“All flesh is coupled by the wave of       circular rotational similarity”                     B. L. Pasternak            ...
Ultralow doses2
RUSSIAN ACADEMY OF MEDICAL SCIENCES            O. I. EPSTEIN      ULTRALOW DOSES  (HISTORY OF ONE RESEARCH)This edition wa...
Ultralow dosesUDC 615.015.32LBC 52.81E736    Re v i e we r s :    Seredenin Sergey Borisovich,    Academician of the Russi...
Devoted to my teachers            Table of contentsPreface            .......................................................
Ultralow doses            8.1.      Use of medical products from antibodies to S 100 protein                      in the t...
Preface        This book tells you about the history of a 10 year study, which was performed at the interface between immu...
Ultralow doses        In stage II, an unusual application was found for ultralow doses. It wasshown that ultralow dose of ...
Prefacepathic medicine and homeopathic medicine). At a particular fine structure level,the effects of normal and homeopath...
Ultralow doses       List of abbreviationsAWS — alcohol withdrawal syndromeBP — blood pressureAID50 — aerogenic infective ...
List of abbreviationsLV — left ventricleLC — latencyLPS — lipopolysaccharideIIEF — International index of erectile functio...
Ultralow dosesCHF — chronic heart failurecAMP — cyclic adenosine 3,5 monophosphatecGMP — cyclic guanosine 3,5 monophosphat...
IntroductionT    he author of this book, as well as his colleagues, succeeded in an intriguing     scientific path from ho...
Ultralow dosesand Anaferon for children), urologists (Afala and Impaza), rheumatologists(Artrofoon), narcologists (Proprot...
C h a p t e r           1      Analysis of the      experience of homeopathyT    he author of this monograph, a recent gra...
Ultralow dosesin clinical trials with medical products. There are ambiguous data on pharmaceutical studies in old time. Th...
Chapter 1. Analysis of the experience of homeopathysubstance decreased by 10 times at each of six dilutions (Fig. 1.1). In...
Ultralow dosesto psoriasis, bronchial asthma, and other diseases with common clinical symptoms. A complex description of t...
Chapter 1. Analysis of the experience of homeopathyto consult with a homeopath. Homeopathic therapy also develops in Russi...
Ultralow dosesa protective response. In this case, the substance in high doses serves as a“pathogen” for all individuals. ...
Chapter 1. Analysis of the experience of homeopathycertain drug were evaluated in trials with healthy volunteers. However,...
Ultralow dosessimilar “psychological characteristics” have the same therapeutic effect. These datasuggest the systemic nat...
Chapter 1. Analysis of the experience of homeopathy      Homeopathy suggests the use of activated agents that are prepared...
Ultralow doses       C h a p t e r         2       Three types of effects       of ultralow dosesT     he first profession...
Chapter 2. Three types of effects of ultralow doses       Such “discrepancies” with the homeopathic doctrine did not alter...
Ultralow doses        Bipathic administration of prednisolone was performed at the Laboratory ofBiophysics (Kiev Institute...
Chapter 2. Three types of effects of ultralow dosesTable 2.1. Protective effects of potentiated prednisolone              ...
Ultralow dosesmethods. Electrical activity of the brain and self stimulation of the “pleasurecenter” in the lateral hypoth...
Chapter 2. Three types of effects of ultralow dosesadministration of epinephrine in a concentration of 10—16 wt % has a si...
Ultralow dosesremoval of the corresponding ion from the extracellular medium (E. Danevaset al., 1988).        These result...
Chapter 2. Three types of effects of ultralow dosesreactions in some of these individuals. They serve as a clinical criter...
Ultralow doseselectrochemical system, which contained these electrolytes in normalconcentrations (S. I. Petrov et al., 200...
Chapter 2. Three types of effects of ultralow dosesceutical companies. Unexpectedly, our study gained a new direction. We ...
Ultralow doses        The development of LTPTP is a calcium dependent process. S 100 protein is acalcium binding protein, ...
Chapter 2. Three types of effects of ultralow dosesFig. 2.2. General view of an experimental device to study LTPTP in surv...
Ultralow dosesfrom 10 to 30 V. EPSP were recorded on a 12 digit analog to digital converter(Digidata, Axon Instruments Inc...
Chapter 2. Three types of effects of ultralow doses(Fig. 2.5), which is consistent with the results of previous experiment...
Ultralow doses                  0.6                  0.5                  0.4                  0.3                  0.2   ...
Chapter 2. Three types of effects of ultralow dosesmV                                        a1.00.80.6                   ...
Ultralow doses                       V, mV                       0.7                       0.6                       0.4  ...
Chapter 2. Three types of effects of ultralow dosesUkrainian Institute of Neurology and Psychiatry, and “Materia MedicaHol...
