of treatment with TRAUMEEL S suggest that it is almost free from adverse effects. In addition to the patients in this trial, TRAUMEEL S has been given to over 80 patients receiving chemotherapy on an outpatient basis at the Schneider Children’s Medical Center. With the exception of one patient in the trial who stopped treatment on the first day and two other children who complained of nausea, no other acute adverse effects have been reported.
The mechanism of action of TRAUMEEL S re- mains unknown. It also is unclear whether only one of its components is biologically active or whether the effects are due to the action of several components. The marked effects seen in this study were achieved using a solution of TRAUMEEL S containing ingredi-
ents in very low concentrations. Some of the ingredi- ents of TRAUMEEL S are regarded by homeopaths as remedies with anti-inflammatory properties (Bella- donna, Aconitum, Mercurius, Hepar, and Chamo- milla) or mucoprotective properties (Calendula and Hamamelis). Arnica is one of the main remedies used in homeopathic treatment of trauma. Arnica, Calen- dula, Hamamelis, and Milefolium are believed to have antihemorrhagic properties. Echinacea angustifolia and Echinacea purpurea are thought to be immunos- timulatory. Hypericum has been used in patients with neural injury. This suggests that several components may play a role in the mechanism of action of TRAUMEEL S. Indeed, the observation that such a strong response is associated with such small quanti- ties of the different remedies in TRAUMEEL S suggests that a synergistic effect may be involved. However, further research is needed to identify which compo- nent(s) are the active compound(s).
The effect of orally administered TRAUMEEL S seems to be isolated to the oral mucosa. Patients with mucositis of other areas of the alimentary tract, for example, esophagitis, enteritis, or proctitis as assessed by subjective complaint (diarrhea and rectal or esoph- ageal pain), did not respond to the TRAUMEEL S administered orally in our trial. Furthermore, there was no difference between the two groups in the me- dian number of days with severe neutropenia. This supports the hypothesis that the effect of this homeo- pathic drug is a local one.
The localized effect of TRAUMEEL S also is im- portant for another reason, which has relevance to the general problem of complementary medicine in the treatment of patients with malignant disease. If com- plementary medical treatment in reality has no bio- logic effect, then at least it will do no harm. However, if it does have a biologic effect, and given our lack of understanding of the mechanisms of action of TRAUMEEL S and homeopathic medicine in general, concerns may be raised about deleterious systemic effects, for example, increasing the resistance of the malignant cells to chemotherapy. Because the effect of TRAUMEEL S appears to be only local, this concern becomes less relevant.
In conclusion, this double-blind, controlled study showed that TRAUMEEL S significantly reduces the severity and duration of chemotherapy-induced sto- matitis in children undergoing BMT. TRAUMEEL S appears capable, at least in part, of ameliorating a problem that not only causes considerable suffering to patients but often limits the possibilities of aggressive treatment with chemotherapy. Because there are few effective, conventional treatments for patients with chemotherapy-induced stomatitis currently available, the significance of treatment with TRAUMEEL S be-
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690 CANCER August 1, 2001 / Volume 92 / Number 3
comes apparent. An effective treatment for stomatitis would allow more aggressive chemotherapy treat- ments, particularly in children, and, consequently, would be likely to improve the success rates of many chemotherapy programs. Our study population is small and includes patients with a variety of diagnoses who received several different forms of conditioning regimens. Confirmation of our results in a larger trial in patients receiving BMT or other intensive chemo- therapy protocols is needed. Therefore, we are plan- ning to extend our investigations to a large-scale, mul- ticenter study to evaluate the efficacy and safety of TRAUMEEL S in the treatment of adults who are at risk for chemotherapy-induced stomatitis.
REFERENCES
1. Wilkes RW. Prevention and treatment of oral mucositis fol- lowing cancer chemotherapy. Semin Oncol 1998;25:538 –51. 2. Sonis ST, Eiler EP, Epstein EB, Le Veque FG, Liggett WH Jr., Mulagha MT, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced
by radiation or chemotherapy. Cancer 1999;85:2103–13. 3. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athman LM, Therneau TM, et al. Inhibition of 5-fluoro-uracil-in- duced mucositis by oral cryotherapy. J Clin Oncol 1991;9:
449 –52. 4. Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iversen RK,
Finck G, et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluoroura- cil-realted stomatitis. Cancer 1993;72:2234 – 8.
5. Peterson DE, Schubert MM. Oral toxicity. In: Perry MC, editor. The chemotherapy source book, 1st edition. Balti- more: Williams & Wilkins, 1991:508 –30.
6. Pizzo PA. Granulocytopenia and cancer therapy: past prob- lems, current solutions, future challenges. Cancer 1984;54: 2649 – 61.
7. Overholser CD, Peterson DE, Williams LT, Schimpff SC. Periodontal infections in patients with acute nonlympho- cytic leukemia: prevalence of acute exacerbations. Arch In- tern Med 1982;142:551–5.
8. Levine RS. Saliva 1—the nature of saliva. Dent Update 1989; 4:102– 6.
9. De Conno F, Ripamonti C, Sbanatto A, Ventafridda V. Oral complications in patients with advanced cancer. J Palliat Care 1989;5:7–15.
10. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328(18): 1323–33.
11. Miascowski C. Management of mucositis during therapy. NCR Monogr 1990;9:95–8.
12. Peterson DE. Pretreatment strategies for infection preven- tion in chemotherapy patients. NCR Monogr 1990;9:61–71.
13. Oberbaum M. Experimental treatment of chemotherapy- induced stomatitis, using a homeopathic-complex remedy: a preliminary study. Biomed Ther 1998;16:261–5.
14. Lloyd ME. Oral medicine concerns the BMT patient. In: Buchsel P, Whedon M, editors. Bone marrow transplanta- tion administrative and clinical strategies, 1st edition. Bos- ton: Jones and Bartlett Publishers, 1995:257–281.
15. Auterhoff G. Manufacture of investigational medicinal prod- ucts. European Commission, Directorate-General III, Indus- try: Consumer goods industries, III/E/3: Pharmaceuticals. Pharm Ind 59, 1997;2:121– 4.
16. Verordnung u ̈ ber Trinkwasser und u ̈ ber Wasser fu ̈ r Lebens- mittelbetriebe (Trinkwasserverordnung) vol 5.12.1990. Bundesgesetztblatt Jahrgang 66:Teil 1.
17. World Health Organization. Handbook for reporting results of cancer treatment (offset publication 48). Geneva: World Health Organization, 1979:15–22.
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Influence of Potassium Dichromate on * Tracheal Secretions in Critically Ill Patients
/Influence of Potassium Dichromate on * Tracheal Secretions in Critically Ill Patients
Michael Frass, Christoph Dielacher, Manfred Linkesch, Christian Endler, Ilse Muchitsch, Ernst Schuster and Alan Kaye
Chest 2005;127;936-941 DOI 10.1378/chest.127.3.936
The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/127/3/936.full.html
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Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2005by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692
Influence of Potassium Dichromate on Tracheal Secretions in Critically Ill Patients*
Michael Frass, MD; Christoph Dielacher, RN; Manfred Linkesch, MD; Christian Endler, PhD; Ilse Muchitsch, PhD; Ernst Schuster, PhD; and Alan Kaye, MD
Background: Stringy, tenacious tracheal secretions may prevent extubation in patients weaned from the respirator. This prospective, randomized, double-blind, placebo-controlled study with parallel assignment was performed to assess the influence of sublingually administered potassium dichromate C30 on the amount of tenacious, stringy tracheal secretions in critically ill patients with a history of tobacco use and COPD.
Methods: In this study, 50 patients breathing spontaneously with continuous positive airway pressure were receiving either potassium dichromate C30 globules (group 1) [Deutsche Ho- mo ̈opathie-Union, Pharmaceutical Company; Karlsruhe, Germany] or placebo (group 2). Five globules were administered twice daily at intervals of 12 h. The amount of tracheal secretions on day 2 after the start of the study as well as the time for successful extubation and length of stay in the ICU were recorded.
Results: The amount of tracheal secretions was reduced significantly in group 1 (p Conclusion: These data suggest that potentized (diluted and vigorously shaken) potassium dichromate may help to decrease the amount of stringy tracheal secretions in COPD patients.
(CHEST 2005; 127:936–941)
Key words: COPD; double-blind, randomized, placebo-controlled study; extubation; homeopathy; tracheal secretions
Abbreviations: APACHE acute physiology and chronic health evaluation; BMI body mass index; CPAP con- tinuous positive airway pressure; Fio2 fraction of inspired oxygen
Weaning from a respirator is a significant prob- lem in patients receiving mechanical ventilation in the ICU.1 Some factors involved in the assessment for extubation include the severity of the patient’s premorbid condition and the extent to which the patient’s respiratory muscles have been decondi- tioned by mechanical support. Most patients are easily weaned and extubated following short periods
*From the Ludwig Boltzmann Institute for Homeopathy (Drs. Frass, Endler, and Muchitsch), Vienna, Austria; II Department of Internal Medicine (Mr. Dielacher and Dr. Linkesch); Depart- ment of Medical Computer Sciences (Dr. Schuster), University of Vienna, Vienna, Austria; and Department of Anesthesiology (Dr. Kaye), Texas Tech University Lubbock, TX.
Manuscript received March 17, 2004; revision accepted July 17, 2004. Reproduction of this article is prohibited without written permis- sion from the American College of Chest Physicians (e-mail: permissions@chestnet.org).
Correspondence to: Michael Frass, MD, Professor of Medicine, Ludwig Boltzmann Institute for Homeopathy, Duerergasse 4, A 8010 Graz, Austria; e-mail: michael.frass@kabsi.at
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of mechanical ventilation. While most patients need only a short period of nonaugmented spontaneous breathing through the endotracheal tube before extubation, patients receiving mechanical ventilation as the result of ARDS, pneumonia, exacerbations of COPD, septicemia, pulmonary edema, or other com- plicated medical conditions often require prolonged periods to be successfully weaned. Besides weaning, extubation may be difficult because of multiple causes, including the presence of profuse, stringy, tenacious tracheal secretions.
COPD is the fourth leading cause of death in the United States, and it accounts for approximately 500,000 hospitalizations for exacerbations each year.2 One of the problems of COPD and tobacco-use patients encountered in the ICU is difficulty in extubating related to profuse tracheal secretions. Weaning before extubation may be facilitated using different ventilatory modes, such as spontaneous breathing with continuous positive airway pressure
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spontaneous breathing with CPAP with a Fio2 varying between 0.21 and 0.3, and positive airway pressure from 5 to 7 cm H2O after weaning from controlled mechanical ventilation. Addition- ally, extubation was impossible due to profuse tenacious, stringy tracheal secretions according to the criteria listed above.
Exclusion Criteria
Exclusion criteria included signs of additional lung diseases other than COPD at the time of enrollment or during the study observational period; positive blood culture results during the period of controlled mechanical ventilation; concomitant disease of the larynx and trachea obstructing the airway or inhibiting the extubation process; concomitant heart disease; need for cat- echolamines; pregnancy; and failure to give written informed consent.
Medication
In homeopathic concentrations, potassium dichromate acts primarily by its mucolytic properties.5 In this study, we used a preparation of C30, which is equivalent to a potentiation of 30 dilutions, in which each of the 30 dilution steps is followed by subsequent vigorous succussions. Therefore, the above-described toxic effects were eliminated. In addition, the original orange-red color disappeared during the preparation. Onset of action may vary from patient to patient but is generally observed within 24 to 48 h.
Potassium dichromate (Deutsche Homo ̈opathie-Union, Phar- maceutical Company; Karlsruhe, Germany) was prepared accord- ing to the German Homeopathic Pharmacopoeia6 by repeated dilution and vigorous shaking. Saccharose globules with a spher- ical shape and a diameter of approximately 1 mm were impreg- nated with a C30 dilution of potassium dichromate (group 1). Same-sized globules for placebo in group 2 were impregnated with the same water-alcohol diluent used for the preparation of the globules in group 1, without inclusion of any drug. Placebo globules exhibited the same appearance as the homeopathic globules and were therefore indistinguishable from the globules of group 1 according to the double-blind design of the study. Neither patients nor members of the critical care team or members of the study group knew whether the globules admin- istered to the respective patient belonged to group 1 or group 2.
Randomization Process
Patients were sequentially randomized into two groups: group 1 received the therapeutic agent, and group 2 received according to a computer-generated code. An independent physician not involved into the study held the code. A person not involved in the decision and/or application process of the study filled glob- ules of group 1 and group 2 into separate flasks for each study patient with an increasing number.
Sublingual Administration of the Globules
Globules were administered by pouring five globules into the lid of the flask containing the globules. Then, the globules were poured from the lid directly underneath the patient’s tongue. In patients intubated endotracheally, the globules were adminis- tered just aside the endotracheal tube. Globules were adminis- tered twice daily at an interval of 12 h until extubation of the patient. Fifteen minutes before and after administration of the globules, no oral fluid or oral hygiene was allowed.
Suctioning Procedures and Classification of Sputum Volume
An open suctioning system was used during this study. Suc- tioning was performed routinely every 6 h and in addition when
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(CPAP). A problem preventing successful extubation may be profuse tracheal secretions.3
Potassium dichromate is a drug that is commonly used in homeopathy for treatment of profuse, stringy, tenacious tracheal secretions. It is prepared according to homeopathic rules and is preferably administered by help of globules.
The aim of this prospective, double-blind, ran- domized, placebo-controlled study was to evaluate the influence of potassium dichromate on the amount of the described secretions with respect to the time of successful extubation as well as to length of stay in the ICU in these patients after start of the study.
Materials and Methods
The study was approved by the local Institutional Review Board. Patients signed informed consent before enrollment into the study. To ensure patient understanding, information was provided in the presence of their respective relatives and/or next of kins and documented. The study was planned prospectively, randomized, placebo controlled, and double blind.
