Boiron Research and Development by Boiron USA

Research and Development

Table of contents

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Research at the heart of the Boiron project

PAGES

4&5

Consolidate the evaluation of the effectiveness of homeopathic medicines

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Developing new medicines

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Demonstrate the benefits of homeopathy for public health

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Improve the understanding of how homeopathic medicines work

PAGES

9,10 & 11

Bibliography

Research at the heart of the Boiron project S ince 2005,we have made unprecedented efforts to innovate in the field of homeopathy. Our research programmes (more than 80 at present) are divided into four main areas: • Consolidate the evaluation of the effectiveness of our medicines,already tested in practice, • Develop new medicines and test the potential of existing medicines in new therapeutic domains. This is why,for example,we are evaluating some of our medicines in the treatment of serious diseases, notably to reduce the side effects of intensive treatments; • Show the benefits of homeopathy for public health, •Improve the understanding of how homeopathic medicines work.

Group Sales 2008: 466 million euros 55.45 % Non-proprietary homeopathic medicines

These programmes involve university research groups in about ten different countries and general practitioners from many countries.These are giving a new boost to homeopathy in the world and are creating the image for tomorrow,confirming the basis of our commitment to contribute to the emergence of a therapy more respectful of the individual and of its environment.

0.25 %

44.30 %

Other products

OTC specialities

DISTRIBUTION OF SALES BY PRODUCT CATEGORY (%)

Gilles Chaufferin, Deputy General Manager

Steep increase in R&D expenses • Boiron invested 6.5 million euros in R&D in 2008, i.e 1.4% of Group’s sales. • 85 research projects were undertaken between 2005 and 2009 in partnership with independent R&D groups. • Ten or so research scientists work within the Boiron R&D department.

Consolidate the evaluation of the effectiveness of homeopathic medicines Clinical trials are carried out taking into account the different practices of homeopathic doctors with: - either one or several medicines for a specific indication, - or an individualized approach to treatment. Clinical research helps to consolidate the evaluation of the therapeutic effectiveness of medicines already well-tried through medical practice. RESULTS Inflluenza-like symptoms As one of the most frequently used medicines against influenza-like symptoms, Oscillococcinum® has been the subject of clinical studies in several countries throughout the world. •Treatment In a randomized double blind placebo-controlled study(1) on 487 patients,after 48 hours of treatment,the medicine tested resulted in a significantly higher cure rate than with the placebo.In particular,the intensity of flu symptoms was alleviated from the first evening of treatment in the active group.This French study published in the British Journal of Clinical Pharmacology in1989 was commented on inThe Lancet(2).Ten years later,a British group repeated the study with 372 patients with very similar results(3). • Prevention A double-blind placebo-controlled study, carried out in 2004 in Kalouga (Russia) on 227 medical students not vaccinated against flu showed that the medicine significantly reduced the occurrence of flu and acute viral respiratory infections,without visible side effects.

1. FERLEY J.P.,ZMIROU D.,D’ADHEMAR D.,BALDUCCI F. A controlled evaluation of a homeopathic preparation in the treatment of influenza-like syndromes. British Journal of Clinical Pharmacology 1989,27 :p.329-335 3. PAPP R.,SCHUBACK G.,BECK E.,BURKARD G.,BENGEL J.,LEHRL S.,BELON P. Oscillococcinum(R) in patients with influenza-like syndromes:a placebo-controlled doubleblind evaluation. British Homeopathic Journal 1998,87,p.69-76 4. SELKOVA E.P.,SEMENENKO T.A.,GORBATCHEV I.A. Utilisation du médicament Oscillococcinum dans la prévention et le traitement de la grippe et de l’Infection Respiratoire Virale Aiguë (IRVA). Maladies Infectieuses 2005,3(4),p.20-24

Acute diarrhoea in children An American group repeated several times in the 1990s a series of clinical studies showing that prescribing homeopathic medicines significantly reduced acute diarrhoea in infants.These studies were carried out in Nepal, Nicaragua and Honduras. Based on groups of a hundred to two hundred children aged from 6 months to 5 years, this work involved individualized follow-ups of the young patients,each of whom received specific treatment based on his/her clinical needs,as prescribed by a homeopathic doctor(5).

5. JACOBS J.,JONAS W.B.,JIMENEZ-PEREZ M.,CROTHERS D. Homeopathy for childhood diarrhea :combined results and metaanalysis from three randomized,controlled clinical trials. The Pediatric Infectious Disease Journal 2003,22(3),p.229-234 JACOBS J.,JIMENEZ L.M.,GLOYD S.,CARARES F.E.,GAITAN M.P.,CROTHERS D. Homeopathic treatment of acute childhood diarrhea. British Homeopathic Journal 1993,82,p.83-86

Chronic irritant dermatitis A double-blind randomized study(6) has shown the effectiveness and tolerance of Homeoplasmine® ointment compared to a placebo in the treatment of chronic irritant dermatitis. Performed in Romania between June and December 2001 on 61 workers suffering from work-related irritant dermatitis, it showed that Homeoplasmine® significantly reduces the intensity of symptoms.