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Ultralow doses (history of one research)

  1. 1. “All flesh is coupled by the wave of circular rotational similarity” B. L. Pasternak 1
  2. 2. Ultralow doses2
  3. 3. RUSSIAN ACADEMY OF MEDICAL SCIENCES O. I. EPSTEIN ULTRALOW DOSES (HISTORY OF ONE RESEARCH)This edition was recommended and approved for publication by the Editorial Advisory Board of the Presidium of the Russian Academy of Medical Sciences Moscow RAMS Publishing House 2009 3
  4. 4. Ultralow dosesUDC 615.015.32LBC 52.81E736 Re v i e we r s : Seredenin Sergey Borisovich, Academician of the Russian Academy of Medical Sciences Chereshnev Valeriy Akeksandrovich, Academician of the Russian Academy of Sciences S c i e n c e e d i to r: Sergeeva Svetlana Aleksandrovna, Doctor of Biological Sciences, Professor E736 Epstein O. I. Ultralow doses (history of one research). Moscow: Publishing Office of the Russian Academy of Medical Sciences, 2008. 336 pages. ISBN 978 5 7901 0101 4 This monograph is devoted to a systemic study of the effects of potentiated (activated) preparations that contain an active substance in ultralow concentrations. The activated preparations were shown to have previously unknown modifying properties. Taking into account these data, a new class of medical products (antibodies in ultralow doses) was developed. A new direction of bipathic pharmacotherapy was proposed. The first part of this monograph not only illustrates the results of our studies, but also describes the physiological and physical aspects and world outlook of ultralow doses. The final chapters are devoted to experimental and clinical pharmacology of antibodies in ultralow doses. The monograph is addressed to physicians of various specialties. ISBN 978 5 7901 0101 4 © RAMS Publishing House, 20094
  5. 5. Devoted to my teachers Table of contentsPreface ............................................................................................ 7List of abbreviations ............................................................................ 10Introduction ......................................................................................... 13Chapter 1. Analysis of the experience of homeopathy ....................... 15Chapter 2. Three types of effects of ultralow doses ........................... 24Chapter 3. Dual organization of vital activity .................................... 45Chapter 4. Holographic control of vital activity by the immune system ...................................................... 62Chapter 5. Principle of maintenance of the initial integrity .............. 77Chapter 6. On the way to pharmacology of ultralow doses ............... 91Chapter 7. Experimental pharmacology of products from ultralow doses of antibodies .................................. 111 7.1. Experimental study of antibodies to S 100 protein in ultralow doses ................................................................ 111 7.2. Preclinical study of Impaza .................................................. 152 7.3. Preclinical study of Anaferon and Anaferon for children ........... 160 7.4. Preclinical study of Artrofoon ............................................... 173 7.5. Preclinical study of Epigam .................................................. 180 7.6. Preclinical study of Afala ..................................................... 190 7.7. Preclinical study of Kardos ................................................... 198 7.8. Study for antidiabetic activity of a new product from ultralow doses of antibodies on the model of streptozotocin induced diabetes in rats .............................. 204Chapter 8. Clinical pharmacology of products from ultralow doses of antibodies .................................. 210 5
  6. 6. Ultralow doses 8.1. Use of medical products from antibodies to S 100 protein in the therapy for alcoholism and anxiety disorders ................. 210 8.2. Use of Impaza in monotherapy and combined treatment for erectile dysfunction ......................................... 223 8.3. Clinical effectiveness and mechanisms for action of Anaferon ......................................................... 241 8.4. Artrofoon as a promising drug for pathogenetic therapy of chronic arthropathies ........................................... 252 8.5. Epigam in the therapy for gastric ulcer and duodenal ulcer ............................................................. 259 8.6. Afala in the therapy for benign prostate hyperplasia ................ 262 8.7. Clinical pharmacology of Kardos .......................................... 265 Conclusion ........................................................................................ 275 References ........................................................................................ 2776
  7. 7. Preface This book tells you about the history of a 10 year study, which was performed at the interface between immunology, pharmacology, pathophysiology,and problem of ultralow doses and resulted in the development of a new classof medical products. Ultralow doses were used in alternative academic medicine (homeopathy)over two centuries. Hence, this problem received little attention of scientists. Atthe beginning of the 1980s, advanced technology studies in Russia and othercountries showed that ultralow doses have biological activity. The scientists showed a cautious attitude toward these results, although they were not associated withhomeopathic doctrine. Moreover, such studies did not attract much attention ofthose investigators who was interested in them (primarily, of pharmacologists). Due to certain reasons, a systemic pharmacological study of ultralowdoses was first performed in Russia. The author of this book, O. I. Epstein, wasan initiator of such investigations in 1995. Now O. I. Epstein is the Doctor ofMedical Sciences and Professor. He was awarded the prize of the Governmentof the Russian Federation in the field of science and technology. During thatperiod, a young physician was enthusiastic in homeopathy. He was the head ofa small pharmaceutical company, who searched for a specific direction of activity. Famous Russian specialists (investigators and clinicians) became interestedin the idea of O. I. Epstein, which determined the success of a scientific search.The scientific way of O. I. Epstein extends from orthodox homeopathy to pharmacology (i.e., immunopharmacology). Success attended him, since the direction of many researches was selected intuitively. Initially, the goal of his studywas to develop new indications for the use of homeopathic remedies. If someGod of Science protected O. I. Epstein, it was the God of Immunology. The study may be divided into three stages. Stage I may be designated as“non homeopathy”. The author assumed that ultralow doses and homeopathyare not identical to each other. It was proposed that the phenomenon of homeopathy is associated with hypersensitivity of the organism to ultralow doses.Hence, the effects of ultralow doses were explained by immunological mechanisms. 7