Patients
Due to the severity of the acute respiratory failure, patients received controlled mechanical ventilation with a respirator (Servo 900C; Siemens Elema; Solna, Sweden) between 3 days and 7 days before study enrollment in a university hospital. The study lasted 18 months. The pulmonary status of the patients did not allow for noninvasive positive airway pressure ventilation during this period. Patients enrolled into the study could be successfully weaned from controlled or assisted mechanical ventilation and were switched to spontaneous breathing with CPAP provided by a continuous flow machine (Dra ̈ger CF 800; Dra ̈ger; Lu ̈beck, Germany). All patients were intubated with either a conventional endotracheal tube (8-mm inner diameter; Mallinckrodt; Athlone, Ireland) or a tracheostomy tube (8-mm inner diameter; Mallinckrodt). Despite regular suctioning and therapeutic bronchoscopy, extubation for these patients was impossible due to profuse, tenacious, stringy tracheal secretions (equal to grade 3 as described below) for 36 to 48 h before enrollment into the study. Administration of mucolytic agents was avoided due to observation of increased secretions in previ- ous patients. -Agonist bronchodilators were stopped at the start of the study to avoid any potential influence and/or interaction. A daily screening was performed in accordance with the methods described by Ely et al.4 Criteria used to decide extubation were that patients should be alert, with stable vital signs, and have an intact gag reflex. Physiologic guidelines were Pao2 60 mm Hg during spontaneous breathing with CPAP (fraction of inspired oxygen [Fio2] 50%) and positive end-expiratory pressure from 3 to 5 cm H2O, and respiratory rate 20 breaths/min. Extuba- tion failure was defined as need for reintubation within the following 72 h except for respiratory deterioration due to newly developed pneumonia. Physicians not involved into the study decided when patients would be extubated.
Inclusion Criteria
Inclusion criteria included a documented history of tobacco use and COPD for at least 10 years before acute deterioration;
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patients had profuse secretions. Flow-volume loops could not be used during spontaneous breathing with CPAP. The quantity of tracheal secretions during routine suctioning was distinguished by volume of suctioned sputum in a graduated vial interposed between suctioning catheter and the tubes leading to the suc- tioning pump. Tracheal secretions were classified into three grades (grade 1, 0 to 5 mL; grade 2, 6 to 10 mL; grade 3, 11 to 15 mL). Sputum did not exceed 15 mL in the investigated patients. The amount and viscosity of sputum production prior to study enrollment were not different between both groups as evaluated three times in subsequent order within 24 h. In this study, sputum was classified as grade 3 in all patients before administration of medication. Furthermore, the volume of spu- tum was evaluated again on day 2 after administration of the globules. The mean of three grades was used for classification.
Parameters Recorded
Prehospital historical and demographic information included age, sex, weight, height, BMI, FEV1, stage of COPD (1, mild; 2, moderate; 3, severe), tobacco use, need of long-term oxygen therapy, and home noninvasive ventilation before admission.7 In the hospital prior to entry into the treatment period, APACHE (acute physiology and chronic health evaluation) II, Pao2/Fio2, and Paco2 were measured. During the treatment period, suc- tionings per day and therapeutic bronchoscopies in hospital after randomization, antibiotic regimen during the period of controlled mechanical ventilation, time to extubation, and length of stay in the ICU after enrollment into the study were recorded.
Statistical Analysis
Statistical analysis was done at the Department of Medical Computer Sciences, University of Vienna, using a software package (Statistical Analysis System; SAS Institute; Cary, NC). All statistical analyses were done before breaking the randomiza- tion code. Statistical analysis of the data was performed using Kruskal-Wallis test for comparing the two groups. Values are expressed as mean SD.
Results
Fifty-five patients were evaluated for the study. Five patients (two patients in group 1 and three
patients in group 2) had to be excluded because of the development of pulmonary infiltrates described as pneumonia by independent radiologists within 2 days after enrollment into the study. Therefore, 25 patients remained in each group. Three patients in each group were breathing via a tracheostomy tube. No patients refused to participate in the study.
With respect to parameters recorded before hos- pitalization and historical and demographic informa- tion, three was no difference in age, sex, height, weight, BMI, FEV1, stage of COPD, and need of long-term oxygen therapy, as well as home noninva- sive ventilation (Table 1). Severity and duration of COPD and tobacco use was equal in both groups.
With respect to parameters recorded in the hos-
pital prior to entry into the treatment period, no
differences were found between both groups for
APACHE II, Pao /Fio , and Paco (Table 1). There 222
was no difference in the number of regular suction- ings and therapeutic bronchoscopies between both groups (Table 2).
With respect to parameters recorded during treat- ment period, there was no significant change of the amount of tracheal secretions between both groups on day 1 after start of the study; tracheal secretions were reduced significantly in group 1 (p 0.0001, Table 2) on day 2. Extubation could be performed significantly earlier in group 1 (p 0.0001, Table 2). Similarly, length of stay at the ICU was significantly shorter in group 1 (p 0.0001, Table 2).
All patients underwent a trial of extubation. None of the patients in group 1 had to be reintubated or needed noninvasive ventilation. In group 1, the amount of secretions remained stable and did not increase. Similarly, blood gas analyses after extuba- tion remained stable in group 1 and did not show
Parameters
Pre-hospital information Age, yr
Male/female gender, No. Weight, kg Height, cm BMI
FEV1, % Stage of COPD‡ Need for long-term oxygen therapy, No. Home noninvasive ventilation, No.
In-hospital (prior to study entry) information APACHE II Pao2/Fio2 Paco2, torr
Table 1—Patient Characteristics*
Group 1, Potassium Dichromate (n 25)
69.2 9.1 (49–89) 19/6
81.0 9.8 (59–102) 170.2 6.3 (157–179)
28.0 2.8 (21.7–33.3) 54.0 5.3 (32–60) 1.08 0.4 (1–3)
5 1
21.2 2.2 (18–25) 222.5 18.6 (178–250)
61.6 4.5 (53–69)
Group 2, Placebo (n 25)
68.4 10.1 (45–88) 20/5 78.8 10.2 (59–101)
171.2 5.8 (161–183) 26.8 2.8 (21.1–32.6) 52.4 5.5 (32–59) 1.20 0.5 (1–3)
9 1
21.6 2.2 (18–26) 219.4 22.4 (176–250)
59.8 4.1 (51–67)
p Value†
0.748
0.599 0.763 0.174 0.152 0.178
0.583 0.985 0.140
*Data are presented as mean SD (range) unless otherwise indicated. †Kruskal-Wallis test. ‡COPD stage: 1 mild, 2 moderate, 3 severe.
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Table 2—Parameters Recorded During Treatment Period (Secretions and Suctionings per Day on Day 2)*
Variables
Secretions Grade 1 Grade 2 Grade 3 Suctionings per day Therapeutic bronchoscopies Extubation, d
Length of stay, d
*Data are presented as mean SD (range). †Kruskal-Wallis test.
Group 1, Potassium Dichromate (n 25)
1.52 0.59 1 (1–3) 13 11
1 7.2 0.7 (6–8)
0.64 0.57 (0–2) 2.88 1.20 (1–6) 4.20 1.61 (2–8)
Group 2, Placebo (n 25)
2.44 0.65 3 (1–3) 2
10
13 6.9 0.8 (6–8)
0.76 0.66 (0–2) 6.12 3.13 (3–14) 7.68 3.60 (4–17)
p Value†
0.0001
0.206
0.555 0.0001 0.0001
significant differences as compared to pre-extubation values. Four patients in group 2 had to be reintu- bated because of deterioration of blood gas analysis results due to recurrence of tracheal secretions grade 2 to 3.
Discussion
Potassium dichromate (kalium bichromicum, K2 Cr2 O7 ) is a drug widely used in natural and homeopathic medicine. One of its features is its efficacy to treat patients with stringy, tenacious nasal and tracheal secretions. An open-label, practice- based homeopathic study5 described the efficacy and safety of a fixed-combination homeopathic medica- tion containing potassium dichromate in 119 male and female patients with clinical signs of acute sinusitis not previously treated. At the first visit, after a mean of 4.1 days of treatment, mucolysis had increased significantly and typical sinusitis symp- toms, such as headache, pressure pain at nerve exit points, and irritating cough, were reduced. Adverse drug effects were not reported.5
The physical properties of potassium dichromate are its appearance as bright orange-red crystals, a melting point of 398°C, and a specific gravity of 2.67. When swallowed undiluted, it can be harmful or fatal.8–11 As a systemic poison, it may be primarily toxic to kidneys,8 liver,8–9 and GI tract.10 Further- more, it can cause severe irritation of the eyes and conjunctivitis. Contact with breaks in the skin can cause “chrome sores” (skin ulcers). Dichromates are skin sensitizers.12 In the construction industry of Northern Bavaria, potassium dichromate is still the most important allergen. Potassium dichromate caused roughly half of all cases of sensitization such as allergic contact dermatitis and irritant contact dermatitis found to be occupationally relevant in the construction industry.12
The use of in vitro release of interferon- in the www.chestjournal.org
diagnosis of contact allergy to potassium dichromate was studied in 20 patients who had positive patch test results to chromate and in 30 control subjects (10 patients with contact dermatitis, allergic to other allergens, 10 patients with other dermatologic dis- eases, and 10 healthy subjects).13 The release of interferon- in the supernatants of the peripheral blood lymphocytes was significantly higher in the patients with proven allergy to chromate (p 0.001).13 In an animal toxicity study,14 a protec- tive effect of SnCl2 on K2 Cr2 O7 -induced nephrotox- icity could be observed in rats.
The data suggest that potassium dichromate may be a substance allowing earlier extubation due to a reduction in stringy, tenacious tracheal secretions. While the basic parameters were comparable in both groups, the group receiving potassium dichromate showed a statistical significant improvement within a short time period.
The presence of one or more of the following findings defines acute COPD exacerbation: increase in sputum purulence, increase in sputum volume, and worsening of dyspnea.15 Patients with COPD typically present with acute decompensation of their disease one to three times a year, and 3 to 16% of these will require hospital admission. Hospital mor- tality from these admissions ranges from 3 to 10% in severe COPD patients, and it is much higher for patients requiring ICU admission.15 One of the problems encountered in the ICU is difficulty in extubating the patient because of profuse tracheal secretions. This is a special problem in patients with tenacious, stringy tracheal secretions who have to- bacco use and COPD in their history. In some patients, these secretions are resistant to antimicro- bial and mucolytic therapy, administration of glyco- pyrroniumbromide is contraindicated because it may worsen the patient’s situation. There is no evidence for mucolytic agents or chest physiotherapy in the acute exacerbation setting of COPD.2
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Weaning before extubation may be facilitated using different ventilatory modes. One of them, spontaneous breathing with CPAP, is used fre- quently for weaning from mechanical ventilation. Heart-lung interaction, fluid retention, and renal dysfunction can be observed with CPAP too, al- though the extent of these alterations is generally lower when compared to mechanical ventilation with positive end-expiratory pressure. Interestingly, pro- tocol-guided weaning of mechanical ventilation, as performed by nurses and respiratory therapists, is safe and leads to extubation more rapidly than physician-directed weaning.16 In contrast with adult patients, the majority of children are weaned from mechanical ventilator support in 2 days. Weaning protocols did not significantly shorten this brief duration of weaning.17
If a patient tolerates successive decreases in ven- tilator support, that patient is successfully weaned.1 It is important to separate weaning from extubation. A patient may tolerate being on a minimum amount of ventilator support for an extended period of time from which no further decreases are considered necessary. However, a physician may refuse to extu- bate the patient for other reasons. Some reasons may be related to the patient, such as the inability to tolerate profuse secretions, the need for sedation for a scheduled diagnostic study, or the concern that another organ system is deteriorating.
Profuse stringy, tenacious tracheal secretions may be responsible for postponed extubation. While the weaning process was successful and the patient was able to breathe spontaneously with CPAP, extuba- tion sometimes may be postponed because of the presence of intense tracheal secretions.
The present study suggests that potassium dichro- mate C30 may be able to minimize the amount of tracheal secretions and therefore to allow earlier extubation when compared to placebo. Since the potentiation (dilution and vigorously shaking) of the study drug beyond the Avogadro number imposes no interaction with the patient’s metabolism, and due to the low cost of the drug, its use in the ICU may be beneficial, minimizing morbidity and mortality.18,19 Studies give some insight into the potential way of action of homeopathically prepared drugs. Cluster- cluster aggregation phenomena in aqueous solutions of fullerene-cyclodextrin conjugates, b-cyclodextrin, sodium chloride, sodium guanosine monophosphate, and a DNA oligonucleotide revealed that there are larger aggregates existent in dilute aqueous solutions than in more concentrated solutions.20 In another study, ultra-high dilutions of lithium chloride and sodium chloride (10-30 g cm-3) have been irradiated by x-rays and gamma-rays at 77 K, then progressively rewarmed to room temperature.21 During that
phase, their thermoluminescence has been studied and it was found that, despite their dilution beyond the Avogadro number, the emitted light was specific of the original salts dissolved initially.
This is the first scientific study of the effect of potassium dichromate on tracheal secretions. While the mechanism of potentized (diluted and vigorously shaken) drugs still remains subject to research, sev- eral articles describe its clinical usefulness.22–24 The effect may be best explained by cybernetics, which means that the information of the homeopathic drug acts consensually on the regulator. Thereby, the body regains its original property to regulate physical parameters.