6. BADULICI S.;RADU R.;MAZENOT C.;BELON P.;POPESCU S. Tratamentul dermatitelor ortoergice cu pomada Homéoplasmine. Dermatologia i Venerologia 2003,48,p.285-291

Treatment for arsenic poisoning In India,a clinical study(7) was carried out on patients suffering from endemic arsenic poisoning after drinking groundwater contaminated with arsenic. The results show a notable reduction in arsenic levels in the blood and urine,as well as an improvement in the symptoms,especially cutaneous in patients who had followed a homeopathic treatment.

Homeopathic medicines • Homeopathic medicines are made from dilutions of plant, animal and mineral substances. The manufacturing process consists in transforming the original substance into a medicine following a precise protocol of successive deconcentrations to reach the desired dilution. The European, French and American Pharmacopoeias codify homeopathic medicines and their method of preparation.

PERSPECTIVES Boiron is working on clinical study projects aimed at reducing anticipatory anxiety, teething pain in infants, flu prevention, post exercise muscular pain, as well chronic lumbago within a physical re-adaptation programme.

Two hundred years of clinical experimentation has given birth to a specific homeopathic pharmacopoeia with, on the one hand, medicines that require medical expertise and on the other, OTC specialties for informed self-medication.

AND ALSO... Pilot clinical trials and studies on practices have produced encouraging results on the treatment of irritation and discomfort of the eyes,breast engorgement pain after giving birth,hot flushes in menopausal women,preliminary work that requires more in-depth study and confirmation.

Veterinary medicine 7. BELON P.; BANERJEE A.; KARMAKAR S.R.; BISWAS S.J.; CHOUDHURY S.C.; BANERJEE P.; DAS J.K.; PATHAK S.; GUHA B.; PAUL S.; BHATTACHARJEE N.; KHUDA-BUKHSH A.R. Homeopathic remedy for arsenic toxicity ? : evidence-based findings from a randomized placebo-controlled double blind human trial. Science of the Total Environment 2007, 384, p.141-150

Experimenting in veterinary medicine on farms means that medicines can be tested on large numbers of animals. Homeopathic medicines can be equally substituted for heavier treatments which render the meat or milk unfit for consumption. The medicine Wombyl® has proved to be effective post-partum, during a double-blind study(8) on 134 cows that had just calved. The number of inseminations required for conception was 1.68 (against 2.55 for controls), the level of success at the first insemination was 44% (33% in controls) and the interval between calving and successful artificial insemination was 52.67 days, against 83.35 days for controls. A clinical study(9) comparing PVB Phytolac to a placebo was carried out on 187 dairy cows. It showed that the leucocyte count of the treated group dropped from the start of treatment and remained significantly low for several months after treatment had stopped. At the same time the leucocyte count of the placebo group rose.

8. ASKRI Contribution à l’étude de l’efficacité d’un produit homéopathique, le Wombyl®, dans la prévention des complications du vêlage dans le déroulement du post-partum chez la vache. Thèse de doctorat vétérnaire, Sidi Thabet, 2001. 9. PAYEN L. Etude de l'efficacité clinique d'une préparation homéopathique sur les mammites des vaches laitières. Thèse vétérinaire, ENVL, Université Claude-Bernard, Lyon 1, 1996.

Developing new medicines Evaluating the effectiveness of new medicines and testing the possibilities of existing medicines in new areas is an important line of research, a priority being to improve help to patients suffering from serious illnesses over a long time,with the aid of effective and non-iatrogenic treatments. Boiron homeopathic medicines NON-PROPRIETARY HOMEOPATHIC SPECIALITIES Single medicines manufactured from a single strain, available in various dilutions designated by the latin name of the strain, followed by the extent and method of dilution (example: Arnica montana 9 CH). Their therapeutic uses can be very varied.

RESULTS AND PERSPECTIVES Homeopathic treatments in oncology Several studies have proved particularly interesting in oncology: • Pommade au calendula par digestion® ointment has proved its effectiveness for 250 patients suffering from acute radiodermatitis compared toTrolamine, making it possible to reduce the number of interruptions of radiotherapy sessions because of dermatosi(10). • Cocculine®,a Boiron speciality prescribed for travel sickness,proved its effectiveness for 80 patients against post-chemotherapy nausea and vomiting, as a complement to normal prescribed anti-nausea medicines(11).

OTC SPECIALITIES These medicines, created and developed exclusively by Boiron often combine several active homeopathic principles for a specific therapeutic use.

These first actions have encouraged Boiron to develop other experiments for the following pathologies: • prevention of radiodermatitis in patients undergoing radiotherapy as part of their treatment for breast cancer; • delayed nausea in patients treated with Cisplatin for thoracic cancer; • hot flushes induced by auxiliary anti-hormonal treatment in women with non-metastic breast cancer. Hyperactive children As the standard treatment is only authorized for children aged 6 years or older,the evaluation of the effectiveness of a standardised homeopathic treatment for hyperactive children could prove worthwhile. A study will soon be conducted on this in children under six.

10. POMMIER P., GOMEZ F., SUNYACH M.P., D’HOMBRES A., CARRIE C., MONTBARBON X. Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. Journal of Clinical Oncology 2004, 22(8), p.1447-1453.