  8. 8. Ultralow doses In stage II, an unusual application was found for ultralow doses. It wasshown that ultralow dose of a certain medical product modifies activity of theoriginal substance. Therefore, ultralow doses of modern pharmaceutical products may be used to potentiate their effects and to reduce toxicity. Combinedtreatment with the medical product in normal dose and ultralow dose receivedthe name “bipathy” (O. I. Epstein). Bipathy holds much promise for pharmacology. The researches could focus their attention on study of bipathy. However, the direction of investigations sharply changed. In stage III,these researches were in close contact with immunology. To confirm the phenomenon of bipathy, O. I. Epstein in collaboration with M. B. Shtark (Academician of the Russian Academy of Medical Sciences) and high colleagues studied the effects of antibodies in ultralow doses on neurobiological models. Theyshowed that antibodies in ultralow and normal doses have various effects. Antibodies in ultralow doses did not inhibit, but modified the activity of a specific antigenic molecule. The discovery of “pro antigenic” effects of antibodies inultralow doses resulted in the development of new effective and safe drugs forthe therapy of various diseases. As an immunologist, I know that very low doses (or sometimes nanoquantities) of immunogenic proteins, peptides, and polysaccharides may inducea strong physiological and pathophysiological effect. It mainly concerns antibodies, allergens, and other immunologically active molecules. This monograph illustrates the results of advanced technology experiments and clinical studies. However, the data that extremely low concentrationsof medical products (from the viewpoint of molecular biology) exhibit the activity seem to be unexpected and paradoxical. At the modern of stage of sciencedevelopment, the mechanism for action of ultralow doses can be described hypothetically. The author gives his opinion on this problem. Sometimes, the unusual effects of ultralow doses are explained by uncommon events. As a pioneerin this field, O. I. Epstein can do it. Numerous preclinical and clinical trials were performed in leading institutions of the Russian Academy of Medical Sciences and Russian Ministry ofHealth and Social Development. The results of these studies indicate that ultralow doses have a reproducible effect, which may be evaluated and used inevidence based medicine. However, the author notes that the exception is homeopathic therapy. “An individual (similar) prescription of medical products issimilar to art. The methodology of homeopathy is not associated with generalpathophysiological approaches in pharmacology”. It is really true. O. I. Epstein is so infatuated with his hypotheses that sometimes he passesfrom a strongly scientific presentation to the emotional, speculative, or evenphilosophical conclusions. It is not necessarily that strong evidence exists forthese conclusions. O. I. Epstein believes that there are no two medicines (allo8
  9. 9. Prefacepathic medicine and homeopathic medicine). At a particular fine structure level,the effects of normal and homeopathic doses in an organism are mediated bysimilar mechanisms. This level includes the distant intermolecular relationships,which are unique for each individual. O. I. Epstein assumes that the preservation of individuality is an evolutionary purpose of vital activity of the organism.This theory is close to the principles of immunology. M. Bernet, one of thefounders of modern immunology, believed that a major role of the immune system is regulation of genetic integrity in an organism. This monograph integrates the author’s notion of distant interactions inan organism with general principles of physiology. A lot of surprising and, sometimes, doubtful facts will be of interest to the reader. The monograph is written in a vigorous and interesting style, which facilitates the understanding ofcomplex biological problems. O. I. Epstein not only tells us about new medical products, which have high therapeutic effectiveness and hold promise for thetreatment of various diseases. He wants the reader to form an opinion of newdrugs in ultralow doses (particularly of those from antibodies). R. M. Khaitov Academician of the Russian Academy of Medical Sciences and Russian Academy of Sciences 9
  10. 10. Ultralow doses List of abbreviationsAWS — alcohol withdrawal syndromeBP — blood pressureAID50 — aerogenic infective doseAnti S100 — antiserum to brain specific protein S 100AFC — antibody forming cellsAPC — antigen presenting cellsACE — angiotensin converting enzymeARA — American Rheumatology AssociationAT — angiotensinAT1 — type 1 angiotensin II receptorAB IRβ — antibodies to insulin receptor beta subunitATP — adenosine triphosphateATPase — adenosine triphosphataseADC — analog to digital converterEPSP — evoked postsynaptic potentialGABA — gamma aminobutyric acidDTHR — delayed type hypersensitivity reactionGCD — glucocorticoid drugsGCSF — granulocyte colony stimulating factorGMP — guanosine 3,5 monophosphateGAD — generalized anxiety disorderBPH — benign prostate hyperplasiaCI 95% — 95% confidence intervalDNA — deoxyribonucleic acidLPTP — long term posttetanic potentiationNK — natural killer cellsGIT — gastrointestinal tractCHD — coronary heart diseaseIL — interleukinEIA — enzyme immunoassayIFN — interferonCIA — collagen induced arthritisLD — lethal dose10