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Randolph AG. Weaning from mechanical ventilation. New Horiz 1999; 7:374–385 Soto FJ, Varkey B. Evidence-based approach to acute exac- erbations of COPD. Curr Opin Pulm Med 2003; 9:117–124 Khamiees M, Raju P, DeGirolamo A, et al. Predictors of extubation outcome in patients who have successfully com- pleted a spontaneous breathing trial. Chest 2001; 120:1262– 1270
Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1864 –1869
Adler M. Efficacy and safety of a fixed-combination homeo- pathic therapy for sinusitis. Adv Ther 1999; 16:103–111 Deutsches Homo ̈ opathisches Arzneibuch 1985 [German Ho- meopathic Pharmacopoeia 1985]. Stuttgart, Germany: Deut- scher Apotheker Verlag, 1985
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 1995; 152:S77–S121 Sharma N, Chauhan S, Varma S. Fatal potassium dichromate ingestion. J Postgrad Med 2003; 49:286 –287
Stift A, Friedl J, Langle F, et al. Successful treatment of a patient suffering from severe acute potassium dichromate poisoning with liver transplantation. Transplantation 2000; 69:2454 –2455
Iserson KV, Banner W, Froede RC, et al. Failure of dialysis therapy in potassium dichromate poisoning. J Emerg Med 1983; 1:143–149 Michie CA, Hayhurst M, Knobel GJ, et al. Poisoning with traditional remedy containing potassium dichromate. Hum Exp Toxicol 1991; 10:129–131
Bock M, Schmidt A, Bruckner T, et al. Occupational skin disease in the construction industry. Br J Dermatol 2003; 149:1165–1171 Trattner A, Akerman L, Lapidoth M, et al. Use of in vitro release of interferon-gamma in the diagnosis of contact allergy to potassium dichromate: a controlled study. Contact Dermatitis 2003; 48:191–193
Barrera D, Maldonado PD, Medina-Campos ON, et al. Protective effect of SnCl2 on K2Cr2O7-induced nephrotoxic- ity in rats: the indispensability of HO-1 preinduction and lack of association with some antioxidant enzymes. Life Sci 2003; 73:3027–3041
Anthonisen NR, Manfreda J, Warren CPW, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary
Clinical Investigations in Critical Care
disease. Ann Intern Med 1987; 106:196–204 16 Kollef MH, Shapiro SD, Silver P, et al. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit Care Med 1997;
25:567–574 17 Randolph AG, Wypij D, Venkataraman ST. Effect of mechan-
tomy vs surgical cricothyroidotomy. Chest 2003; 123:151–158 20 Samal S, Geckeler KE. Unexpected solute aggregation in
water on dilution. Chem Commun 2001; 2224–2225 21 Rey L. Thermoluminescence of ultra-high dilutions of lithium
chloride and sodium chloride. Physica A 2003; 323:67–74 22 Jacobs J, Jimenez LM, Gloyd SS, et al. Treatment of acute childhood diarrhea with homeopathic medicine: a random- ized clinical trial in Nicaragua. Pediatrics 1994; 93:719–
ical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial. JAMA 2002; 288:2561–2568 725
18 Koh WY, Lew TW, Chin NM, et al. Tracheostomy in a neuro-intensive care setting: indications and timing. Anaesth Intensive Care 1997; 25:365–368
19 Francois B, Clavel M, Desachy A, et al. Complications of tracheostomy performed in the ICU: subthyroid tracheos-
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23 Reilly DT, Taylor MA, Beattie NGM, et al. Is evidence for homeopathy reproducible? Lancet 1994; 344:1601–1606 24 Linde K, Clausius N, Ramirez G, et al. Are the clinical effects
of homeopathy placebo effects? A meta-analysis of placebo- controlled trials. Lancet 1997; 350:834 – 843
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Influence of Potassium Dichromate on Tracheal Secretions in Critically Ill Patients * Michael Frass, Christoph Dielacher, Manfred Linkesch, Christian Endler, Ilse
Muchitsch, Ernst Schuster and Alan Kaye Chest 2005;127; 936-941 DOI 10.1378/chest.127.3.936
This information is current as of October 27, 2010
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Michael Frass, Christoph Dielacher, Manfred Linkesch, Christian Endler, Ilse Muchitsch, Ernst Schuster and Alan Kaye
Chest 2005;127;936-941 DOI 10.1378/chest.127.3.936
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Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2005by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692
Influence of Potassium Dichromate on Tracheal Secretions in Critically Ill Patients*
Michael Frass, MD; Christoph Dielacher, RN; Manfred Linkesch, MD; Christian Endler, PhD; Ilse Muchitsch, PhD; Ernst Schuster, PhD; and Alan Kaye, MD
Background: Stringy, tenacious tracheal secretions may prevent extubation in patients weaned from the respirator. This prospective, randomized, double-blind, placebo-controlled study with parallel assignment was performed to assess the influence of sublingually administered potassium dichromate C30 on the amount of tenacious, stringy tracheal secretions in critically ill patients with a history of tobacco use and COPD.
Methods: In this study, 50 patients breathing spontaneously with continuous positive airway pressure were receiving either potassium dichromate C30 globules (group 1) [Deutsche Ho- mo ̈opathie-Union, Pharmaceutical Company; Karlsruhe, Germany] or placebo (group 2). Five globules were administered twice daily at intervals of 12 h. The amount of tracheal secretions on day 2 after the start of the study as well as the time for successful extubation and length of stay in the ICU were recorded.
Results: The amount of tracheal secretions was reduced significantly in group 1 (p Conclusion: These data suggest that potentized (diluted and vigorously shaken) potassium dichromate may help to decrease the amount of stringy tracheal secretions in COPD patients.
(CHEST 2005; 127:936–941)
Key words: COPD; double-blind, randomized, placebo-controlled study; extubation; homeopathy; tracheal secretions
Abbreviations: APACHE acute physiology and chronic health evaluation; BMI body mass index; CPAP con- tinuous positive airway pressure; Fio2 fraction of inspired oxygen
Weaning from a respirator is a significant prob- lem in patients receiving mechanical ventilation in the ICU.1 Some factors involved in the assessment for extubation include the severity of the patient’s premorbid condition and the extent to which the patient’s respiratory muscles have been decondi- tioned by mechanical support. Most patients are easily weaned and extubated following short periods
*From the Ludwig Boltzmann Institute for Homeopathy (Drs. Frass, Endler, and Muchitsch), Vienna, Austria; II Department of Internal Medicine (Mr. Dielacher and Dr. Linkesch); Depart- ment of Medical Computer Sciences (Dr. Schuster), University of Vienna, Vienna, Austria; and Department of Anesthesiology (Dr. Kaye), Texas Tech University Lubbock, TX.
Manuscript received March 17, 2004; revision accepted July 17, 2004. Reproduction of this article is prohibited without written permis- sion from the American College of Chest Physicians (e-mail: permissions@chestnet.org).
Correspondence to: Michael Frass, MD, Professor of Medicine, Ludwig Boltzmann Institute for Homeopathy, Duerergasse 4, A 8010 Graz, Austria; e-mail: michael.frass@kabsi.at
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of mechanical ventilation. While most patients need only a short period of nonaugmented spontaneous breathing through the endotracheal tube before extubation, patients receiving mechanical ventilation as the result of ARDS, pneumonia, exacerbations of COPD, septicemia, pulmonary edema, or other com- plicated medical conditions often require prolonged periods to be successfully weaned. Besides weaning, extubation may be difficult because of multiple causes, including the presence of profuse, stringy, tenacious tracheal secretions.
COPD is the fourth leading cause of death in the United States, and it accounts for approximately 500,000 hospitalizations for exacerbations each year.2 One of the problems of COPD and tobacco-use patients encountered in the ICU is difficulty in extubating related to profuse tracheal secretions. Weaning before extubation may be facilitated using different ventilatory modes, such as spontaneous breathing with continuous positive airway pressure
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spontaneous breathing with CPAP with a Fio2 varying between 0.21 and 0.3, and positive airway pressure from 5 to 7 cm H2O after weaning from controlled mechanical ventilation. Addition- ally, extubation was impossible due to profuse tenacious, stringy tracheal secretions according to the criteria listed above.
Exclusion Criteria
Exclusion criteria included signs of additional lung diseases other than COPD at the time of enrollment or during the study observational period; positive blood culture results during the period of controlled mechanical ventilation; concomitant disease of the larynx and trachea obstructing the airway or inhibiting the extubation process; concomitant heart disease; need for cat- echolamines; pregnancy; and failure to give written informed consent.
Medication
In homeopathic concentrations, potassium dichromate acts primarily by its mucolytic properties.5 In this study, we used a preparation of C30, which is equivalent to a potentiation of 30 dilutions, in which each of the 30 dilution steps is followed by subsequent vigorous succussions. Therefore, the above-described toxic effects were eliminated. In addition, the original orange-red color disappeared during the preparation. Onset of action may vary from patient to patient but is generally observed within 24 to 48 h.
Potassium dichromate (Deutsche Homo ̈opathie-Union, Phar- maceutical Company; Karlsruhe, Germany) was prepared accord- ing to the German Homeopathic Pharmacopoeia6 by repeated dilution and vigorous shaking. Saccharose globules with a spher- ical shape and a diameter of approximately 1 mm were impreg- nated with a C30 dilution of potassium dichromate (group 1). Same-sized globules for placebo in group 2 were impregnated with the same water-alcohol diluent used for the preparation of the globules in group 1, without inclusion of any drug. Placebo globules exhibited the same appearance as the homeopathic globules and were therefore indistinguishable from the globules of group 1 according to the double-blind design of the study. Neither patients nor members of the critical care team or members of the study group knew whether the globules admin- istered to the respective patient belonged to group 1 or group 2.
Randomization Process
Patients were sequentially randomized into two groups: group 1 received the therapeutic agent, and group 2 received according to a computer-generated code. An independent physician not involved into the study held the code. A person not involved in the decision and/or application process of the study filled glob- ules of group 1 and group 2 into separate flasks for each study patient with an increasing number.
Sublingual Administration of the Globules
Globules were administered by pouring five globules into the lid of the flask containing the globules. Then, the globules were poured from the lid directly underneath the patient’s tongue. In patients intubated endotracheally, the globules were adminis- tered just aside the endotracheal tube. Globules were adminis- tered twice daily at an interval of 12 h until extubation of the patient. Fifteen minutes before and after administration of the globules, no oral fluid or oral hygiene was allowed.
Suctioning Procedures and Classification of Sputum Volume
An open suctioning system was used during this study. Suc- tioning was performed routinely every 6 h and in addition when
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(CPAP). A problem preventing successful extubation may be profuse tracheal secretions.3
Potassium dichromate is a drug that is commonly used in homeopathy for treatment of profuse, stringy, tenacious tracheal secretions. It is prepared according to homeopathic rules and is preferably administered by help of globules.
The aim of this prospective, double-blind, ran- domized, placebo-controlled study was to evaluate the influence of potassium dichromate on the amount of the described secretions with respect to the time of successful extubation as well as to length of stay in the ICU in these patients after start of the study.
Materials and Methods
The study was approved by the local Institutional Review Board. Patients signed informed consent before enrollment into the study. To ensure patient understanding, information was provided in the presence of their respective relatives and/or next of kins and documented. The study was planned prospectively, randomized, placebo controlled, and double blind.
Patients
Due to the severity of the acute respiratory failure, patients received controlled mechanical ventilation with a respirator (Servo 900C; Siemens Elema; Solna, Sweden) between 3 days and 7 days before study enrollment in a university hospital. The study lasted 18 months. The pulmonary status of the patients did not allow for noninvasive positive airway pressure ventilation during this period. Patients enrolled into the study could be successfully weaned from controlled or assisted mechanical ventilation and were switched to spontaneous breathing with CPAP provided by a continuous flow machine (Dra ̈ger CF 800; Dra ̈ger; Lu ̈beck, Germany). All patients were intubated with either a conventional endotracheal tube (8-mm inner diameter; Mallinckrodt; Athlone, Ireland) or a tracheostomy tube (8-mm inner diameter; Mallinckrodt). Despite regular suctioning and therapeutic bronchoscopy, extubation for these patients was impossible due to profuse, tenacious, stringy tracheal secretions (equal to grade 3 as described below) for 36 to 48 h before enrollment into the study. Administration of mucolytic agents was avoided due to observation of increased secretions in previ- ous patients. -Agonist bronchodilators were stopped at the start of the study to avoid any potential influence and/or interaction. A daily screening was performed in accordance with the methods described by Ely et al.4 Criteria used to decide extubation were that patients should be alert, with stable vital signs, and have an intact gag reflex. Physiologic guidelines were Pao2 60 mm Hg during spontaneous breathing with CPAP (fraction of inspired oxygen [Fio2] 50%) and positive end-expiratory pressure from 3 to 5 cm H2O, and respiratory rate 20 breaths/min. Extuba- tion failure was defined as need for reintubation within the following 72 h except for respiratory deterioration due to newly developed pneumonia. Physicians not involved into the study decided when patients would be extubated.
Inclusion Criteria
Inclusion criteria included a documented history of tobacco use and COPD for at least 10 years before acute deterioration;
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patients had profuse secretions. Flow-volume loops could not be used during spontaneous breathing with CPAP. The quantity of tracheal secretions during routine suctioning was distinguished by volume of suctioned sputum in a graduated vial interposed between suctioning catheter and the tubes leading to the suc- tioning pump. Tracheal secretions were classified into three grades (grade 1, 0 to 5 mL; grade 2, 6 to 10 mL; grade 3, 11 to 15 mL). Sputum did not exceed 15 mL in the investigated patients. The amount and viscosity of sputum production prior to study enrollment were not different between both groups as evaluated three times in subsequent order within 24 h. In this study, sputum was classified as grade 3 in all patients before administration of medication. Furthermore, the volume of spu- tum was evaluated again on day 2 after administration of the globules. The mean of three grades was used for classification.
Parameters Recorded
Prehospital historical and demographic information included age, sex, weight, height, BMI, FEV1, stage of COPD (1, mild; 2, moderate; 3, severe), tobacco use, need of long-term oxygen therapy, and home noninvasive ventilation before admission.7 In the hospital prior to entry into the treatment period, APACHE (acute physiology and chronic health evaluation) II, Pao2/Fio2, and Paco2 were measured. During the treatment period, suc- tionings per day and therapeutic bronchoscopies in hospital after randomization, antibiotic regimen during the period of controlled mechanical ventilation, time to extubation, and length of stay in the ICU after enrollment into the study were recorded.
Statistical Analysis
Statistical analysis was done at the Department of Medical Computer Sciences, University of Vienna, using a software package (Statistical Analysis System; SAS Institute; Cary, NC). All statistical analyses were done before breaking the randomiza- tion code. Statistical analysis of the data was performed using Kruskal-Wallis test for comparing the two groups. Values are expressed as mean SD.
Results
Fifty-five patients were evaluated for the study. Five patients (two patients in group 1 and three
patients in group 2) had to be excluded because of the development of pulmonary infiltrates described as pneumonia by independent radiologists within 2 days after enrollment into the study. Therefore, 25 patients remained in each group. Three patients in each group were breathing via a tracheostomy tube. No patients refused to participate in the study.
With respect to parameters recorded before hos- pitalization and historical and demographic informa- tion, three was no difference in age, sex, height, weight, BMI, FEV1, stage of COPD, and need of long-term oxygen therapy, as well as home noninva- sive ventilation (Table 1). Severity and duration of COPD and tobacco use was equal in both groups.