Prevention of benign summer light eruption with Hypericum An observational study has permitted the effectiveness of Hypericum perforatum to be tested in the treatment of photodermatosis. Conducted by dermatologists,its aim was to see if the administration of dilutions (5,9 and 15 CH) of this medicine (St John’s wort) does or does not provide protection against the recurrence of benign summer light eruption.Having often tried other treatments in previous years,105 patients received the medicine before the period of sun exposure. 85.7 % of patients saw their symptoms improve,with no appearance of clinical signs in 69.5% of them.

11. GENRE D.,TARPIN C., BRAUD A.C., CAMERLO J., PROTIERE C., EISINGER F.,VIENS P. Randomized, double-blind study comparing homeopathy (Cocculine) to placebo in prevention of nausea/vomiting among patients receiving adjuvant chemotherapy for breast cancer. Breast Cancer Research and treatment 2003 ; 82(suppl 1) : p.637

The benefits of homeopathy for public health The aim of pharmaco-epidemiological research is to evaluate the place of homeopathy and its public health advantages in medical practice. In France, several recent studies compared efficacy and cost and the usefulness of homeopathy in medical practice.Several very large protocols are being run at the moment and will give rise to publications shortly.

Therapeutic areas in homeopathy 12 % 15 %

RESULTS Recurrent rhinopharyngitis in children A homeopathic course of treatment can reduce the recurrence and complications,improve the quality of life and approach public health recommendationsnotably in relation to antibiotic prescriptions associated with standard treatments (study(12) involving 499 children aged 18 months to 4 years old followed in general practice).

Cardiology,phlebology

Ear,nose and throat

12 % General symptoms

15 %

11 %

Neuropsychiatry

Infant bronchiolitis A homeopathic course of treatment,compared to conventional medicine,can reduce significantly the number and length of acute bronchiolitis episodes, as well as the number of complications(13). It is also the most economic for Health Service and more closely respects public health recommendations (notably concerning antibiotic and corticoid prescriptions).

Rheumatology

7% Gastroenterology

20 % Others

Anxiety problems in adults A French study(14) in 1999 compared the treatment of anxiety problems in adults by homeopathic doctors and non-homeopathic doctors in terms of effectiveness,satisfaction and cost.394 patients were included in this study,divided into groups of 200 and 194.Concerning the efficacy and satisfaction criteria and overall cost for the Health Service,the results were identical for both groups.It also established the fact that homeopathic doctors prescribed fewer psychotropic medicines and less sick leave notices.

4% Dermatology

Gynaecology

Source : Homeopathy (2003),92,135-139,Study of the practice of homeopathic general practitioners in France,M.Trichard and al.

Homeopathic therapies treat the most frequently encountered pathologies. Boiron concentrates its research on those which constitute the main reasons for medical consultation and represent a challenge to public health.

PERSPECTIVES Compare the practices of general practitioners To extend the results already acquired, four large studies were launched to describe and compare the practices of homeopathic and non-homeopathic prescribing medical in two ways: • the prevalence of reasons for consultation as well as patient characteristics; • the impact of the follow-up and homeopathic and allopathic treatments in terms of clinical evolution,quality of life,collateral effects and risk in three pathologies:infections of the upper respiratory tract;sleeping problems,anxiety and depression;muscular-skeletal pain.

12.TRICHARD M., CHAUFFERIN G., DUBREUIL C., NICOLOYANNIS N., DURU G. Effectiveness, quality of life and cost of caring for children in France with recurrent acute rhinopharyngitis managed by homeopath or non-homeopath general practitioners : a pragmatic, prospective observational study. Disease Management and Health Outcomes 2004, 12(6), p.419-427 13. STAGNARA J., DEMONCEAUX A.,VAINCHTOCK A., NICOLOYANNIS N., DURU G. Etude sur la prise en charge de la bronchiolite du nourrisson en médecine ambulatoire. Etude observationnelle prospective à propos de 520 patients. Le Pédiatre 2004, XXXX(204), p.1-7

Cancerology One study will evaluate the role of homeopathy in treatment strategies for the most frequent cancers (breast,prostate,digestive and lung),in particular in the treatment of side effects of anticancer medicines and in the treatment of secondary pathologies in patients followed by their general practitioner, whether or not a prescriber of homeopathic medicines.

14.VAINCHTOCKA.,DANSETTEG.Y.,NICOLOYANNISN.,DURUG.,CHAUFFERING.,LAMARSALLEL. Medicoeconomic evaluation of anxiety disorders management in outpatient care. Health and System Science 2000, 4 : p.103-115

Improve our understanding of how homeopathic medicines work Homeopathy,since its origins,rests on the use of therapeutic effects of substances whose toxicity has been eliminated by the use of very weak doses,reaching as far as the "infinitesimal".Available results confirm that very dilute substances have biological or physical activity that is detectable, measurable, reproducible and specific to the diluted substance, even when sometimes no molecular traces remain.

Pr Louis Rey Scientific adviser to the Boiron Group “Today it is justified to say that the preparation of homeopathic dilutions, by dilution and electronic excitation, provokes large, permanent changes in the original liquid, even when the theoretical concentration of dissolved substance has become immeasurable.”