  11. 11. List of abbreviationsLV — left ventricleLC — latencyLPS — lipopolysaccharideIIEF — International index of erectile functionICD — International classification of diseasesMTD — maximum tolerable doseISIAH — inherited stress induced arterial hypertensionNAID — nonsteroid antiinflammatory drugsAE — adverse eventOA — osteoarthritisARVI — acute respiratory viral infectionsHTP — hydroxytryptophanAP — action potentialEPM — elevated plus mazeRP — resting potentialCGM — complete growth mediumPSA — prostate specific antigenRA — rheumatoid arthritisLBTR — lymphocyte blast transformation reactionRNA — ribonucleic acidRSV — respiratory syncytial virusSBP — systolic blood pressureDM — diabetes mellitusDBPM — daily (24 h) blood pressure monitoringULD — ultralow dosesULDH — ultralow doses of haloperidolULDP — ultralow doses of phenazepamALS — average lifespanMADD — mixed anxiety and depression disorderTRUSE — transrectal ultrasound examinationTS — testosteroneUA — urogenic reactive arthritisUSE ultrasound examinationCAAR — conditioned active avoidance reflexCPAR — conditioned passive avoidance reflexLVEF — left ventricular ejection fractionPHA — phytohemagglutininPDE 5 — type 5 phosphodiesterasePI — phagocytic indexTNF β — tumor necrosis factor βPBS — phosphate buffered salinePN — phagocytic number 11
  12. 12. Ultralow dosesCHF — chronic heart failurecAMP — cyclic adenosine 3,5 monophosphatecGMP — cyclic guanosine 3,5 monophosphateCNS — central nervous systemCP — cyclophosphaneHR — heart rateSE — sheep erythrocytesED — erectile dysfunctionECG — electrocardiogram5 HT — serotonin receptorsACR20 — 20% improvement by American College of Rheumatology criteriaARA — American Rheumatology AssociationAS 100 — antiserum to brain specific protein S 100AUC — trapezoid method for estimation of the areaunder the concentration time curveC — centesimal dilutionD — decimal dilutionEGF — epidermal growth factoreNOS — endothelial NO synthaseFDA — USA Food and Drug AdministrationHAMA — Hamilton anxiety scaleIg — immunoglobulinIPSS — International questionnaire for symptomsof prostate diseases (International Prostate Symptom Score)ITT — analysis of the results for patients included in the trial(intention to treat analysis)MHC — major histocompatibility complexNMMA — NG monomethyl L arginineNOS — NO synthaseNYHA — New York Heart AssociationQoL — quality of life index (IPSS questionnaire)STAI — Spielberger scale (State Trait Anxiety Inventory)STAI S and STAI T — state and trait anxiety by the Spielberger scaleVEGF — vascular endothelial growth factorWOMAC — index for the severity of osteoarthritis(Western Ontario and Mc Master Universities Osteoarthritis Index)12
  13. 13. IntroductionT he author of this book, as well as his colleagues, succeeded in an intriguing scientific path from homeopathy to immunopharmacology, and fromtraditional homeopathic remedies to high technology, safe, and effective medicalproducts. These drugs were developed on the basis of a newly discoveredphenomenon of ultralow doses of antibodies. Several preparations from ultralow doses of antibodies, including Anaferon, Impaza, and Proproten 100, are well known. However, many physiciansand specialists do not have enough information on the mechanism for actionof these products. The phenomenon of antibodies in ultralow doses was openedat the boundary of the following three medical disciplines: pharmacology,immunology, and homeopathy. Therefore, this monograph includes some dataon homeopathy and immunology. Experimental and clinical trials allowed us to obtain new data, which arenot consistent with the common notions about vital functions of the organism.The interpretation of these facts requires other approaches and new knowledge.The pragmatic purpose of this monograph is to develop the notion of a newpharmacological direction. During the preparation of this manuscript, the author should becomefamiliar with previously unknown areas of knowledge. It was necessary for himto learn the notions and terminology that exist in each field of science. Medicalscience consists of several special directions. A fruitful professional dialog doesnot necessarily occur between experimenters and clinicians. We would like thisbook to be available not only for representatives of theoretical medicine(pharmacologists, physiologists, and immunologists), but also for physicians. Tosimplify the understanding of some facts that require special biologicalknowledge, they are given in a popular scientific form (history of one research).Fundamentally, the monograph is divided into two sections. The first sixchapters are devoted to the general problem of ultralow doses. The final twochapters show some data on experimental and clinical effectiveness of newproducts. It may be of interest to various specialists, including neurologists(Tenoten), infectious disease physicians and podiatrists (Tenoten for children 13
  14. 14. Ultralow dosesand Anaferon for children), urologists (Afala and Impaza), rheumatologists(Artrofoon), narcologists (Proproten 100 and Anar), and cardiologists (Kardos). The author is grateful to Professor S. A. Sergeeva, Yu. L. Dugina, I. A.Kheifets, and all colleagues from the Science Department of the “MateriaMedica Holding” Research and Production Company for their help in thepreparation of this monograph.14
  15. 15. C h a p t e r 1 Analysis of the experience of homeopathyT he author of this monograph, a recent graduate of the Medical Institute, received the book “Homeopathy” (G. Kohler) as a gift from his father in1989. It was a rare book in the period of commodity deficit. A period of 1 yearwas required to overcome a skeptical attitude of the Soviet physician toward this“superficial” discipline. The book was opened and read. This moment may beconsidered as the first successful step in a study described here. As differentiatedfrom various manuals on homeopathy, the general part in the book of G. Kohlerwas written in down to earth language. Otherwise, the familiarity and furtherfascination with homeopathy could not occur. After ten years of neglect of homeopathy in our country, thousands ofphysicians were able to learn this discipline by visiting a variety of quasi legaltraining courses. However, only some of them became the practitioners. It wasvery difficult to learn homeopathy without assistance of a teacher. The authorof this monograph was successful. A twist of fate introduced him to a famousphysician T. D. Popova, who headed the Kiev school of homeopathy. She wasa bright person. O. I. Epstein had the possibility to collaborate with Tat’yanaDem’yanovna and to look for the reception of patients. It helped him to learnthe basic principles of homeopathy. Homeopathy is inseparably linked with the name of S. F. Hahnemann. In1976, he published the manuscript on a new therapeutic direction. He describedthe method for preparation of medical products in ultralow doses, principles ofprescription, and results of clinical trials. S. Hahnemann is one of the pioneers 15