With respect to parameters recorded in the hos-
pital prior to entry into the treatment period, no
differences were found between both groups for
APACHE II, Pao /Fio , and Paco (Table 1). There 222
was no difference in the number of regular suction- ings and therapeutic bronchoscopies between both groups (Table 2).
With respect to parameters recorded during treat- ment period, there was no significant change of the amount of tracheal secretions between both groups on day 1 after start of the study; tracheal secretions were reduced significantly in group 1 (p 0.0001, Table 2) on day 2. Extubation could be performed significantly earlier in group 1 (p 0.0001, Table 2). Similarly, length of stay at the ICU was significantly shorter in group 1 (p 0.0001, Table 2).
All patients underwent a trial of extubation. None of the patients in group 1 had to be reintubated or needed noninvasive ventilation. In group 1, the amount of secretions remained stable and did not increase. Similarly, blood gas analyses after extuba- tion remained stable in group 1 and did not show
Parameters
Pre-hospital information Age, yr
Male/female gender, No. Weight, kg Height, cm BMI
FEV1, % Stage of COPD‡ Need for long-term oxygen therapy, No. Home noninvasive ventilation, No.
In-hospital (prior to study entry) information APACHE II Pao2/Fio2 Paco2, torr
Table 1—Patient Characteristics*
Group 1, Potassium Dichromate (n 25)
69.2 9.1 (49–89) 19/6
81.0 9.8 (59–102) 170.2 6.3 (157–179)
28.0 2.8 (21.7–33.3) 54.0 5.3 (32–60) 1.08 0.4 (1–3)
5 1
21.2 2.2 (18–25) 222.5 18.6 (178–250)
61.6 4.5 (53–69)
Group 2, Placebo (n 25)
68.4 10.1 (45–88) 20/5 78.8 10.2 (59–101)
171.2 5.8 (161–183) 26.8 2.8 (21.1–32.6) 52.4 5.5 (32–59) 1.20 0.5 (1–3)
9 1
21.6 2.2 (18–26) 219.4 22.4 (176–250)
59.8 4.1 (51–67)
p Value†
0.748
0.599 0.763 0.174 0.152 0.178
0.583 0.985 0.140
*Data are presented as mean SD (range) unless otherwise indicated. †Kruskal-Wallis test. ‡COPD stage: 1 mild, 2 moderate, 3 severe.
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Table 2—Parameters Recorded During Treatment Period (Secretions and Suctionings per Day on Day 2)*
Variables
Secretions Grade 1 Grade 2 Grade 3 Suctionings per day Therapeutic bronchoscopies Extubation, d
Length of stay, d
*Data are presented as mean SD (range). †Kruskal-Wallis test.
Group 1, Potassium Dichromate (n 25)
1.52 0.59 1 (1–3) 13 11
1 7.2 0.7 (6–8)
0.64 0.57 (0–2) 2.88 1.20 (1–6) 4.20 1.61 (2–8)
Group 2, Placebo (n 25)
2.44 0.65 3 (1–3) 2
10
13 6.9 0.8 (6–8)
0.76 0.66 (0–2) 6.12 3.13 (3–14) 7.68 3.60 (4–17)
p Value†
0.0001
0.206
0.555 0.0001 0.0001
significant differences as compared to pre-extubation values. Four patients in group 2 had to be reintu- bated because of deterioration of blood gas analysis results due to recurrence of tracheal secretions grade 2 to 3.
Discussion
Potassium dichromate (kalium bichromicum, K2 Cr2 O7 ) is a drug widely used in natural and homeopathic medicine. One of its features is its efficacy to treat patients with stringy, tenacious nasal and tracheal secretions. An open-label, practice- based homeopathic study5 described the efficacy and safety of a fixed-combination homeopathic medica- tion containing potassium dichromate in 119 male and female patients with clinical signs of acute sinusitis not previously treated. At the first visit, after a mean of 4.1 days of treatment, mucolysis had increased significantly and typical sinusitis symp- toms, such as headache, pressure pain at nerve exit points, and irritating cough, were reduced. Adverse drug effects were not reported.5
The physical properties of potassium dichromate are its appearance as bright orange-red crystals, a melting point of 398°C, and a specific gravity of 2.67. When swallowed undiluted, it can be harmful or fatal.8–11 As a systemic poison, it may be primarily toxic to kidneys,8 liver,8–9 and GI tract.10 Further- more, it can cause severe irritation of the eyes and conjunctivitis. Contact with breaks in the skin can cause “chrome sores” (skin ulcers). Dichromates are skin sensitizers.12 In the construction industry of Northern Bavaria, potassium dichromate is still the most important allergen. Potassium dichromate caused roughly half of all cases of sensitization such as allergic contact dermatitis and irritant contact dermatitis found to be occupationally relevant in the construction industry.12
The use of in vitro release of interferon- in the www.chestjournal.org
diagnosis of contact allergy to potassium dichromate was studied in 20 patients who had positive patch test results to chromate and in 30 control subjects (10 patients with contact dermatitis, allergic to other allergens, 10 patients with other dermatologic dis- eases, and 10 healthy subjects).13 The release of interferon- in the supernatants of the peripheral blood lymphocytes was significantly higher in the patients with proven allergy to chromate (p 0.001).13 In an animal toxicity study,14 a protec- tive effect of SnCl2 on K2 Cr2 O7 -induced nephrotox- icity could be observed in rats.
The data suggest that potassium dichromate may be a substance allowing earlier extubation due to a reduction in stringy, tenacious tracheal secretions. While the basic parameters were comparable in both groups, the group receiving potassium dichromate showed a statistical significant improvement within a short time period.
The presence of one or more of the following findings defines acute COPD exacerbation: increase in sputum purulence, increase in sputum volume, and worsening of dyspnea.15 Patients with COPD typically present with acute decompensation of their disease one to three times a year, and 3 to 16% of these will require hospital admission. Hospital mor- tality from these admissions ranges from 3 to 10% in severe COPD patients, and it is much higher for patients requiring ICU admission.15 One of the problems encountered in the ICU is difficulty in extubating the patient because of profuse tracheal secretions. This is a special problem in patients with tenacious, stringy tracheal secretions who have to- bacco use and COPD in their history. In some patients, these secretions are resistant to antimicro- bial and mucolytic therapy, administration of glyco- pyrroniumbromide is contraindicated because it may worsen the patient’s situation. There is no evidence for mucolytic agents or chest physiotherapy in the acute exacerbation setting of COPD.2
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Weaning before extubation may be facilitated using different ventilatory modes. One of them, spontaneous breathing with CPAP, is used fre- quently for weaning from mechanical ventilation. Heart-lung interaction, fluid retention, and renal dysfunction can be observed with CPAP too, al- though the extent of these alterations is generally lower when compared to mechanical ventilation with positive end-expiratory pressure. Interestingly, pro- tocol-guided weaning of mechanical ventilation, as performed by nurses and respiratory therapists, is safe and leads to extubation more rapidly than physician-directed weaning.16 In contrast with adult patients, the majority of children are weaned from mechanical ventilator support in 2 days. Weaning protocols did not significantly shorten this brief duration of weaning.17
If a patient tolerates successive decreases in ven- tilator support, that patient is successfully weaned.1 It is important to separate weaning from extubation. A patient may tolerate being on a minimum amount of ventilator support for an extended period of time from which no further decreases are considered necessary. However, a physician may refuse to extu- bate the patient for other reasons. Some reasons may be related to the patient, such as the inability to tolerate profuse secretions, the need for sedation for a scheduled diagnostic study, or the concern that another organ system is deteriorating.
Profuse stringy, tenacious tracheal secretions may be responsible for postponed extubation. While the weaning process was successful and the patient was able to breathe spontaneously with CPAP, extuba- tion sometimes may be postponed because of the presence of intense tracheal secretions.
The present study suggests that potassium dichro- mate C30 may be able to minimize the amount of tracheal secretions and therefore to allow earlier extubation when compared to placebo. Since the potentiation (dilution and vigorously shaking) of the study drug beyond the Avogadro number imposes no interaction with the patient’s metabolism, and due to the low cost of the drug, its use in the ICU may be beneficial, minimizing morbidity and mortality.18,19 Studies give some insight into the potential way of action of homeopathically prepared drugs. Cluster- cluster aggregation phenomena in aqueous solutions of fullerene-cyclodextrin conjugates, b-cyclodextrin, sodium chloride, sodium guanosine monophosphate, and a DNA oligonucleotide revealed that there are larger aggregates existent in dilute aqueous solutions than in more concentrated solutions.20 In another study, ultra-high dilutions of lithium chloride and sodium chloride (10-30 g cm-3) have been irradiated by x-rays and gamma-rays at 77 K, then progressively rewarmed to room temperature.21 During that
phase, their thermoluminescence has been studied and it was found that, despite their dilution beyond the Avogadro number, the emitted light was specific of the original salts dissolved initially.
This is the first scientific study of the effect of potassium dichromate on tracheal secretions. While the mechanism of potentized (diluted and vigorously shaken) drugs still remains subject to research, sev- eral articles describe its clinical usefulness.22–24 The effect may be best explained by cybernetics, which means that the information of the homeopathic drug acts consensually on the regulator. Thereby, the body regains its original property to regulate physical parameters.
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References
Randolph AG. Weaning from mechanical ventilation. New Horiz 1999; 7:374–385 Soto FJ, Varkey B. Evidence-based approach to acute exac- erbations of COPD. Curr Opin Pulm Med 2003; 9:117–124 Khamiees M, Raju P, DeGirolamo A, et al. Predictors of extubation outcome in patients who have successfully com- pleted a spontaneous breathing trial. Chest 2001; 120:1262– 1270
Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1864 –1869
Adler M. Efficacy and safety of a fixed-combination homeo- pathic therapy for sinusitis. Adv Ther 1999; 16:103–111 Deutsches Homo ̈ opathisches Arzneibuch 1985 [German Ho- meopathic Pharmacopoeia 1985]. Stuttgart, Germany: Deut- scher Apotheker Verlag, 1985
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 1995; 152:S77–S121 Sharma N, Chauhan S, Varma S. Fatal potassium dichromate ingestion. J Postgrad Med 2003; 49:286 –287
Stift A, Friedl J, Langle F, et al. Successful treatment of a patient suffering from severe acute potassium dichromate poisoning with liver transplantation. Transplantation 2000; 69:2454 –2455
Iserson KV, Banner W, Froede RC, et al. Failure of dialysis therapy in potassium dichromate poisoning. J Emerg Med 1983; 1:143–149 Michie CA, Hayhurst M, Knobel GJ, et al. Poisoning with traditional remedy containing potassium dichromate. Hum Exp Toxicol 1991; 10:129–131
Bock M, Schmidt A, Bruckner T, et al. Occupational skin disease in the construction industry. Br J Dermatol 2003; 149:1165–1171 Trattner A, Akerman L, Lapidoth M, et al. Use of in vitro release of interferon-gamma in the diagnosis of contact allergy to potassium dichromate: a controlled study. Contact Dermatitis 2003; 48:191–193
Barrera D, Maldonado PD, Medina-Campos ON, et al. Protective effect of SnCl2 on K2Cr2O7-induced nephrotoxic- ity in rats: the indispensability of HO-1 preinduction and lack of association with some antioxidant enzymes. Life Sci 2003; 73:3027–3041
Anthonisen NR, Manfreda J, Warren CPW, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary
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"vaccine vs homeopathic remedy for swine flu"
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| ** I do not own this video and it is copyright of channel 10 Australia ** this doesn't really provide much in depth information but is interesting to note difference in the way each vaccine was presented. For more information on homeopathic remedies and their effectiveness look on pub med or do some research yourself. note that homeopathy is considered a pseudoscience by the vast majority of the medical community with an effect tantamount to that of a placebo. | |
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Check out this awesome directory of Homeopaths
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Check out this awesome directory of Homeopaths
Alternative to Vaccines. A Personal Quest
/
By Elena Cecchetto DCH, CCH, RSHom(NA)
Certified Homeopath
For a while I had been reading about homeopathy and knew that Homeopathic Remedies for Immunizations existed (Homeoprophylaxis). I knew that somehow you could use Homeopathic Remedies for the purpose of protection against targeted infectious diseases. I just didn’t know exactly how to do this. My fear of needles (specifically the vaccine dangers) sent me on this quest. So I called a few people to find out if they knew how. I called my friend’s cousin who had studied Homeopathy. I
called a few Homeopaths listed in the yellow pages (yes, back in the days of the yellow pages). I told them what I would like to do and asked if they knew how. I got a few different responses.
They all agreed that indeed it is entirely fitting for the system of medicine known as homoeopathy to be able to perform this function. But they just weren’t sure exactly how to do this. Keep in mind that I was investigating this many years ago. Now there are many Homeopaths internationally working with Homeopathic Remedies for Immunization.
Homeopathy has been well known for its incredible results during epidemics. In the era of the 1912 epidemic, the Homeopathic Remedy called Gelsemium had high success rates among the Homeopathic Doctors of the day. Yes, in the early 1900’s, in North America, Homeopaths were considered Doctors. Some excellent anecdotes and statistics that stick in my mind describing the use of Homeopathy for epidemics go something
like this:
1. One of the earliest tests of the homeopathic system was in the treatment of Typhus Fever (spread by lice) in an 1813 epidemic which followed the devastation of Napoleon’s army marching through Germany to attack Russia, followed by their retreat. When the epidemic came through Leipzig as the army pulled back from the east, Samuel Hahnemann, the founder of homeopathy, was able to treat 180 cases of Typhus, only losing two (1.11%). This was at a time when the conventional treatments were having a mortality rate of over 30%.
2. Within three years of the Diphtheria outbreak in Broome County, NY from 1862 to 1864, there was a report of an 83.6% mortality rate amongst the conventional medical Doctors and a 16.4% mortality rate amongst the Homeopaths.
3. The May 1921 edition of the Journal of the American Institute for Homeopathy had an article about the use of homeopathy during the Influenza Pandemic of 1918. Dr. T. A. McCann, from Dayton, Ohio reported that 24,000 cases of flu treated with conventional medicine had a mortality rate of 28.2%, while 26,000 cases of flu treated homeopathically had a mortality rate of 1.05%.