Numerous studies have shown a specific pharmacology of very small doses.They provide evidence of the activity of homeopathic dilutions and have improved our knowledge of how they work,although the mechanism of action still needs to be discovered. REPRODUCIBLE RESULTS Dilutions of Gelsemium stimulate neuroactive steroids Gelsemium sempervirens (Carolina jasmine) is routinely prescribed for its sedative, anxiolytic and analgesic properties. One research group has put forward the hypothesis that this medicine can act by regulating the secretion of allopregnanolone,a neuroactive steroid that produces analgesic,anxiolytic and neuroprotector effects.Three dilutions of Gelsemium (5CH, 9CH and 15CH), with the active principle gelsemine in the majority, were tested on the biosynthesis of allopregnanolone by nerve cells in the spinal chord in rat.It was shown that it stimulates the level of allopregnanolone synthesis,particularly the 5 and 9 CH dilutions of Gelsemium(15).

With a PhD in science and university professor, Pr Louis Rey was a student at the Ecole Normale Supérieure of Paris and has taught physico-chemical biology. He worked on lyophilization, before he took an interest in the study of water and high dilutions by thermo-luminescence.

15.VENARD C. Régulation de la neurostéroidogenèse dans la moelle épinière et le système limbique par la gelsémine et Gelsemium sempervirens :analyse cellulaire et implications neurophysiologiques. Thèse de Doctorat ès science (2008).

The activity of histamine dilutions on human basophiles Four different laboratories showed, in the same publication(16) that high dilutions of histamine (15 to 19 CH) inhibit the activation of human basophiles. This multi-centre study completes twenty years of research using several different models and dilution levels, leading to several publications(17) in top journals.

16. BELON P.;CUMPS J.;ENNIS M.;MANNAIONI P.F.;SAINTE-LAUDY J.;ROBERFROID M.; WIEGANT F.A.C. Inhibition of human basophil degranulation by successive histamine dilutions :results of a European multi-centre trial. Inflammation Research 1999,48 suppl,p.S17-S18

Aspirin and bleeding time Although aspirin (acetylsalicylic acid), used in heavy doses, is known for increasing the time of bleeding and inhibiting platelet aggregation, it reduces the time of bleeding and increases platelet aggregation when used in high dilutions, at 5 and 15 CH.This has been the subject of more than twenty publications(18).

19. REY L. Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride. Physica A,2003,323,p.67-74

Dilution studies by thermo-luminescence Physical research is studying the structural organisation and physicochemical properties of high dilutions.Work carried out in thermo-luminescence has shown modifications in the physical structure of dilutions of lithium chloride and sodium chloride in relation to their solvents.These observations published(19) in 2003 still need to completed to be able to explain the mechanism of action and analyse the changes in structure that occur when the granule is impregnated with the dilution, then at the level of the living organism.

The abundant bibliography relating to these research studies is found on page 11. (17),(18)

BOIRON RESEARCH PUBLICATIONS ON HOMEOPATHY CLINICAL RESEARCH Following surgical operations • PARIS A., GONNET N., CHAUSSARD C., BELON P., ROCOURT F., SARAGAGLIA D., CRACOWSKI J.L. Effect of homeopathy on analgesic intake following knee ligament reconstruction : a phase III monocentre randomized placebo controlled study. British Journal of Clinical Pharmacology 2007,65(2) p.180-187 Dermatology • BADULICI S.;RADU R.;MAZENOT C.;BELON P.;POPESCU S. Tratamentul dermatitelor ortoergice cu pomada Homéoplasmine. Dermatologia i Venerologia 2003,48,p.285-291 Anxiety • CIALDELLA P.,BOISSEL J.P.,BELON P.,GROUPE DE RECHERCHE ASTRHO Spécialités homéopathiques en substitution de benzodiazépines :étude en doubleinsu vs. placebo. Thérapie 2001,56(4),p.397-402

• REILLY D.T.,TAYLOR M.A. Potent placebo or potency ? A proposed study model with initial findings using homeopathically prepared pollens in hayfever. British Homeopathic Journal 1985 ;74 :p.65-75 Flu-like symptoms • VICKERS AJ,SMITH C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes (review) Cochrane Database Syst Rev. 2006 Jul 19;3:CD001957. Review • SELKOVA E.P.,SEMENENKO T.A.,GORBATCHEV I.A. Utilisation du médicament Oscillococcinum dans la prévention et le traitement de la grippe et de l’Infection Respiratoire Virale Aiguë (IRVA). Maladies Infectieuses 2005,3(4),p.20-24 • PAPP R.,SCHUBACK G.,BECK E.,BURKARD G.,BENGEL J.,LEHRL S.,BELON P. Oscillococcinum(R) in patients with influenza-like syndromes: a placebo-controlled double-blind evaluation. British Homeopathic Journal 1998,87,p.69-76

Accompanying serious diseases • BISSUEL F.,COTTE L.,CRAPANNE J.B.,ROUGIER P.,SCHLIENGER I.,TREPO C. Trimethoprim-sulphamethoxazole rechallenge in 20 previously allergic HIV-infected patients after homeopathic desensitization. AIDS 1995,9,n°4,p.407-408

• FERLEY J.P.,ZMIROU D.,D’ADHEMAR D.,BALDUCCI F. A controlled evaluation of a homeopathic preparation in the treatment of influenzalike syndromes. British Journal of Clinical Pharmacology 1989,27 :p.329-335