  16. 16. Ultralow dosesin clinical trials with medical products. There are ambiguous data on pharmaceutical studies in old time. The first comparative analyses of therapeutic agentswere performed only in the 18th century. However, R. Virchow believed that the“farther of experimental pharmacology” is S. Hahnemann. Before Hahnemann,there was no integral and intelligent approach to study of medical products. Hereceived a fine education and learned the ancient languages. In previousmanuscripts, Hahnemann could learn the “like cures like” principle. The development of a new rational scientific method for medicinal treatment of variousdiseases was associated with activity of this unique man. Hahnemann decidedto test the effect of cinchona bark with himself to confirm the reliability ofpublished data. This substance caused fever, which was typical of malaria. Thescientist concluded that a medicine for the therapy of some disease can inducea similar state in healthy individuals. S. Hahnemann tested the effects of various medical products (mainly ofherbs and minerals) on healthy volunteers. Clearly the trial did not meet modern requirements and was performed with a small number of people (relatives,friends, pupils, and colleagues). The results confirmed the hypothesis of Hahnemann. The reactions induced by some substance in healthy volunteers maybe considered as an indication for therapy of similar disorders with the sameagent. The Hahnemann’s Law of Similars was formulated for the first time inthe journal of Hufeland. “One should apply in the disease to be healed, particularly if chronic, that remedy which is able to stimulate another artificially produced disease, as similar as possible; and the former will be healed – similiasimilibus*”. It should be emphasized that the Law of Similars was discovered by S. Hahnemann with normal doses**. Some patients were characterized by severe druginduced exacerbation. Hence, Hahnemann decided to reduce the dose of remedies. Due to pedantry, the scientist developed a method for dilution of theoriginal substance. He empirically showed that it is necessary to combine(exactly to combine!) a repeated dilution of the initial solution and tenfoldmechanical shaking. Hahnemann proposed to use the centesimal (C) scale ofdilution. At each stage of preparation, the initial amount of medical product isdiluted by 100 times. In the follow up period, homeopaths introduced the socalled “decimal dilution” (D, successive tenfold dilution of the original substance). For example, dilution C30 means that the original substance was diluted30 times. Moreover, the concentration of this substance was reduced by 100times at each dilution. D6 means that the concentration of the original* Similia similibus (lat.) likes with likes.** The term “homeopathy” originates from the Greek word “homo” (similar). It mainly designates the principle of “remedy prescription”, but not the dose.16
  17. 17. Chapter 1. Analysis of the experience of homeopathysubstance decreased by 10 times at each of six dilutions (Fig. 1.1). In the SIsystem, high dilutions by the method of Hahnemann correspond to 10—n M and100—n M. Formally, the dilutions of more than 10—24 M (D24) and 100—12 M(C12) are submolar. They do not contain molecules of the original substance.This fact did not disturb the founder of homeopathy. Hahnemann did not knowabout the unit of “mole”, which was proposed by the physician AmedeoAvogadro (1776 1856). Hence, Hahnemann operated with submolar doses. In the 18th century, drug manufacturers were in conflict with Hahnemann. It was related to commercial reasons, but not to the absence of moleculesof the original substance in homeopathic remedies. Hahnemann prepared thesehomeopathic remedies by himself and, therefore, deprived the manufacturers ofearnings. S. Hahnemann and his followers studied the effects of various preparations on healthy volunteers. They showed that treatment with these agents insubmolar concentrations is followed by drug induced exacerbation. Even at highdilution of one or another substance, there were two or three individuals(respondents) with hypersensitivity to the prescribed remedy. It should be emphasized that the respondents had similar personalcharacteristics, appearance, behavioral habits, and dietary predilections. Theywere predisposed to certain diseases, including inherited disorders. For example,the subjects reacting to ultralow doses of arsenic mainly appeared as lean, fineboned, and light skinned individuals. They usually had a geographic tongue,drank a considerable amount of fluid in small sips, and felt comfortable in warmclimate. These subjects differed in pedantry, anxious mood, and predisposition 1/100 1/100 1/100 1/100 1/100 ⏐ ↓ ⏐ ↓ ⏐ ↓ ⏐ ↓ ⏐ ↓ Alcohol solution (Н2О) (Н2О) (Н2О) (Н2О) (Н2О)Molecular 1:1 1:102 1:104 1:106 1:108 1:1010dilutionHomeopathic Basic 1С 2С 3С 4С 5Сpotency solution Increase in the potency of remediesFig. 1.1. Scheme for the preparation of homeopathic remedies (V. G. Zilov et al.,2000). 17
  18. 18. Ultralow dosesto psoriasis, bronchial asthma, and other diseases with common clinical symptoms. A complex description of the effects of any substance in ultralow dose andcharacteristics of hypersensitive patients received the name “pathogenesis ofhomeopathic remedy” (in this case, arsenic pathogenesis). It includes the pharmacodynamic properties of a substance and markers of individual sensitivity,which should be taken into account in the prescription of this remedy*. S.Hahnemann demonstrated that the maximum individualization of therapy isnecessary for clinical practice. The major therapeutic principle appeared asfollows: “cure only with a similar drug”. The similarity was considered not onlyas the prescription of a medical product for certain symptoms (indications), butalso as the use of a specific remedy in patients with high individual sensitivity. Hundreds of medical products are extensively used in homeopathy. Thereare 2000 homeopathic remedies. Homeopathy was born 200 years ago. Therefore, homeopathic remedies are prepared from available raw materials (plants,minerals and, more rarely, biological substances). The major advantage ofhomeopathic remedies is that their effects were studied in details. Undoubtedly,the arsenal of homeopathy will always include well known “ancient” preparations. Some modern pharmaceutical (allopathic) products, including aspirin,nitroglycerine, insulin, and prednisolone, are sometimes given in ultralow doses.The quintessence of homoeopathy is the evaluation of sensitivity of each patientto