My quest wasn’t successful and I got the shots to go travelling. Luckily, I had no side effects that I know of, so far. Even better, I spent months reading the Homeopathic literature that I carted around with me and became completely enamored with the Philosophy of Homeopathy.
More than a decade later and I am finally one of the handful of Homeopaths in Vancouver with the level of education and accreditation that gives me the title of “Certified Classical Homeopath”. Even better, I have the opportunity to offer Homeopathic Remedies to help people be protected for specific infectious diseases. There are various protocols that can be used depending on the disease.
There is a great personal satisfaction that I get when I receive postcards from the travellers who have received excellent Homeopathic Care. Imagine going to India without experiencing any gastro-intestinal complaints! Amazing! Fun! That is how travel is meant to be. I am determined to be able to support people in attaining this kind of travel experience.
Certified Homeopath
For a while I had been reading about homeopathy and knew that Homeopathic Remedies for Immunizations existed (Homeoprophylaxis). I knew that somehow you could use Homeopathic Remedies for the purpose of protection against targeted infectious diseases. I just didn’t know exactly how to do this. My fear of needles (specifically the vaccine dangers) sent me on this quest. So I called a few people to find out if they knew how. I called my friend’s cousin who had studied Homeopathy. I
called a few Homeopaths listed in the yellow pages (yes, back in the days of the yellow pages). I told them what I would like to do and asked if they knew how. I got a few different responses.
They all agreed that indeed it is entirely fitting for the system of medicine known as homoeopathy to be able to perform this function. But they just weren’t sure exactly how to do this. Keep in mind that I was investigating this many years ago. Now there are many Homeopaths internationally working with Homeopathic Remedies for Immunization.
Homeopathy has been well known for its incredible results during epidemics. In the era of the 1912 epidemic, the Homeopathic Remedy called Gelsemium had high success rates among the Homeopathic Doctors of the day. Yes, in the early 1900’s, in North America, Homeopaths were considered Doctors. Some excellent anecdotes and statistics that stick in my mind describing the use of Homeopathy for epidemics go something
like this:
1. One of the earliest tests of the homeopathic system was in the treatment of Typhus Fever (spread by lice) in an 1813 epidemic which followed the devastation of Napoleon’s army marching through Germany to attack Russia, followed by their retreat. When the epidemic came through Leipzig as the army pulled back from the east, Samuel Hahnemann, the founder of homeopathy, was able to treat 180 cases of Typhus, only losing two (1.11%). This was at a time when the conventional treatments were having a mortality rate of over 30%.
2. Within three years of the Diphtheria outbreak in Broome County, NY from 1862 to 1864, there was a report of an 83.6% mortality rate amongst the conventional medical Doctors and a 16.4% mortality rate amongst the Homeopaths.
3. The May 1921 edition of the Journal of the American Institute for Homeopathy had an article about the use of homeopathy during the Influenza Pandemic of 1918. Dr. T. A. McCann, from Dayton, Ohio reported that 24,000 cases of flu treated with conventional medicine had a mortality rate of 28.2%, while 26,000 cases of flu treated homeopathically had a mortality rate of 1.05%.
My quest wasn’t successful and I got the shots to go travelling. Luckily, I had no side effects that I know of, so far. Even better, I spent months reading the Homeopathic literature that I carted around with me and became completely enamored with the Philosophy of Homeopathy.
More than a decade later and I am finally one of the handful of Homeopaths in Vancouver with the level of education and accreditation that gives me the title of “Certified Classical Homeopath”. Even better, I have the opportunity to offer Homeopathic Remedies to help people be protected for specific infectious diseases. There are various protocols that can be used depending on the disease.
There is a great personal satisfaction that I get when I receive postcards from the travellers who have received excellent Homeopathic Care. Imagine going to India without experiencing any gastro-intestinal complaints! Amazing! Fun! That is how travel is meant to be. I am determined to be able to support people in attaining this kind of travel experience.
500 Million people in the world use Homeopathy
/An EU commission statement estimates that some 30 million people in the EU use homeopathy, while the WHO estimates that around 500 million in the world use it.
Nobel Prize winner scientifically describes Homeopathy
/ABSTRACT
A novel property of DNA is described: the capacity of some bacterial DNA sequences to induce electromagnetic waves at high aqueous dilutions. It appears to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. The genomic DNA of most pathogenic bacteria contains sequences which are able to generate such signals. This opens the way to the development of highly sensitive detection system for chronic bacterial infections in human and animal diseases. http://www.springerlink.com/content/0557v31188m3766x/ Interdiscip Sci Comput Life Sci (2009) 1: 8190 DOI: 10.1007/s12539-009-0036-7
Electromagnetic Signals Are Produced by Aqueous Nanostructures Derived from Bacterial DNA Sequences
Luc MONTAGNIER1,2?, Jamal A ?ISSA1, St ?ephane FERRIS1, Jean-Luc MONTAGNIER1, Claude LAVALLE ?E1
1(Nanectis Biotechnologies, S.A. 98 rue Albert Calmette, F78350 Jouy en Josas, France) 2(Vironix LLC, L. Montagnier 40 Central Park South, New York, NY 10019, USA)
Recevied 3 January 2009 / Revised 5 January 2009 / Accepted 6 January 2009
Abstract: A novel property of DNA is described: the capacity of some bacterial DNA sequences to induce electromagnetic waves at high aqueous dilutions. It appears to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. The genomic DNA of most pathogenic bacteria contains sequences which are able to generate such signals. This opens the way to the development of highly sensitive detection system for chronic bacterial infections in human and animal diseases.
Key words: DNA, electromagnetic signals, bacteria.
Pathogenic microorganisms in this day of age are not only submitted to high selective pressure by the im- mune defenses of their hosts but also have to survive un- der highly active antiviral or antibiotic treatments. Not surprisingly, they have evolved in finding many ways to escape these hostile conditions, such as mutations of re- sistance, hypervariability of surface antigens, protective biofilms, latency inside cells and tissues.
We initially observed (Montagnier and Lavallee, per- sonal communication) that some filtration procedures aimed at sterilizing biological fluids can yield under some defined conditions the infectious microorganism which was present before the filtration step. Thus, fil- tration of a culture supernatant of human lymphocytes infected with Mycoplasma pirum, a microorganism of about 300 nM in size, through filters of 100 nM or 20 nM porosities, yielded apparently sterile fluid. The latter however was able to regenerate the original my- coplasma when incubated with a mycoplasma negative culture of human lymphocytes within 2 to 3 weeks.
Similarly, a 20 nM filtration did not retain a minor in- fective fraction of HIV, the causal agent of AIDS, whose viral particles have a diameter averaging 100-120 nM.
In the course of investigating the nature of such filter- ing infectious forms, we found another property of the filtrates, which may or may not be related to the former: their capacity to produce some electromagnetic waves of low frequency in a reproducible manner after appro-
*Corresponding author. E-mail: nadiacpt@yahoo.fr
priate dilutions in water. The emission of such waves is likely to represent a resonance phenomenon depending on excitation by the ambient electromagnetic noise. It is associated with the presence in the aqueous dilutions of polymeric nanostructures of defined size. The super- natant of uninfected eukaryotic cells used as controls did not exhibit this property.
In this paper we provide a first characterization of the electromagnetic signals (EMS) and of their underlying nanostructures produced by some purified bacteria.
In addition to M. pirum, a more classical bacterium, E. Coli, was utilized for the purpose of the analysis. The nanostructures produced by HIV will be the sub- ject of another paper.
M. pirum is a peer-shaped small bacterial cell, ressembling M. pneumoniae, which can be grown in syn- thetic enriched medium (SP4) (Tully et al., 1977) but also mutiplies at the surface of human T lymphocytes.
The strain (Ber) used in our experiments was isolated from a T lymphocyte culture derived from the blood of an apparently healthy subject (Grau et al., 1993). The strong mycoplasma adherence to lymphocytes is mediated by a specific adhesin, whose gene had been previously cloned and sequenced by the authors (Tham et al., 1994).
We used as primary source of the mycoplasma, super- natants of infected human T lymphocyte cultures or of cultures of the CEM tumor T cell line. All cell cultures were first tested for the lack of M. pirum contamination by polymerase chain reaction (PCR) and nested PCR, before starting the experiments. Titers of 106-107 infec-
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Interdiscip Sci Comput Life Sci (2009) 1: 8190
tious Units/ml of M. pirum were readily achieved after 5-6 days of incubation following deliberate infection of both types of cultures.
Filtration of the clarified supernatant was first per- formed on 0.45 ?M (450 nM) Millipore filters to remove debris, and subsequently on 0.1 ?M (100 nM) Milli- pore filters or on 0.02 ?M (20 nM) Whatman filters, to remove mycoplasma cells. Indeed, the two 100 nM and 20 nM filtrates were confirmed sterile when aliquots were incubated for several weeks in SP4 medium. Re- peated search for traces of mycoplasma DNA by PCR and nested PCR using specific primers for the adhesin gene or for the 16S ribosomal gene was consistently neg- ative.
However when the filtrates were incubated for two weeks (100 nM filtrate) or three weeks (20 nM filtrate) with a culture of human activated T lymphocytes, the mycoplasma was recovered in the medium with all its original characteristics as previously observed.
The same filtrates were analyzed just after filtra- tion for production of electromagnetic waves of low fre- quency. For this purpose we used a device previously designed by Benveniste and Coll (1996; 2003) for the detection of signals produced by isolated molecules en- dowed with biological activity. The principle of this technology is shown in Fig. 1.
Blaster Card itself connected to a laptop computer, preferentially powered by its 12 volt battery. Each emission is recorded twice for 6 seconds, amplified 500 times and processed with different softwares for vizual- ization of the signals on the computer's screen (Fig. 1).
The main harmonics of the complex signals were an- alyzed by utilizing several softwares of Fourier transfor- mation.
In each experiment, the internal noise generated by the different pieces of the reading system was first recorded (coil alone, coil with a tube filled with water). Fourier analysis shows (Fig. 2(c, d)) that the noise was predominantly composed of very low frequencies, prob- ably generated at least in part by the 50/60 Hz ambi- ent electric current. The use of the 12 V battery for the computer power supply did reduce, but not abolish this noise, which was found to be necessary for the induc- tion of the resonance signals from the specific nanos- tructures.
When dilutions of the M. pirum filtrate were recorded for wave emission, the first obvious phenomenon ob- served was an increase of the overall amplitude of the signals at certain dilutions over the background noise (Fig. 2(a)) and also an increase in frequencies (Fig. 2(b)). This change was abolished if the tube to be analyzed was placed inside a box sheltered with sheets of copper and mumetal (David, 1998).
Fourier analysis of the M. pirum signals showed a shift towards higher frequencies close to 1000 Hz and multiples of it. Profiles were identical for all the dilu- tions showing an increase in amplitude (Fig. 2(c) and 2(d)).
The first low dilutions were usually negative, showing the background noise only. Positive signals were usu- ally obtained at dilutions ranging from 10-5 to 10-8 or 10-12. Higher dilutions were again negative (Fig. 3).
The positive dilutions varied according to the type of filtration, the 20 nM filtrate being generally positive at dilutions higher than those of the 100 nM filtrate.
The original unfiltered suspension was negative at all dilutions, a phenomenon observed for all the microor- ganisms studied. Size and density of the structures producing the signals in the aqueous dilutions:
An aliquot of the 20 nM filtrate was layered on the top of a 5-20% (w/v) sucrose gradient in water and centrifuged for 2 hours at 35,000 rpm in a swinging bucket rotor. These conditions had previously been used to obtain the density equilibrium of the intact my- coplasma cells wich formed a sharp bound at 1,21 den- sity. Fractions were collected from the bottom of the tubes, pooled 2 by 2 and assayed for signal emission.
Fig. 4 shows that the signal emitting structures were distributed in a large range of densities from 1.15 to 1.25 and also had a high sedimentation coefficient.
Fig. 1
Device for the capture and analysis of electromag- netic signals (EMS): (1) Coil: a bobbin of copper wire, impedance 300 Ohms; (2) Plastic stoppered tube containing 1 mL of the solution to be analyzed; (3) Amplifier; (4) Computer with softwares.
Briefly, the 100 nM or 20 nM filtrates are serially di- luted 1 in 10 (0,1 +0,9 in sterile water (medical grade). The first 2 dilutions (1/10 and 1/100) are done in serum-free RPMI medium, in order to avoid eventual protein precipitation in deionized water.
Each dilution is done in 1.5 mL Eppendorf plastic tubes, which are then tightly stoppered and strongly agitated on a Vortex apparatus for 15 seconds . This step has been found critical for the generation of signals.
After all dilutions have been made (generally 15-20 decimal dilutions), the stoppered tubes are read one by one on an electromagnetic coil, connected to a Sound
Interdiscip Sci Comput Life Sci (2009) 1: 8190 83
Fig. 2
Fig. 3
Detection of EMS from a suspension of Mycoplasma pirum: Left: background noise (from an unfiltered suspension or a negative low dilution). Right: positive signal (from a high dilution D-7 (10-7)). (a) actual recording (2 seconds from a 6 second recording) after WaveLab (Steinberg) treatment; (b) detailed analysis of the signal (scale in millisecondes); (c) Matlab 3D Fourier transform analyzis (abcissa: 0-20 kHz, ordinate: relative intensity, 3D dimension: recording at different times); Frequencies are visualized in different colors; (d) Sigview Fourier transform: note the new harmonics in the range of 1 000-3 000 Hz.
A typical recording of signals from aqueous dilutions of M. Pirum (Matlab software): note the positive signals from D-7 to D-12 dilutions.
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1.25
SN CEM/M.pirum Filtered 0.02?
1.20
1.15
1.30
1.20
10,000 rpm for 15 minutes, the supernatant was fil- tered on 450 nM filter and the resulting filtrate was filtered again on a 100 nM filter. The final filtrate was found sterile, when plated on nutrient agar medium and was analyzed for electromagnetic wave emission, as de- scribed above for M. pirum. Signal producing dilutions usually range from 10-8 to 10-12, with profiles upon Fourier transformation, similar to those of M. Pirum (Fig. 5). In one experiment, some very high dilutions were found positive, ranging from 10-9 to 10-18. An aliquot of the unfiltered supernatant did not show any signals above background up to the 10-38 dilution, in- dicating again the critical importance of the filtration step for the generation of specific signals.