Fibromyalgia • FISHER P.,GREENWOOD A.,HUSKISSON E.C.,TURNER P.,BELON P. Traitement homéopathique de la fibromyalgie primaire : à propos de deux essais cliniques en double insu. L’Homéopathie Française 1991,79(4),p.15-22

Acute diarrhoea • JACOBS J., GUTHRIE B.L., MONTES G.A., JACOBS L.E., MICKEY-COLMAN N.,WILSON A.R.,DI GIACOMO R. Homeopathic combination remedy in the treatment of acute childhood diarrhea in Honduras. The Journal of Alternative and Complementary Medicine 2006,12(8),p.723-732

• FISHER P.,GREENWOOD A.,HUSKISSON E.C.,TURNER P.,BELON P. Effect of homeopathic treatment on fibrositis (primary fibromyagia). British Medical Journal 1989,299,p.365-366 Eye rritation • VINGOLO E.M.,DOMANICO D.,LEOPARDI S.,PERROTTA E. Trattamento della irritazione oculare con collirio omeopatico Euphrasia – Calendula - Magnesia carbonica BOIRON®. Bollettino di Oculistica 2007,86(1) :p.9-14 Allergies/asthma • MATUSIEWICZ R. The homeopathic treatment of corticosteroid-dependent asthma. A doubleblind,placebo-controlled study. Biomedical Therapy 1997,XV(4) :p.117-121 • REILLY D.,TAYLOR M.A.,BEATTIE N.G.M.,CAMPBELL J.H.,MC SHARRY C.,AITCHISON T.C.,CARTER R.,STEVENSON R.D. Is evidence for homeopathy reproducible? The Lancet 1994,344,p.1601-1606 •REILLYD.T.,TAYLORM.A.,MCSHARRYC.,AITCHISONT.C. Is homeopathy a placebo response ? Controlled trial of homeopathic potency, with Pollen in hayfever as model. The Lancet 1986,2(8512),p.881-886

• JACOBS J.,JONAS W.B.,JIMENEZ-PEREZ M.,CROTHERS D. Homeopathy for childhood diarrhea :combined results and metaanalysis from three randomized,controlled clinical trials. The Pediatric Infectious Disease Journal 2003,22(3),p.229-234 • JACOBS J., JIMENEZ M., MALTHOUSE S., CHAPMAN E., CROTHERS D., MASUK M., JONAS W. Homeopathictreatmentofacutechildhooddiarrhea:results from a clinical trial in Nepal. Journal of Alternative and Complementary Medicine 2000,6(2),p.131-139 • JACOBS J.,JIMENEZ LM.,GLOYD S.,GALE J.L.,CROTHERS D. Treatment of acute childhood diarrhea with homeopathic medicine :a randomized clinical trial in Nicaragua. Pediatrics 1994,93(5),p.719-725 • JACOBS J.,JIMENEZ L.M.,GLOYD S.,CARARES F.E.,GAITAN M.P.,CROTHERS D. Homeopathic treatment of acute childhood diarrhea. British Homeopathic Journal 1993,82,p.83-86 Breast-engorgement pain • BERREBI A.,PARANT O.,FERVAL F.,THENE M.,AYOUBI J.M.,CONNAN L.,BELON P. Traitement de la douleur de la montée laiteuse non souhaitée par homéopathie dans le post-partum immédiat. Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2001,30,p.353-357

Prevention of acute radiodermatitis • POMMIER P.,GOMEZ F.,SUNYACH M.P.,D’HOMBRES A.,CARRIE C.,MONTBARBON X. Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. Journal of Clinical Oncology 2004,22(8),p.1447-1453. Prevention of nausea and vomiting associated with chemotherapy • GENRE D.,TARPIN C.,BRAUD A.C.,CAMERLO J.,PROTIERE C.,EISINGER F.,VIENS P. Randomized, double-blind study comparing homeopathy (Cocculine) to placebo in prevention of nausea/vomiting among patients receiving adjuvant chemotherapy for breast cancer. Breast Cancer Research and treatment 2003 ;82(suppl 1) :p.637 Treatment for arsenic poisoning • BELON P.; BANERJEE A.; KARMAKAR S.R.; BISWAS S.J.; CHOUDHURY S.C.; BANERJEE P.;DAS J.K.;PATHAK S.;GUHA B.;PAUL S.;BHATTACHARJEE N.;KHUDA-BUKHSH A.R. Homeopathic remedy for arsenic toxicity ? :evidence-based findings from a randomized placebo-controlled double blind human trial. Science of the Total Environment 2007,384,p.141-150 • KHUDA-BUKHSH A.R.;BELON P.;BISWAS S.J.;KARMAKAR S.R.;BANERJEE P.;BANERJEE A.;DAS J.K.;PATHAK S.;CHOUDHURY S.C.;BHATTACHARJEE N.;GUHA B. Is an elevated antinuclear antibody titer in subjects living in two groundwater arsenic contaminated villages indicative of a time-dependent effect of arsenic exposure. Environmental Science 2007,2(1),p.10-16 • BELON P.; BISWAS S.J.; PATHAK S.; GUHA B.; CHATTERJEE S.; KHUDA-BUKHSH A.R.; BANERJEE P.; CHOUDHURY S.C.; BANERJEE A.; KARMAKAR S.R.; BHATTACHARJEE N.; DAS J.K. Can administration of potentized homeopathic remedy, Arsenicum album, alter antinuclear antibody (ANA) titer inpeople livinginhigh-riskarseniccontaminatedareas ? I.A correlation with certain haematological parameters. Evidence-based Complementary and Alternative Medicine : eCAM 2006,3(1),p.99-107 • KHUDA-BUKHSH A.R.;PATHAK S.;GUHA B.;KARMAKAR S.R.;DAS J.K.;BANERJEE P.; BISWASS.J.;MUKHERJEEP.;BHATTACHARJEEN.;CHOUDHURYS.C.;BANERJEEA.;BHADRA S.;MALLICK P.;CHAKRABARTI J.;MANDAL B. Can homeopathic Arsenic remedy combat Arsenic poisoning in humans exposed to groundwater Arsenic contamination ? :a preliminary report on first human trial. Evidence-based Complementary and Alternative Medicine : eCAM 2005,2(4),p.537-548 • DATTA S.;BISWAS S.J.;KHUDA-BUKHSH A.R. Comparative efficacy of pre-feeding,post-feeding and combined pre- and post-feeding of twomicrodosesofapotentizedhomeopathicdrug,Mercuriussolubilis,inameliorating genotoxic effects produced by mercuric chloride in mice Evidence-based Complementary and Alternative Medicine : eCAM 2004,1(3),p.291-300