one of the homeopathic remedies. In this case, the treatment will producea therapeutic effect. Hahnemann developed the integral therapeutic disciplineof homeopathy, which differs in all sufficiency. Potentially, a skilled homeopathmay affect any disease state. The success of therapy strongly depends on the“appropriateness” of medical treatment, but not on the nosological form orseverity of disease. A skilled homeopath is a general practitioner and good specialist in propaedeutic. The prescriptions of a homeopath are based on historytaking, thorough examination, power of observation, and evaluation of patientcharacteristics. By the 20th century, homeopathy was widely distributed in Europe, Northand South America, India, and Russia. Pharmaceutical chemistry, experimentalpharmacology, and molecular biology became the specific areas of knowledgeat a later period. They determine the type of modern medicine. Due to severalreasons, homeopathy was separated from modern science. Symbiotic relationships between academic medicine and homeopathy developed in the follow upperiod. Traditionally, a European patient knows the problems that require him* The term “drug pathogenesis” is very close to the modern notion of constitution in psychiatry and pediatrics. Hahnemann did not use the term “constitution” or “constitutional type”. They were introduced into the homeopathic lexicon by followers of Hahnemann.18
  19. 19. Chapter 1. Analysis of the experience of homeopathyto consult with a homeopath. Homeopathic therapy also develops in Russia.After long term neglect, this method was officially approved in Russia in 1995. Let’s consider the main principles of the Hahnemann theory. Principle of similarity. First of all, it should be remembered that the principle of similarity is not a prerogative of ultralow doses. The first prescriptions byHahnemann were made in “normal” doses. This principle suggests that the remedyshould be prescribed for a “similar” clinical manifestation. For example, arseniccauses fever in healthy volunteers. By contrast, arsenic in homeopathic doses maybe used to cure fever in patients. However, arsenic induced fever has several specificfeatures. Fever is observed in a certain time (midnight) and accompanied bytypical chill, which spreads in an upward direction of the back. Arsenic inhomeopathic doses will be therapeutically effective in patients with this type offever. Moreover, the effect will occur only in patients that are susceptible toultralow concentrations of arsenic (primarily in lean and fine boned pedants). These features of symptoms and constitutional characteristics serve as amarker for individual sensitivity. Modern pharmacology also postulates thenecessity of individual pharmacotherapy. Much attention is paid to the searchfor genetic and phenotypic criteria of individual sensitivity. It should be noted that each patient may have various markers. These dataindicate that individual sensitivity (at least, phenotypic sensitivity) to a substanceis determined by several markers, but not by one marker. The experience ofhomeopathy shows that one sign (e.g., geographic tongue) may serve as one ofthe markers for a large group of medical products. Only a specific combinationof various markers is a reliable criterion for individual sensitivity to the remedy*. Trial with healthy volunteers. The trial with healthy volunteers was of considerable significance. This approach allowed S. Hahnemann and his followersto perform a simple, rapid, and safe evaluation of indications for a large numberof medical products. The following two facts are of importance for our study. First, medical products in ultralow concentrations cause exacerbation ina small number of patients. Hence, this state is associated with the reaction ofhypersensitivity. Several types of immediate and delayed type hypersensitivitywere studied and described in immunology. However, little is known about theirmechanisms. All these reactions are nonspecific. For example, anaphylactic shockmay be induced by a variety of substances. By contrast, the symptoms of druginduced exacerbation in homeopathy are always specific for a certain substance. And second, arsenic in toxic doses causes hyperthermia in all subjects.Low doses of arsenic may produce the same clinical symptoms of fever inindividual volunteers, which is related to hypersensitivity. Let’s consider fever as* In the future, this observation allowed the author to develop a new concept of seman tically organized constellations. 19
  20. 20. Ultralow dosesa protective response. In this case, the substance in high doses serves as a“pathogen” for all individuals. By contrast, the same substance in low doses hasa pathogenic effect only on several subjects. A similar protective response shouldbe mediated by similar mechanisms. However, the substance in high dosetriggers these mechanisms in all subjects. It remains unclear why the substancein low dose affects only sensitive individuals*. Preparation of ultralow doses. It is known that highly diluted solutions donot have biological activity. Otherwise, biological activity of these solutions isextremely unstable. Moreover, the Hahnemann’s method of mechanical shakingmay be substituted for another external influence (electromagnetic or ultrasoundexposure). However, ultra diluted solutions do not exhibit activity without successive dilutions of the original substance in combination with external treatment. It is surprising that Hahnemann could combine various procedures intoa common system: preparation of medical products, study of pharmacologicalactivity, and principle of prescription (similarity). The physical mechanisms for memory retention of the original substancein highly diluted solutions remain unknown. Several scientists have cast doubton the use of ultralow doses and effectiveness of homeopathy. Modern studieswere performed 200 years after the discovery of homeopathy. They illustratedthat ultra diluted solutions (method of Hahnemann) have fine biological activity. The technological process of S. Hahnemann received the name “potentiation”. The prepared remedies were designated as potentiated or dynamicsubstances. Hahnemann proposed that these agents are characterized by therelease of an “active basis” or “vital force”. A clinical effect of potentiated products was not observed without maximum individualization. Hahnemann suggested that potentiated products are ineffective without the principle of similarity(all or none law). Various properties of potentiated agents were revealed inmodern molecular and cellular studies. Hahnemann had no technicalpossibilities to determine the general properties of ultralow doses, but proposedan approach to their use (homeopathy). The primacy of the principle of similarity took root in the mind of Hahnemann followers. Until the present time, homeopaths know little about other(non homeopathic) variants for the use of medical products in ultralow doses.The term “homeopathic dose” has been commonly accepted. It is morepreferable to tell about the individual (homeopathic) prescription of a medicalproduct in ultralow or low dose, but not about the dose. In our opinion, theterm “homeopathic remedy” means that the indications for treatment with a* The mechanisms of individual sensitivity are a major problem, which underlies the hypothesis on dual (holographic) organization of vital functions in an organism. This problem is discussed in the next chapters.20