The only difference with M. pirum was that no sig- nal appeared after filtration on 20 nM filters, suggesting that the structures associated with the signals were re- tained by these filters and, therefore, had a size greater than 20 nM and lower than 100 nM.
We then asked why the lower dilutions, which logically should contain a larger number of signal- producing structures, were "silent". When we added 0.1 mL of a negative low dilution (e.g. 10-3) to 0.4 mL or 0.9 mL of a positive dilution (10-8), the latter became negative. This indicate that the "silent" low dilutions are self-inhibitory, probably by interference of the multiple sources emitting in the same wave length or slightly out of phase, like a radio jamming. Alterna- tively, the abundance of nanostructures can form a gel in water and therefore are prevented to vibrate. -Evidence for homologous "cross talk" between dilutions
We then wonder whether or not it was possible to generate new signal-emitting structures from tube to tube by using wave transfer. The following experiment
107
106 1.10 105
104
1 2 3 4 5 6 7 8 9 10 11 12 13
Fig. 4
Sucrose density centrifugation (35000 rpm, 2 Hr) of a 0.02? filtrate of Mycoplasma pirum suspension. The collected fractions were pooled 2 by 2 and di- luted up to D-15 and tested for EMS. The bars in- dicate the fractions positive for EMS.
We then turned to a more classical bacterium, E. Coli, using the laboratory strain K1.
A culture of E. Coli in agitated (oxygenated) con- ditions, yielded 109 bacterial units/mL, measured by spectrometry. The suspension was then centrifuged at
Density
E.M.S. naneons
Interdiscip Sci Comput Life Sci (2009) 1: 8190 85
Fig. 5 EMS from E. Coli 0.1 ? filtrate. EMS positive from dilution D-8 to D-11: (a) Actual recording; (b) millisecond analysis; (c) Fourier transform analysis Matlab; (d) Fourier transform analysis SigView. NF: not filtered.
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Interdiscip Sci Comput Life Sci (2009) 1: 8190
which was repeated several times showed that indeed this was the case.
A donor tube of a low "silent" dilution of E. Coli (10-3) was placed side by side close to a receiver tube of the positive "loud" highest dilution of the same prepa- ration (10-9). Both tubes were placed in a mumetal box for 24 hours at room temperature, so that the tubes were not exposed to external electromagnetic noise, and only exposed to the signals generated by the structures present in the tubes themselves.
The tubes were then read again by the signal detect- ing device: the donor tube was still silent, however the receiver tube became also silent.
Moreover, when further dilutions were made from the receiver tube (10-10, 10-11, 10-12), these dilutions had became positive (Fig. 6). These results suggest that the receiver tube was made silent by formation of an excess of new nanostructures, which could emit signals upon further dilution.
Finally, two others problems were investigated in the E. Coli system: the first was the role of the initial number of bacterial cells in the induction of the fil- terable signal-producing structures. For this a station- ary culture of E. Coli was counted and adjusted to 109 cells/mL and serial dilutions from 100 to 100 were done down to 1 cell/mL. Each dilution was filtered at 100 nM and then analyzed for signal emission. Surprisingly, the range of positive dilutions were not strictly depen- dent on the initial concentration of E. Coli cells, being roughly the same from 109 cells down to 10 cells, sug- gesting that the same final number of nanostructures was reached at all concentrations. Thus, paradoxically, 10 cells are giving the same signals than 109 cells.
We were also concerned by the possible personal in- fluence of the operator in the reading.
To address this point, two healthy operators were asked to measure independantly the same dilutions of E. Coli, each one unknowing the results of the other. The results of their readings were identical.
In addition, the results were independant of the order in which the samples were read, whether in descending dilutions from to the lowest to the highest or in ascend- ing the dilutions from the highest to the lowest.
Finally an other laboratory worker placed the diluted samples in a random order, the labels being unknown from the person reading the samples. The same range of positive dilutions was detected again provided each tube was well separated from the other, to avoid their "cross talk".
We also found that the results were also indepen- dant of the location of the reading site: starting from the same unfiltered preparation of E. Coli, positive di- lutions of the filtrates were found to be the same in two different locations in France (Paris center and sub- urb), one in Canada (Montreal), and one in Cameroun (Yaound ?e).
As shown in the figures, the background noise was variable, according to the location and time of record- ing. It was generally higher in large cities than in iso- lated aeras. However, positive signals always clearly differenciate over the background by higher frequency peaks.
Nature of the aqueous nanostructures:
Treatments by RNAseA (Promega, 1 ?g/ml, 37 °C 1 h), Dnase I (Invitrogen, 10 U/?g DNA, 37°C, 18 h), Lysozyme (Fisher, 1 mg/mL, 37 °C 10 min), Proteinase K (Promega, 0.12 mg/mL, in 1% sodium dodecyl sul- phate, 56°C 1 h) did not suppress the EMS produc- ing activity of the "loud" dilutions nor did activate the "silent" dilutions.
However, heating at 70 °C for 30 min suppressed irre- versiblly the activity, as well as did freezing for 1 hour at -20 °C or -60 °C. DMSO (10%), and formamide (10%) had no effect.
Treatment with lithium cations, known to affect the
Fig. 6
Cross-talk between dilutions (from an E. Coli 0.1 ? filtrate), see explanation in the text.
This effect was suppressed by interposing a sheat of mumetal between the two tubes during the 24 hours contact period, pointing to a role of low frequency waves in the phenomenon.
Emission of similar electromagnetic signals was also observed with some other bacterial species such as: Streptococcus B, Staphylococcus aureus, Pseu- domonas aeroginosa, Proteus mirabilis, Bacillus sub- tilis, Salmonella, Clostridium perfringens, all in the same range of dilutions observed for E. Coli, and only after filtration at 100 nM (and not at 20 nM).
Importantly, the transfer effect between two tubes, one silent, one loud, was only observed if both contained dilutions of the same bacterial species. In other words, a Staphylococcus donor tube could only "talk" with a receiver tube containing a Staphylococcus dilution, and not with a tube of Streptococcus or E. Coli, and reciprocally.
These results indicate that the transfer effect is medi- ated by species-specific signals, the frequencies of which remain to be analyzed.
Interdiscip Sci Comput Life Sci (2009) 1: 8190
87
hydrogen bonding of water molecules, was able to re- duce the intensity of the signals, while the range of the positive dilutions remained unchanged.
Nature of the bacterial molecules at the origin of the nanostructures:
In preliminary experiments, we had observed that a pretreatment of a suspension of E. Coli by 1% formaldehyde did not alter its capacity to induce the electromagnetic signals, while killing the bacteria. This treatment alters the surface proteins of the bacte- rial cells without attacking their genetic material, i.e. double- helical DNA. This suggested that the source of the signals may be the DNA itself.
Indeed, DNA extracted from the bacterial suspension by the classical phenol: chloroform technique was able upon filtration and appropriate dilutions in water to emit EMS similar to those produced by intact bacteria under the same conditions. DNAse treatment of the extracted DNA solution abolishes its capacity to emit signals, at the condition that the nanostructures pre- viously induced by the DNA are destroyed. A typical experiment is described as follows:
E. Coli DNA was treated by Proteinase K in the presence of SDS (sodium dodecyl sulfate) and further deproteinized by phenol-chloroform mixture. The pel-
let obtained by ethanol precipitation was resuspended in Tris 10-2 M, pH 7,6 and an aliquot was diluted 1/100 in water. The dilution (10-2) was filtered first through a 450 nM filter and the resulting filtrate was then fil- tered again on a 100 nM filter. The filtrate was further diluted in serial decimal dilutions in water as previously described.
As for the intact microorganisms, the filtration step was found to be essential for detection of the EMS in the DNA dilutions. In its absence, no signals could be detected at any dilutions.
In contrast to the microorganism suspension, where the filtration was supposed to retain the intact cells, the filtration at 100 nM did not retain the DNA, which was still present in the filtrate, as measured by optical density. However, filtration with a 20 nM Whatman filter retained the nanostructures emitting the EMS, suggesting that they have the same range of sizes than those originating from intact bacteria.
In the case of DNA, the role of the 100 nM filtration is probably to dissociate the network of nanostructures organized in a gel-like liquid crystal at high concen- trations in water, allowing their dispersion in further dilutions. As shown in Fig. 7, the dilutions positive for EMS were in the same range that those observed for the intact bacteria, generally between 10-7 to 10-13.
Fig. 7 DNAse effect on EMS production. The DNAse treated E. Coli DNA solution and the untreated DNA are diluted from D-2 to D-15. Analyzis of the EMS as described in Fig. 5. D-2 dilution (negative for EMS) is shown as control. D-9 is positive for EMS (from a range of positive dilutions D-8 to D-11). Note the signal disappearance in the DNAse treated DNA.
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At the high dilution of 10-13, calculations indicate that there is no DNA molecule of MW larger than 105 in the solution, making it unlikely that the EMS are pro- duced directely by the DNA itself, but rather by the self-sustained nanostructures induced by the DNA.
Generally, all the bacterial species shown to be posi- tive for EMS yielded also DNA preparations positive for EMS. Further demonstration that the EMS produced by bacteria come from their DNA was shown by their disappearance after DNAse treatement.
This inactivation was however only complete when the nanostructures induced in the DNA solution which are themselves resistant to DNAse were previously fully destroyed.
This destruction was obtained either by freezing the DNA solution at -20°C for 1 hour or heating it at 90 °C for 30 minutes.
After slow cooling to allow the heated DNA to re- anneal, DNAse 1 at a final concentration of 10 U/?g of DNA was added and the mixture was incubated at 37°C for 18 hours in the presence of 5 mM of MgCl2. An aliquot of the untreated DNA solution was kept as a positive control.
The DNAse-treated preparation was found com-
pletely devoid of EMS emission at any dilution (Fig. 7). Treatment of the DNA solution by a restriction en- zyme acting at many sites of E. Coli DNA (EcoRV) did not suppress the production of EMS, suggesting that this emission is linked to rather short sequences or is
associated with rare sequences.
Nature of the DNA sequences at the origin of the EMS:
A non exhaustive survey of the bacterial species and of their DNA able to display EMS suggests that most of bacteria pathogenic for humans are in this category.
By contrast, probiotic "good" bacteria as Lactobacil- lus and their DNA are negative for EMS emission.
In the case of E. Coli, we found that some strains used to carry plasmids for gene cloning were also nega- tive (Fig. 8).
This suggested that only some sequences of DNA are at the origin of the EMS.
As pathogenicity is often associated with the capac- ity of the microorganism to bind eukaryotic cells, par- ticulary mucosal cells, we focussed our analysis again to M. pirum DNA, where a single gene (adhesin: 126- kDa protein) is responsible for the adhesion of the my- coplasma to human cells.
Fig. 8 EMS produced by the 1.5 kb fragment of the adhesin DNA of M. Pirum. The plasmid DNA containing the 1.5 Kb fragment was used to transform an E. Coli vector, XL1blue. The whole DNA was extracted and diluted for EMS analysis. Left: control background noise of a negative dilution (D-2). Right: positive signal at D-10 (range from D-9 to D-12). Bottom: Note the lack of EMS produced by the DNA extracted from the strain transformed by the plasmid alone.
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This gene had previously been cloned and sequenced in our laboratory (Tham et al., 1994). The cloned DNA existed as two fragments in two plasmids, corresponding respectively to the N terminal (1.5 Kbp) and the C terminal (5 Kbp) of the protein.
The two plasmids (pBluescript SK, Stratagene) con- taining the DNA fragments were amplified in a E. Coli strain, XL1blue.
The DNA of the E. Coli strain (with or without the plasmid) alone did not yield EMS at any dilutions.
By contrast when the strain was transformed with ei- ther plasmids carrying an adhesin gene fragment, EMS were produced (Fig. 8).
The two adhesin DNA fragments were then cut by specific restriction enzymes (N Terminal: 1.5 kbp/SpeI- EcoRI) (C Terminal: 5 kbp/HindIII-XbaI) and isolated by electrophoresis in 0.8% agarose gel. Each DNA frag- ment was able to induce EMS (not shown).
We also purified a large fraction of the adhesin DNA from the whole mycoplasma genomic DNA using spe- cific primers and amplification by PCR.
Again this fragment induced EMS, thus indicating that no contaminant DNA coming from the plasmid carried by E. Coli was involved (not shown).
Discussion
We have discovered a novel property of DNA, that is the capacity of some sequences to emit electromag- netic waves in resonance after excitation by the ambient electromagnetic background.
Owing to the low sensitivity and specificity of our signal capture and analysis, the frequencies emitted are all alike, regardless of the bacterial species involved.
However, the experiments of transfer of information through plastic tubes suggest that, by refining the analysis and eliminating the variability of the excit- ing signals, we might detect specific differences between species, and even between sequences. Indeed, this prop- erty may be a general one shared by all double-helical DNAs, including human DNA.
But in our conditions of detection, it seems to be associated with only certain bacterial sequences.
It remains to be seen whether they are restricted to some genes involved in diseases.
Experiments to be reported elsewhere indeed indi- cate that this detection applies also at the scale of the human body: we have detected the same EMS in the plasma and in the DNA extracted from the plasma of patients suffering of Alzheimer, Parkinson disease, mul- tiple Sclerosis and Rheumatoid Arthritis. This would suggest that bacterial infections are present in these diseases.
Morever, EMS can be detected also from RNA viruses, such as HIV, influenza virus A, Hepatitis C Virus. In these cases, optimal filtration for detection
of EMS requires prior 20 nM filtration suggesting that the nanostructures produced are smaller that those pro- duced by bacterial DNA.
In patients infected with HIV, EMS can be detected mostly in patients treated by antiretroviral therapy and having a very low viral load in their plasma. Such nanostructures persisting in the plasma may contribute to the viral reservoir which escapes the antiviral treat- ment, assuming that they carry genetic information of the virus.
The physical nature of the nanostructures which sup- port the EMS resonance remains to be determined.
It is known from the very early X-ray diffraction stud- ies of DNA, that water molecules are tightly associated with the double helix, and any beginner in molecular biology knows that DNA in water solution forms gels associating a larger number of water molecules.