OBSERVATIONAL STUDIES Hot flushes BORDET M.F.,COLAS A.,MARIJNEN P.,MASSON J.L.,TRICHARD M. Treating hot flushes in menopausal women with homeopathic treatment. Results of an observational study. Homeopathy 2008,97(1),p.10-15

BOIRON RESEARCH PUBLICATIONS ON HOMEOPATHY PHARMACO-EPIDEMIOLOGICALSTUDIES Anxiety management • VAINCHTOCK A., DANSETTE G.Y., NICOLOYANNIS N., DURU G., CHAUFFERIN G., LAMARSALLE L. Medicoeconomic evaluation of anxiety disorders management in outpatient care. Health and System Science 2000,4 :p.103-115 Recurrent rhinopharyngitis in children • TRICHARD M.,CHAUFFERIN G.,DUBREUIL C.,NICOLOYANNIS N.,DURU G. Effectiveness, quality of life and cost of caring for children in France with recurrent acute rhinopharyngitis managed by homeopath or non-homeopath general practitioners :a pragmatic,prospective observational study. Disease Management and Health Outcomes 2004,12(6),p.419-427 Infant bronchiolitis • STAGNARA J.,DEMONCEAUX A.,VAINCHTOCK A.,NICOLOYANNIS N.,DURU G. Etude sur la prise en charge de la bronchiolite du nourrisson en médecine ambulatoire. Etude observationnelle prospective à propos de 520 patients. Le Pédiatre 2004,XXXX(204),p.1-7

VETERINARY RESEARCH Enteritis prevention in guinea fowl • ISSAUTIER M.N.,FILLIAT C. Homéopathie et syndrome entérite frilosité de la pintade. Filières avicoles,1999,p.61-62 Haematoma of turkey wings • BRUCHERT K. Les hématomes à l’abattoir chez la dinde,Essai de prévention homéopathique. Thèse vétérinaire,ENVL,Université Claude-Bernard,Lyon 1,1997. • ISSAUTIER M.N.,FILLIAT C. L’homéopathie réduit le taux d’hématomes des dindes. Filières avicoles, 1996. Subclinical mastitis in dairy cows • PAYEN L. Etude de l'efficacité clinique d'une préparation homéopathique sur les mammites des vaches laitières. Thèse vétérinaire,ENVL,Université Claude-Bernard,Lyon 1,1996. • ASKRI Contribution à l’étude de l’efficacité d’un produit homéopathique,leWombyl®,dans la prévention des complications du vêlage dans le déroulement du post-partum chez la vache. Thèse de doctorat vétérnaire, Sidi Thabet, 2001.

BASIC RESEARCH 1. BIOLOGICAL RESEARCH Histamine and allergic sensitization • SAINTE-LAUDY J.,BOUJEDAINI N.,BELON P. Confirmation of biological effects of high dilutions. Effects of submolecular concentrations of histamine and 1-, 3- and 4-methylhistamines on human basophil activation. Inflammation Research 2008,57 (suppl 1),p.S27-S28 • SAINTE-LAUDY J.,BELON P. Use of four different flow cytometric protocols for the analysis of human basophil activation : application to the study of the biological activity of high dilutions of histamine. Inflammation Research 2006,55(suppl1),p.S23-S24 • SAINTE-LAUDY J.,BELON P. Improvement of flow cytometric analysis of basophil activation inhibition by high histamine dilutions. A nove basophil specific marker:CD 203c. Homeopathy 2005,95(1),p.3-8 • SAINTE-LAUDY J. Histamine release from mast cells, basophils and other cell types : modulation of allergen and anti-IgE induced human basophil activation by serial histamine dilutions. Inflammation Research 2000,49(suppl1),p.5-6 • BELON P.;CUMPS J.;ENNIS M.;MANNAIONI P.F.;ROBERFROID M.;SAINTE-LAUDY J.; WIEGANT F.A.C. Histamine dilutions modulate basophil activation. Inflammation Research 2004,53,p.181-188 • SAINTE-LAUDY J. Stimulatory effect of high dilutions of histamine on activation of human basophils induced by anti-IgE. Inflammation Research 2001,50 (suppl 2),p.S63-S64 • SAINTE-LAUDY J. Modulation of allergen and anti-igE induced human basophil activation by serial histamine dilutions. Inflammation Research 2000,49 (suppl 1),p.S5-S6 • BELON P.;CUMPS J.;ENNIS M.;MANNAIONI P.F.;SAINTE-LAUDY J.;ROBERFROID M.; WIEGANT F.A.C. Inhibition of human basophil degranulation by successive histamine dilutions :results of a European multi-centre trial. Inflammation Research 1999,48 suppl,p.S17-S18 • SAINTE-LAUDY J.;BELON P. Application of flow cytometry to the analysis of the immunosuppressive effect of histamine dilutions on human basophil activation :effect of cimetidine. Inflammation Research 1997,46(suppl1),p.S27-S28