  21. 21. Chapter 1. Analysis of the experience of homeopathycertain drug were evaluated in trials with healthy volunteers. However, theindications for modern pharmaceutics are estimated by other methods. The terms “low” and “ultralow” dose are also indefinite. Some authorsbelieve that the doses of up to 10—12 M original substance are low (molar) doses. The doses of not more than 10—24 M are ultralow doses. However, activityof the potentiated agent depends little on the presence or absence of several molecules of the original substance (see below). By contrast, this activity is determined by the technology of preparation. The method of potentiation suppliesbiological activity to ultra diluted solutions. Hence, these solutions can be usedaccording to the doctrine of homeopathy. It is more appropriate to use the term“potentiated” or “activated” substance, but not the homeopathic, low, or ultralow dose. The scale of preparation (C or D) and number of dilution cycles(usually 6, 12, 30, 200, or 1000) should be designated. The term “activated” preparation seems to be preferable. First, this term indicates than biological activity of the ultra diluted solution is related to externaltreatment. Second, the term “potentiation” has another meaning in modernpharmacology. And third, we showed that medical products in ultralow doseshave a potentiating effect under certain conditions. These features may introduceterminological difficulties. However, the preparation of ultralow doses shouldretain its historical name of “potentiation” or “dynamization” (S. Hahnemann). Besides a rational analysis of homeopathy experience, it is necessaryto consider the subjective feelings of homeopathic physicians. At a certain stageof professional activity, any homeopath notices that nearly all (even rarelyobserved) physiological signs are manifested in the description or pathogenesisof homeopathic remedies. For example, you see that one of the guests asks youto prepare tea. Then he gulps down boiling water. Another guest asks you toclose the window since he cannot hear a noise (the yard keeper cleans asphaltwith a scraper). Under these conditions a homeopath will remember thepathogenesis of Lycopodium (club moss) and Asarum (snakeroot), respectively. When studying the temperamental characteristics of patients sensitive toone or another homeopathic remedy, you can see that they have a commonfeature (“stem” or “algorithm”). It is difficult to explain this algorithm. However, a homeopath cannot select the effective medical product without understanding this algorithm. Many homeopaths know that the psychological type of patients sensitive tosome medical product is progressively transformed into the psychological type ofanother remedy. This feature contributes to the mosaic pattern, which resemblesa change in the properties of chemical elements in the periodic table of D. I.Mendeleev. Psychological portraits of sensitive patients are similar in thepathogenesis of several preparations (mineral potassium sulfate and Pulsatilla of thefamily Ranunculaceae; calcium carbonate and belladonna; etc.). The remedies with 21
  22. 22. Ultralow dosessimilar “psychological characteristics” have the same therapeutic effect. These datasuggest the systemic nature of homeopathy, which is difficult to verbalize. This impression becomes stronger in learning the other basic principles ofhomeopathy. Using the terminology of the 18th century, homeopaths classify allpathological processes into the following three groups (depending on general characteristics): syphilis (destructive processes), sycosis (productive processes, includingcough), and psora (subacute areactive states). Each type of pathological processesis characterized by a certain group of preferable homeopathic remedies. Otherprinciples of homeopathy are also unusual. For example, some activatedpreparations are tropic for the right sided or left sided disease. Caustic (lime) andLachesis (bushmaster snake venom) are prescribed for the therapy of right sidedand left sided hemiplegia, respectively. The rules of C. Hering also seemuncommon. C. Hering (1800 1880) is the farther of American homeopathy. Hedescribed the spatial and temporal response of patients to homeopathic remedies. C. Hering revealed (1998) that “the patient will be cured and the symptoms will permanently disappear when they develop in the following direction:from within outwards, from above downwards, and from later symptoms toearlier symptoms (i.e. in the reverse order of their coming)”. The use of homeopathic remedies is rarely followed by drug induced exacerbation. When thedynamics of drug induced exacerbation is consistent with the rules of C. Hering,it may be considered as a prognostically favorable process. Under these conditions, the prescribed remedy is not withdrawn by a homeopath. Homeopathic practitioners know that each patient is sensitive to severalhomeopathic remedies (hierarchy of individual sensitivity). The higher is thesensitivity to the remedy, the greater is the effectiveness of this remedy. Summarizing the above we conclude that vital activity of the organism isbased not only on well known physiological and chemical processes, but alsoon spatial and temporal laws of harmony. They are closely related to individualcharacteristics of each patient. Even though the homeopathic knowledge seemsarchaic, it is worthy of notice. This knowledge was obtained in a directedclinical study of medical products. Hence, these data are objective. Moreover,separate observations illustrate the existence of various clinical, phenotypic,psychological, and topic criteria for individual sensitivity of an organism. Chapter Most important in Chapt er 1 Homeopathy is a drug therapy based on the principle of similarity. The principle of similarity suggests maximum individualization in the prescrip tion of medical products, which involves a propaedeutic approach of S. Hah nemann.22