Moreover, a number of physical studies have reported that water molecules can form long polymers of dipoles associated by hydrogen bonds (Ruan et al., 2004; Wer- net et al., 2004).
However these associations appear to be very short- lived (Cowan et al., 2005). Could they live longer, being self-maintained by the electromagnetic radiations they are emitting as previously postulated by Del Guidice, Preparata and Vitielo (1988)?
We have studied the decay with time of the capac- ity of dilutions for emitting EMS, after they have been removed (in mumetal boxes) from exposure to the exci- tation by the background. This capacity lasts at least several hours, some time up to 48 hours, indicating the relative stability of the nanostructures.
Are the latter sufficiently specific of DNA sequences to be able to carry some genetic information?
If so, what could be their role in pathogenicity, par- ticularly in the genesis of chronic diseases?
Further studies involving close collaboration between physicists and biologists are obviously needed to resolve these problems.
Acknowledgments
We thank Dr A. Blanchard for gift of Mycoplasma pirum DNA and Drs D. Guillonnet, R. Olivier, L. Thibodeau and J. Varon for helpful dis-
cussion.
References
[1] Benveniste, J., Jurgens, P., A ??ssa, J. 1996. Digital recording/ transmission of the cholinergic signal. Faseb Journal 10, A1479.
[2] Benveniste, J., Guillonnet, D. 2003. Method, system and device for producing signals from a substance bi- ological and/or chemical activity. US Patent N? 6 541, 978 B1.
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[3] Cowan, M.L., Bruner, B.D., Huse, N., Dwyer, J.R., Chugh, B., Nibbering, E.T., Elsaesser, T., Miller, R.J. 2005. Ultrafast memory loss and energy redistribution in the hydrogen bond network of liquid H2O. Nature 434, 199202.
[4] David, J. 1998. Introduction to Magnetism and Mag- netic Materials. CRC Press. 354.
[5] Del Guidice, E., Preparata, G., Vitielo, G. 1988. Water as a free electric dipole laser. Physical Review Letters 61, 10851088.
[6] Grau, O., Kovacic, R., Griffais, R., Montagnier, L. 1993. Development of a selective and sensitive poly- merase chain reaction assay for the detection of My- coplasma pirum. FEMS Microbiology Letters 106, 327334.
[7] Ruan, C.Y., Lobastov, V.A., Vigliotti, F., Chen, S.,
[8]
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Zewall, A.H. 2004. Ultrafast electron crystallography of interfacial water. Science 304, 8084.
Tham, T.N., Ferris, S., Bahraoui, E., Canarelli, S., Montagnier, L., Blanchard, A. 1994. Molecular char- acterization of the P1-like adhesin gene from My- coplasma pirum. Journal of Bacteriology, 781788.
Tully, J.G., Whitcomb, R.G., Clark, H.F., Williamson, D.L. 1977. Pathogenic mycoplasmas: cultivation and vertebrate pathogenicity of a new spiroplasma. Science 195, 892894.
Wernet, P., Nordlund, D., Bergmann, U., Caval- leri, M., Odelius, M., Ogasawara, H., N ?aslund, L.A., Hirsch, T.K., Ojam ?ae, L., Glatzel, P., Pettersson, L.G., Nilsson, A. 2004. The structure of the first coordina- tion shell in liquid water. Science 304, 995999.
A novel property of DNA is described: the capacity of some bacterial DNA sequences to induce electromagnetic waves at high aqueous dilutions. It appears to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. The genomic DNA of most pathogenic bacteria contains sequences which are able to generate such signals. This opens the way to the development of highly sensitive detection system for chronic bacterial infections in human and animal diseases. http://www.springerlink.com/content/0557v31188m3766x/ Interdiscip Sci Comput Life Sci (2009) 1: 8190 DOI: 10.1007/s12539-009-0036-7
Electromagnetic Signals Are Produced by Aqueous Nanostructures Derived from Bacterial DNA Sequences
Luc MONTAGNIER1,2?, Jamal A ?ISSA1, St ?ephane FERRIS1, Jean-Luc MONTAGNIER1, Claude LAVALLE ?E1
1(Nanectis Biotechnologies, S.A. 98 rue Albert Calmette, F78350 Jouy en Josas, France) 2(Vironix LLC, L. Montagnier 40 Central Park South, New York, NY 10019, USA)
Recevied 3 January 2009 / Revised 5 January 2009 / Accepted 6 January 2009
Abstract: A novel property of DNA is described: the capacity of some bacterial DNA sequences to induce electromagnetic waves at high aqueous dilutions. It appears to be a resonance phenomenon triggered by the ambient electromagnetic background of very low frequency waves. The genomic DNA of most pathogenic bacteria contains sequences which are able to generate such signals. This opens the way to the development of highly sensitive detection system for chronic bacterial infections in human and animal diseases.
Key words: DNA, electromagnetic signals, bacteria.
Pathogenic microorganisms in this day of age are not only submitted to high selective pressure by the im- mune defenses of their hosts but also have to survive un- der highly active antiviral or antibiotic treatments. Not surprisingly, they have evolved in finding many ways to escape these hostile conditions, such as mutations of re- sistance, hypervariability of surface antigens, protective biofilms, latency inside cells and tissues.
We initially observed (Montagnier and Lavallee, per- sonal communication) that some filtration procedures aimed at sterilizing biological fluids can yield under some defined conditions the infectious microorganism which was present before the filtration step. Thus, fil- tration of a culture supernatant of human lymphocytes infected with Mycoplasma pirum, a microorganism of about 300 nM in size, through filters of 100 nM or 20 nM porosities, yielded apparently sterile fluid. The latter however was able to regenerate the original my- coplasma when incubated with a mycoplasma negative culture of human lymphocytes within 2 to 3 weeks.
Similarly, a 20 nM filtration did not retain a minor in- fective fraction of HIV, the causal agent of AIDS, whose viral particles have a diameter averaging 100-120 nM.
In the course of investigating the nature of such filter- ing infectious forms, we found another property of the filtrates, which may or may not be related to the former: their capacity to produce some electromagnetic waves of low frequency in a reproducible manner after appro-
*Corresponding author. E-mail: nadiacpt@yahoo.fr
priate dilutions in water. The emission of such waves is likely to represent a resonance phenomenon depending on excitation by the ambient electromagnetic noise. It is associated with the presence in the aqueous dilutions of polymeric nanostructures of defined size. The super- natant of uninfected eukaryotic cells used as controls did not exhibit this property.
In this paper we provide a first characterization of the electromagnetic signals (EMS) and of their underlying nanostructures produced by some purified bacteria.
In addition to M. pirum, a more classical bacterium, E. Coli, was utilized for the purpose of the analysis. The nanostructures produced by HIV will be the sub- ject of another paper.
M. pirum is a peer-shaped small bacterial cell, ressembling M. pneumoniae, which can be grown in syn- thetic enriched medium (SP4) (Tully et al., 1977) but also mutiplies at the surface of human T lymphocytes.
The strain (Ber) used in our experiments was isolated from a T lymphocyte culture derived from the blood of an apparently healthy subject (Grau et al., 1993). The strong mycoplasma adherence to lymphocytes is mediated by a specific adhesin, whose gene had been previously cloned and sequenced by the authors (Tham et al., 1994).
We used as primary source of the mycoplasma, super- natants of infected human T lymphocyte cultures or of cultures of the CEM tumor T cell line. All cell cultures were first tested for the lack of M. pirum contamination by polymerase chain reaction (PCR) and nested PCR, before starting the experiments. Titers of 106-107 infec-
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tious Units/ml of M. pirum were readily achieved after 5-6 days of incubation following deliberate infection of both types of cultures.
Filtration of the clarified supernatant was first per- formed on 0.45 ?M (450 nM) Millipore filters to remove debris, and subsequently on 0.1 ?M (100 nM) Milli- pore filters or on 0.02 ?M (20 nM) Whatman filters, to remove mycoplasma cells. Indeed, the two 100 nM and 20 nM filtrates were confirmed sterile when aliquots were incubated for several weeks in SP4 medium. Re- peated search for traces of mycoplasma DNA by PCR and nested PCR using specific primers for the adhesin gene or for the 16S ribosomal gene was consistently neg- ative.
However when the filtrates were incubated for two weeks (100 nM filtrate) or three weeks (20 nM filtrate) with a culture of human activated T lymphocytes, the mycoplasma was recovered in the medium with all its original characteristics as previously observed.
The same filtrates were analyzed just after filtra- tion for production of electromagnetic waves of low fre- quency. For this purpose we used a device previously designed by Benveniste and Coll (1996; 2003) for the detection of signals produced by isolated molecules en- dowed with biological activity. The principle of this technology is shown in Fig. 1.
Blaster Card itself connected to a laptop computer, preferentially powered by its 12 volt battery. Each emission is recorded twice for 6 seconds, amplified 500 times and processed with different softwares for vizual- ization of the signals on the computer's screen (Fig. 1).
The main harmonics of the complex signals were an- alyzed by utilizing several softwares of Fourier transfor- mation.
In each experiment, the internal noise generated by the different pieces of the reading system was first recorded (coil alone, coil with a tube filled with water). Fourier analysis shows (Fig. 2(c, d)) that the noise was predominantly composed of very low frequencies, prob- ably generated at least in part by the 50/60 Hz ambi- ent electric current. The use of the 12 V battery for the computer power supply did reduce, but not abolish this noise, which was found to be necessary for the induc- tion of the resonance signals from the specific nanos- tructures.
When dilutions of the M. pirum filtrate were recorded for wave emission, the first obvious phenomenon ob- served was an increase of the overall amplitude of the signals at certain dilutions over the background noise (Fig. 2(a)) and also an increase in frequencies (Fig. 2(b)). This change was abolished if the tube to be analyzed was placed inside a box sheltered with sheets of copper and mumetal (David, 1998).
Fourier analysis of the M. pirum signals showed a shift towards higher frequencies close to 1000 Hz and multiples of it. Profiles were identical for all the dilu- tions showing an increase in amplitude (Fig. 2(c) and 2(d)).
The first low dilutions were usually negative, showing the background noise only. Positive signals were usu- ally obtained at dilutions ranging from 10-5 to 10-8 or 10-12. Higher dilutions were again negative (Fig. 3).
The positive dilutions varied according to the type of filtration, the 20 nM filtrate being generally positive at dilutions higher than those of the 100 nM filtrate.
The original unfiltered suspension was negative at all dilutions, a phenomenon observed for all the microor- ganisms studied. Size and density of the structures producing the signals in the aqueous dilutions:
An aliquot of the 20 nM filtrate was layered on the top of a 5-20% (w/v) sucrose gradient in water and centrifuged for 2 hours at 35,000 rpm in a swinging bucket rotor. These conditions had previously been used to obtain the density equilibrium of the intact my- coplasma cells wich formed a sharp bound at 1,21 den- sity. Fractions were collected from the bottom of the tubes, pooled 2 by 2 and assayed for signal emission.
Fig. 4 shows that the signal emitting structures were distributed in a large range of densities from 1.15 to 1.25 and also had a high sedimentation coefficient.
Fig. 1
Device for the capture and analysis of electromag- netic signals (EMS): (1) Coil: a bobbin of copper wire, impedance 300 Ohms; (2) Plastic stoppered tube containing 1 mL of the solution to be analyzed; (3) Amplifier; (4) Computer with softwares.
Briefly, the 100 nM or 20 nM filtrates are serially di- luted 1 in 10 (0,1 +0,9 in sterile water (medical grade). The first 2 dilutions (1/10 and 1/100) are done in serum-free RPMI medium, in order to avoid eventual protein precipitation in deionized water.
Each dilution is done in 1.5 mL Eppendorf plastic tubes, which are then tightly stoppered and strongly agitated on a Vortex apparatus for 15 seconds . This step has been found critical for the generation of signals.
After all dilutions have been made (generally 15-20 decimal dilutions), the stoppered tubes are read one by one on an electromagnetic coil, connected to a Sound
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Fig. 2
Fig. 3
Detection of EMS from a suspension of Mycoplasma pirum: Left: background noise (from an unfiltered suspension or a negative low dilution). Right: positive signal (from a high dilution D-7 (10-7)). (a) actual recording (2 seconds from a 6 second recording) after WaveLab (Steinberg) treatment; (b) detailed analysis of the signal (scale in millisecondes); (c) Matlab 3D Fourier transform analyzis (abcissa: 0-20 kHz, ordinate: relative intensity, 3D dimension: recording at different times); Frequencies are visualized in different colors; (d) Sigview Fourier transform: note the new harmonics in the range of 1 000-3 000 Hz.
A typical recording of signals from aqueous dilutions of M. Pirum (Matlab software): note the positive signals from D-7 to D-12 dilutions.
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1.25
SN CEM/M.pirum Filtered 0.02?
1.20
1.15
1.30
1.20
10,000 rpm for 15 minutes, the supernatant was fil- tered on 450 nM filter and the resulting filtrate was filtered again on a 100 nM filter. The final filtrate was found sterile, when plated on nutrient agar medium and was analyzed for electromagnetic wave emission, as de- scribed above for M. pirum. Signal producing dilutions usually range from 10-8 to 10-12, with profiles upon Fourier transformation, similar to those of M. Pirum (Fig. 5). In one experiment, some very high dilutions were found positive, ranging from 10-9 to 10-18. An aliquot of the unfiltered supernatant did not show any signals above background up to the 10-38 dilution, in- dicating again the critical importance of the filtration step for the generation of specific signals.
The only difference with M. pirum was that no sig- nal appeared after filtration on 20 nM filters, suggesting that the structures associated with the signals were re- tained by these filters and, therefore, had a size greater than 20 nM and lower than 100 nM.
We then asked why the lower dilutions, which logically should contain a larger number of signal- producing structures, were "silent". When we added 0.1 mL of a negative low dilution (e.g. 10-3) to 0.4 mL or 0.9 mL of a positive dilution (10-8), the latter became negative. This indicate that the "silent" low dilutions are self-inhibitory, probably by interference of the multiple sources emitting in the same wave length or slightly out of phase, like a radio jamming. Alterna- tively, the abundance of nanostructures can form a gel in water and therefore are prevented to vibrate. -Evidence for homologous "cross talk" between dilutions
We then wonder whether or not it was possible to generate new signal-emitting structures from tube to tube by using wave transfer. The following experiment
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106 1.10 105
104
1 2 3 4 5 6 7 8 9 10 11 12 13
Fig. 4
Sucrose density centrifugation (35000 rpm, 2 Hr) of a 0.02? filtrate of Mycoplasma pirum suspension. The collected fractions were pooled 2 by 2 and di- luted up to D-15 and tested for EMS. The bars in- dicate the fractions positive for EMS.