• SAINTE-LAUDY J.;BELON P. Analysis of immunosuppressive activity of serial dilutions of histamine on human basophil activation by flow cytometry. Inflammation Research 1996,45(suppl1),p.S33-S34

• BEAUVAIS F.;AMARA J.;OBERBAUM M.;ROBINZON B.;MIADONNA A.;TEDESCHI A.; POMERANZ B.; FORTNER P.; BELON P.; SAINTE LAUDY J.; DAVENAS E.; POITEVIN B.; BENVENISTE J. Dégranulation des basophiles humains induite par de très hautes dilutions d'un antisérum anti-IgE. L'Homéopathie Française 1988,76(4),p.217-223 Aspirin and bleeding • EIZAYAGA F.X.,AGUEJOUF O.,DESPLAT V.,BELON P.,DOUTREMEPUICH C. Modifications produced by selective inhibitors of cyclooxygenase and ultra low-dose aspirin on platelet activity in portal hypertension. World Journal of Gastroenterology 2007,13(38),p.5065-5070 • EIZAYAGA FX,AGUEJOUF O,DESPLAT V,BELON P,DOUTREMEPUICH C. Modifications Produced by Indomethacin and L -NAME in the Effect of Ultralow-Dose Aspirin on Platelet Activity in Portal Hypertension. Pathophysiology of Haemostasis andThrombosis 2006,35(5),p.357-363 • EIZAYAGA F.X.,AGUEJOUF O.,BELON P.,DOUTREMEPUICH C. Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin. Pathophysiology of Haemostasis andThrombosis 2005,34(1),p.29-34 • AGUEJOUF O.;MALFATTI E.;BELON P.;DOUTREMEPUICH C. Effects of acetyl salicylic acid therapy on an experimental thrombosis induced by laser beam. Thrombosis Research 2000,99(6),p.595-602 • BELOUGNE-MALFATTI E.; AGUEJOUF O.; DOUTREMEPUICH F.; BELON P.; DOUTREMEPUICH C. Combination of two doses of acetyl salicylic acid : experimental studies of arterial thrombosis. Thrombosis Research 1998,90(5),p.215-221 • VESVRES M.H.;DOUTREMEPUICH F.;LALANNE M.C.;DOUTREMEPUICH C. Effects of aspirin on embolization in an arterial model of laser-induced thrombus formation. Haemostasis 1993,23,p.8-12 • DOUTREMEPUICH C.;AGUEJOUF O.;EIZAYAGA F.X.;DESPLAT V. Reverse effect of aspirin : is the prothrombotic effect after aspirin discontinuation mediated by cyclooxygenase 2 inhibition ? Pathophysiology of Haemostasis andThrombosis 2007,36(1),p.40-44 • AGUEJOUF O.;MALFATTI E.;BELON P.;DOUTREMEPUICH C. Time related neutralization of two doses acetyl salicylic acid. Thrombosis Research 2000,100(4),p.317-323

BOIRON RESEARCH PUBLICATIONS ON HOMEOPATHY

• AGUEJOUF O.; BELOUGNE-MALFATTI E.; DOUTREMEPUICH F.; BELON P.; DOUTREMEPUICH C. Thromboembolic complications several days after a single-dose administration of aspirin. Thrombosis Research 1998,89(3),p.123-127

• MITRA K.,KUNDU S.N.,KHUDA BUKHSH A.R. Efficacy of a potentized homeopathic drug (Arsenicum-Album-30) in reducing toxic effects produced by arsenic trioxide in mice :I.On rate of accumulation of arsenic in certain vital organs. Complementary Therapies in Medicine 1998,6,p.178-184

• DOUTREMEPUICH C.;AGUEJOUF O.;SEZE O. de;PINTIGNY D.;SERTILLANGES M.N. Thrombogenic properties of ultra-low-dose of acetylsalicylic acid in a vessel model of laser-induced thrombus formation. Thrombosis Research 1994,76(2),p.225-229 • LALANNE M.C.;RAMBOER I.;SEZE O. de;DOUTREMEPUICH C. In vitro platelets/endothelial cells interactions in presence of acetylsalycilic acid at various dosages. Thrombosis Research 1992,65,p.33-43

• CAZIN J.C., CAZIN M., GABORIT J.L., CHAOUI A., BOIRON J., BELON P., CHERRUAULT Y.,PAPAPANAYOTOU C. A study of the effect of decimal and centesimal dilutions of arsenic on the retention and mobilization of arsenic in the rat. HumanToxicology 1987,6,p.315-320

• LALANNE M.C.;SEZE O. de;DOUTREMEPUICH C.;BELON P. Could proteolytic enzyme modulate the interaction platelets/vessel wall in presence of ASA at ultra low doses ? Thrombosis Research 1991,63,p.419-426

Gelsemium and stress • VENARD C.,BOUJEDAINI N.,MENSAH-NYAGAN A.G.,PATTE-MENSAH C.,BELON P. Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine. Neuroscience, 2008,153,p.154-161

• DOUTREMEPUICH C.;SEZE O. de;LE ROY D.;LALANNE M.C.;ANNE M.C. Aspirin at very ultra low dosage in healthy volunteers :effects on bleeding time,platelet aggregation and coagulation. Haemostasis 1990,20(2),p.99-105

•BOUSTA,D.,SOULIMANI,R.,JARMOUNI,I.,BELON,P.,FALLA,J.,FROMENT,N.,YOUNOS,C. Neurotropic,immunological and gastric effects of low doses of Atropa belladonna L., Gelsemium sempervirens L. and Poumon histamine in stressed mice. J.Ethnopharmacol, 2001,74,P. 205-215

• LALANNE M.C.;DOUTREMEPUICH C.;SEZE O. de;BELON P. What is the effect of acetylsalicylic acid at ultra low dose on the interaction platelets/vessel wall ? Thrombosis Research 1990,60(3),p.231-236

• VENARD C. Régulation de la neurostéroidogenèse dans la moelle épinière et le système limbique par la gelsémine et Gelsemium sempervirens : analyse cellulaire et implications neurophysiologiques. Thèse de Doctorat ès science (2008).

• DOUTREMEPUICH C.;PAILLEY D.;SEZE O.de;ANNE M.C.;PACCALIN J.;QUILICHINI R. Variation du temps de saignement après administration à différentes posologies d'acide acétyl salicylique chez le volontaire sain. Annales Pharmaceutiques Françaises 1988,46(1),p.35-39 • DOUTREMEPUICH C.;PAILLEY D.;ANNE M.C.;SEZE O.de;PACCALIN J.;QUILICHINI R. Template bleeding time after ingestion of ultra low dosages of acetyl salicylic acid in healthy subjects :preliminary study. Thrombosis Research 1987,48,p.501-504 Effects of high dilutions of Arsenicum album • BANERJEE P.;BISWAS S.J.;BELON P.;KHUDA-BUKHSH A.R. A potentized homeopathic drug,Arsenicum album 200,can ameliorate genotoxicity induced by repeated injections of arsenic trioxide in mice. Journal of Veterinary Medicine. A, Physiology, pathology, clinical medicine 2007, 54, p.370-376 • KUNDU S.N.,MITRA K.,KHUDA BUKHSH A.R. Efficacy of a potentized homeopathic drug (Arsenicum-Album-30) in reducing cytotoxic effects produced by arsenic trioxide in mice :IV.Pathological changes,proteinprofiles, andcontent ofDNAandRNA. ComplementaryTherapiesinMedicine 2000,8,p.157-165

• REY L. Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride. Physica A, 2003,323,p.67-74 • DEMANGEAT J.L.;DEMANGEAT C.;GRIES P.;POITEVIN B.;CONSTANTINESCO A. Modifications des temps de relaxation RMN à 4 MHz des protons du solvant dans les très hautes dilutions salines de silice/lactose Journal of Medicine and Nuclear Biophysics 1992,16(2),p.135-145

SOURCES • www.boiron.com :website of Boiron group • www.boiron.fr :website of Boiron in France,with professional profiles access. • Larechercheenhoméopathie,EditionsduCEDH,2005

2. PHYSICAL RESEARCH • DEMANGEAT J.L. NMR water proton relaxation in unheated and heated ultrahigh aqueous dilutions of histamine :evidence for an air-dependent supramolecular organization of water. Journal of Molecular Liquids 2009 ;144(1-2) :p.32-39 • REY L. Can low-temperature thermoluminescence cast light on the nature of ultra-high dilutions ? Homeopathy - Special Issue The Memory ofWater 2007,96(3),p.170-174 • REY L.,GARTIA R.K.,BELON P.,LUMINESCENCE SOCIETY OF INDIA Trap spectroscopic characterization of D20 ice and its potentially in homeopathy. Luminescence and its applications : proceedings of National conference on luminescence and its applications (January,18-20,2007) 2007,p.12-17 • DEMANGEAT J.L.;GRIES P.;POITEVIN B.;DROESBEKE J.J.;ZAHAFT.;MATON F.;PIERART C.;MULLER R.N. Low-field NMR water proton longitudinal relaxation in ultrahighly diluted aqueous solutions of silica-lactose prepared in glass material for pharmaceutical use. Applied Magnetic Resonance 2004,26,p.465-481

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