We then turned to a more classical bacterium, E. Coli, using the laboratory strain K1.
A culture of E. Coli in agitated (oxygenated) con- ditions, yielded 109 bacterial units/mL, measured by spectrometry. The suspension was then centrifuged at
Density
E.M.S. naneons
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Fig. 5 EMS from E. Coli 0.1 ? filtrate. EMS positive from dilution D-8 to D-11: (a) Actual recording; (b) millisecond analysis; (c) Fourier transform analysis Matlab; (d) Fourier transform analysis SigView. NF: not filtered.
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which was repeated several times showed that indeed this was the case.
A donor tube of a low "silent" dilution of E. Coli (10-3) was placed side by side close to a receiver tube of the positive "loud" highest dilution of the same prepa- ration (10-9). Both tubes were placed in a mumetal box for 24 hours at room temperature, so that the tubes were not exposed to external electromagnetic noise, and only exposed to the signals generated by the structures present in the tubes themselves.
The tubes were then read again by the signal detect- ing device: the donor tube was still silent, however the receiver tube became also silent.
Moreover, when further dilutions were made from the receiver tube (10-10, 10-11, 10-12), these dilutions had became positive (Fig. 6). These results suggest that the receiver tube was made silent by formation of an excess of new nanostructures, which could emit signals upon further dilution.
Finally, two others problems were investigated in the E. Coli system: the first was the role of the initial number of bacterial cells in the induction of the fil- terable signal-producing structures. For this a station- ary culture of E. Coli was counted and adjusted to 109 cells/mL and serial dilutions from 100 to 100 were done down to 1 cell/mL. Each dilution was filtered at 100 nM and then analyzed for signal emission. Surprisingly, the range of positive dilutions were not strictly depen- dent on the initial concentration of E. Coli cells, being roughly the same from 109 cells down to 10 cells, sug- gesting that the same final number of nanostructures was reached at all concentrations. Thus, paradoxically, 10 cells are giving the same signals than 109 cells.
We were also concerned by the possible personal in- fluence of the operator in the reading.
To address this point, two healthy operators were asked to measure independantly the same dilutions of E. Coli, each one unknowing the results of the other. The results of their readings were identical.
In addition, the results were independant of the order in which the samples were read, whether in descending dilutions from to the lowest to the highest or in ascend- ing the dilutions from the highest to the lowest.
Finally an other laboratory worker placed the diluted samples in a random order, the labels being unknown from the person reading the samples. The same range of positive dilutions was detected again provided each tube was well separated from the other, to avoid their "cross talk".
We also found that the results were also indepen- dant of the location of the reading site: starting from the same unfiltered preparation of E. Coli, positive di- lutions of the filtrates were found to be the same in two different locations in France (Paris center and sub- urb), one in Canada (Montreal), and one in Cameroun (Yaound ?e).
As shown in the figures, the background noise was variable, according to the location and time of record- ing. It was generally higher in large cities than in iso- lated aeras. However, positive signals always clearly differenciate over the background by higher frequency peaks.
Nature of the aqueous nanostructures:
Treatments by RNAseA (Promega, 1 ?g/ml, 37 °C 1 h), Dnase I (Invitrogen, 10 U/?g DNA, 37°C, 18 h), Lysozyme (Fisher, 1 mg/mL, 37 °C 10 min), Proteinase K (Promega, 0.12 mg/mL, in 1% sodium dodecyl sul- phate, 56°C 1 h) did not suppress the EMS produc- ing activity of the "loud" dilutions nor did activate the "silent" dilutions.
However, heating at 70 °C for 30 min suppressed irre- versiblly the activity, as well as did freezing for 1 hour at -20 °C or -60 °C. DMSO (10%), and formamide (10%) had no effect.
Treatment with lithium cations, known to affect the
Fig. 6
Cross-talk between dilutions (from an E. Coli 0.1 ? filtrate), see explanation in the text.
This effect was suppressed by interposing a sheat of mumetal between the two tubes during the 24 hours contact period, pointing to a role of low frequency waves in the phenomenon.
Emission of similar electromagnetic signals was also observed with some other bacterial species such as: Streptococcus B, Staphylococcus aureus, Pseu- domonas aeroginosa, Proteus mirabilis, Bacillus sub- tilis, Salmonella, Clostridium perfringens, all in the same range of dilutions observed for E. Coli, and only after filtration at 100 nM (and not at 20 nM).
Importantly, the transfer effect between two tubes, one silent, one loud, was only observed if both contained dilutions of the same bacterial species. In other words, a Staphylococcus donor tube could only "talk" with a receiver tube containing a Staphylococcus dilution, and not with a tube of Streptococcus or E. Coli, and reciprocally.
These results indicate that the transfer effect is medi- ated by species-specific signals, the frequencies of which remain to be analyzed.
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hydrogen bonding of water molecules, was able to re- duce the intensity of the signals, while the range of the positive dilutions remained unchanged.
Nature of the bacterial molecules at the origin of the nanostructures:
In preliminary experiments, we had observed that a pretreatment of a suspension of E. Coli by 1% formaldehyde did not alter its capacity to induce the electromagnetic signals, while killing the bacteria. This treatment alters the surface proteins of the bacte- rial cells without attacking their genetic material, i.e. double- helical DNA. This suggested that the source of the signals may be the DNA itself.
Indeed, DNA extracted from the bacterial suspension by the classical phenol: chloroform technique was able upon filtration and appropriate dilutions in water to emit EMS similar to those produced by intact bacteria under the same conditions. DNAse treatment of the extracted DNA solution abolishes its capacity to emit signals, at the condition that the nanostructures pre- viously induced by the DNA are destroyed. A typical experiment is described as follows:
E. Coli DNA was treated by Proteinase K in the presence of SDS (sodium dodecyl sulfate) and further deproteinized by phenol-chloroform mixture. The pel-
let obtained by ethanol precipitation was resuspended in Tris 10-2 M, pH 7,6 and an aliquot was diluted 1/100 in water. The dilution (10-2) was filtered first through a 450 nM filter and the resulting filtrate was then fil- tered again on a 100 nM filter. The filtrate was further diluted in serial decimal dilutions in water as previously described.
As for the intact microorganisms, the filtration step was found to be essential for detection of the EMS in the DNA dilutions. In its absence, no signals could be detected at any dilutions.
In contrast to the microorganism suspension, where the filtration was supposed to retain the intact cells, the filtration at 100 nM did not retain the DNA, which was still present in the filtrate, as measured by optical density. However, filtration with a 20 nM Whatman filter retained the nanostructures emitting the EMS, suggesting that they have the same range of sizes than those originating from intact bacteria.
In the case of DNA, the role of the 100 nM filtration is probably to dissociate the network of nanostructures organized in a gel-like liquid crystal at high concen- trations in water, allowing their dispersion in further dilutions. As shown in Fig. 7, the dilutions positive for EMS were in the same range that those observed for the intact bacteria, generally between 10-7 to 10-13.
Fig. 7 DNAse effect on EMS production. The DNAse treated E. Coli DNA solution and the untreated DNA are diluted from D-2 to D-15. Analyzis of the EMS as described in Fig. 5. D-2 dilution (negative for EMS) is shown as control. D-9 is positive for EMS (from a range of positive dilutions D-8 to D-11). Note the signal disappearance in the DNAse treated DNA.
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At the high dilution of 10-13, calculations indicate that there is no DNA molecule of MW larger than 105 in the solution, making it unlikely that the EMS are pro- duced directely by the DNA itself, but rather by the self-sustained nanostructures induced by the DNA.
Generally, all the bacterial species shown to be posi- tive for EMS yielded also DNA preparations positive for EMS. Further demonstration that the EMS produced by bacteria come from their DNA was shown by their disappearance after DNAse treatement.
This inactivation was however only complete when the nanostructures induced in the DNA solution which are themselves resistant to DNAse were previously fully destroyed.
This destruction was obtained either by freezing the DNA solution at -20°C for 1 hour or heating it at 90 °C for 30 minutes.
After slow cooling to allow the heated DNA to re- anneal, DNAse 1 at a final concentration of 10 U/?g of DNA was added and the mixture was incubated at 37°C for 18 hours in the presence of 5 mM of MgCl2. An aliquot of the untreated DNA solution was kept as a positive control.
The DNAse-treated preparation was found com-
pletely devoid of EMS emission at any dilution (Fig. 7). Treatment of the DNA solution by a restriction en- zyme acting at many sites of E. Coli DNA (EcoRV) did not suppress the production of EMS, suggesting that this emission is linked to rather short sequences or is
associated with rare sequences.
Nature of the DNA sequences at the origin of the EMS:
A non exhaustive survey of the bacterial species and of their DNA able to display EMS suggests that most of bacteria pathogenic for humans are in this category.
By contrast, probiotic "good" bacteria as Lactobacil- lus and their DNA are negative for EMS emission.
In the case of E. Coli, we found that some strains used to carry plasmids for gene cloning were also nega- tive (Fig. 8).
This suggested that only some sequences of DNA are at the origin of the EMS.
As pathogenicity is often associated with the capac- ity of the microorganism to bind eukaryotic cells, par- ticulary mucosal cells, we focussed our analysis again to M. pirum DNA, where a single gene (adhesin: 126- kDa protein) is responsible for the adhesion of the my- coplasma to human cells.
Fig. 8 EMS produced by the 1.5 kb fragment of the adhesin DNA of M. Pirum. The plasmid DNA containing the 1.5 Kb fragment was used to transform an E. Coli vector, XL1blue. The whole DNA was extracted and diluted for EMS analysis. Left: control background noise of a negative dilution (D-2). Right: positive signal at D-10 (range from D-9 to D-12). Bottom: Note the lack of EMS produced by the DNA extracted from the strain transformed by the plasmid alone.
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This gene had previously been cloned and sequenced in our laboratory (Tham et al., 1994). The cloned DNA existed as two fragments in two plasmids, corresponding respectively to the N terminal (1.5 Kbp) and the C terminal (5 Kbp) of the protein.
The two plasmids (pBluescript SK, Stratagene) con- taining the DNA fragments were amplified in a E. Coli strain, XL1blue.
The DNA of the E. Coli strain (with or without the plasmid) alone did not yield EMS at any dilutions.
By contrast when the strain was transformed with ei- ther plasmids carrying an adhesin gene fragment, EMS were produced (Fig. 8).
The two adhesin DNA fragments were then cut by specific restriction enzymes (N Terminal: 1.5 kbp/SpeI- EcoRI) (C Terminal: 5 kbp/HindIII-XbaI) and isolated by electrophoresis in 0.8% agarose gel. Each DNA frag- ment was able to induce EMS (not shown).
We also purified a large fraction of the adhesin DNA from the whole mycoplasma genomic DNA using spe- cific primers and amplification by PCR.
Again this fragment induced EMS, thus indicating that no contaminant DNA coming from the plasmid carried by E. Coli was involved (not shown).
Discussion
We have discovered a novel property of DNA, that is the capacity of some sequences to emit electromag- netic waves in resonance after excitation by the ambient electromagnetic background.
Owing to the low sensitivity and specificity of our signal capture and analysis, the frequencies emitted are all alike, regardless of the bacterial species involved.
However, the experiments of transfer of information through plastic tubes suggest that, by refining the analysis and eliminating the variability of the excit- ing signals, we might detect specific differences between species, and even between sequences. Indeed, this prop- erty may be a general one shared by all double-helical DNAs, including human DNA.
But in our conditions of detection, it seems to be associated with only certain bacterial sequences.
It remains to be seen whether they are restricted to some genes involved in diseases.
Experiments to be reported elsewhere indeed indi- cate that this detection applies also at the scale of the human body: we have detected the same EMS in the plasma and in the DNA extracted from the plasma of patients suffering of Alzheimer, Parkinson disease, mul- tiple Sclerosis and Rheumatoid Arthritis. This would suggest that bacterial infections are present in these diseases.
Morever, EMS can be detected also from RNA viruses, such as HIV, influenza virus A, Hepatitis C Virus. In these cases, optimal filtration for detection
of EMS requires prior 20 nM filtration suggesting that the nanostructures produced are smaller that those pro- duced by bacterial DNA.
In patients infected with HIV, EMS can be detected mostly in patients treated by antiretroviral therapy and having a very low viral load in their plasma. Such nanostructures persisting in the plasma may contribute to the viral reservoir which escapes the antiviral treat- ment, assuming that they carry genetic information of the virus.
The physical nature of the nanostructures which sup- port the EMS resonance remains to be determined.
It is known from the very early X-ray diffraction stud- ies of DNA, that water molecules are tightly associated with the double helix, and any beginner in molecular biology knows that DNA in water solution forms gels associating a larger number of water molecules.
Moreover, a number of physical studies have reported that water molecules can form long polymers of dipoles associated by hydrogen bonds (Ruan et al., 2004; Wer- net et al., 2004).
However these associations appear to be very short- lived (Cowan et al., 2005). Could they live longer, being self-maintained by the electromagnetic radiations they are emitting as previously postulated by Del Guidice, Preparata and Vitielo (1988)?
We have studied the decay with time of the capac- ity of dilutions for emitting EMS, after they have been removed (in mumetal boxes) from exposure to the exci- tation by the background. This capacity lasts at least several hours, some time up to 48 hours, indicating the relative stability of the nanostructures.
Are the latter sufficiently specific of DNA sequences to be able to carry some genetic information?
If so, what could be their role in pathogenicity, par- ticularly in the genesis of chronic diseases?
Further studies involving close collaboration between physicists and biologists are obviously needed to resolve these problems.
Acknowledgments
We thank Dr A. Blanchard for gift of Mycoplasma pirum DNA and Drs D. Guillonnet, R. Olivier, L. Thibodeau and J. Varon for helpful dis-
cussion.
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