  23. 23. Chapter 1. Analysis of the experience of homeopathy Homeopathy suggests the use of activated agents that are prepared by the meth od of potentiation (successive dilutions of the original substance and rhythmic mechanical shaking). Activity of ultra diluted solutions depends on the technology of potentiation, but not on the concentration of the original substance. This fact isproved, but does not have a physical explanation. Ideally low doses in homeopathy are associated with the method of preparation. Over two centuries, potentiated (activated) preparations were believed to produce only the clinical effect. It was postulated that these drugs are ineffective with out individualization of therapy. Recent experiments showed that ultralow doses produce a fine molecular and cellular effect, which is not directly related to the principle of similarity. Acti vated preparations have a small effect that is insufficient for therapeutic activi ty. Taking into account these data, we assumed that homeopathic therapy is based on increasing the strength of ultralow doses by the mechanism of hyper ergia. After studying the ultralow doses of remedies with healthy volunteers, S.Hahnemann revealed the existence of individual sensitivity to certain medicalproducts (complex of clinical, psychological, psychological, and topic criteria). 23
  24. 24. Ultralow doses C h a p t e r 2 Three types of effects of ultralow dosesT he first professional experience of homeopathy showed that it is not necessary to follow the principle of similarity in achieving a therapeuticeffect of remedies in ultralow doses. For example, a group of preparations existsthat are a priori tropic for the liver (Lycopodium, Chelidonium, and Carduusmarianus). Even without individualization of therapy, these medical productsimprove the state of most patients with hepatobiliary disorders. Moreover, travelsickness (acute paroxysmal state) may be treated with several homeopathicremedies that reduce the symptoms of autonomic disorders. Individualization oftherapy is not required under these conditions. The “Materia Medica Holding” company was established in 1992. In theinitial period, this company manufactured the so called “complex homeopathicremedies”. The pharmaceutical formulation consisted of three or four homeopathic drugs (granules and tablets). Other Russian and foreign complexons ofwell known homeopathic components from plants and minerals, as well asorganotropic preparations of animal (embryonic) tissues or organs, appeared onthe pharmaceutical market. The effects of potentiated remedies and tissuepreparations are related to their tropism for a certain pathological condition andorgan, respectively. A complex preparation Agri (homeopathic Antigrippin) was the brand ofthe “Materia Medica Holding” company in the 1990s. Surprisingly, this drughad a preventive effect on influenza and chill. These facts seem to contradictthe principle of similarity.24
  25. 25. Chapter 2. Three types of effects of ultralow doses Such “discrepancies” with the homeopathic doctrine did not alter ourrelation to the basic principles of homeopathy. These data stimulated us tosearch for new indications for ultralow doses. Experimental and clinical trials of potentiated products wereconducted at the “Materia Medica Holding” company beginning from 1995.Several discoveries were made. The first steps of a large scale scientific researchwere devoted to study the effect of combined treatment with a medical productin normal dose and activated form of the same remedy. The phenomenon ofisopathy was well known. It suggests that the symptoms of poisoning with acertain substance are treated by the potentiated form of this substance. Due tohigh risk of chemical attacks of the German army during World War II, Englishvolunteers were exposed to skin burns with mustard gas. These burns were thentreated with potentiated mustard gas. Complications of corticosteroid therapy,including Itsenko Cushing syndrome, are homeopathically treated with Cortex(activated prednisolone). However, isopathy was not subjected to a complexclinical study. Moreover, there are no experimental data on this problem. Similarly to the preventive effect of Agri, we decided to test ultralow dosesof a certain substance for protective activity during intoxication that was inducedby this substance in high (toxic or subtoxic) doses. As differentiated from theisopathic method, ultralow dose (“antidote”) was administered in combination,but not after treatment with the same substance in toxic doses (poison). Webelieved that this approach does not contradict the homeopathic doctrine.Administration of the substance in toxic doses served as a model to induce thesymptoms typical of treatment with the activated form. The principle of our experiments was quite paradoxical. We tried tointroduce a “drop” (activated substance) into the “sea” (toxic dose of thesubstance). Combined treatment with ultralow doses was performed in variousregimens. Ultralow doses were administered simultaneously or before treatmentwith the toxic dose (one to ten minutes). Various routes of treatment with ultralow dose were also analyzed. For example, the potentiated preparation wasmixed with a toxic dose of the same substance. The mixture was administeredperorally through a probe. Otherwise, the original substance was administeredparenterally, while the activated preparation was given perorally. Combined treatment with the substance in ultralow (homeopathic) andnormal (therapeutic or toxic) doses was performed simultaneously or in a smallinterval. This approach received the name bipathic* treatment (O. I. Epstein,1996, 1997). Prednisolone was the first medical product for combined treatment.It was the first step from homeopathy to immunopharmacology. Therefore, thisstudy should be described in details.* Bipathic administration, allopathy + homeopathy. 25
  26. 26. Ultralow doses Bipathic administration of prednisolone was performed at the Laboratory ofBiophysics (Kiev Institute of Otorhinolaryngologist) headed by A.F. Karas’. The animalssimultaneously received prednisolone in “normal” and potentiated doses (dilution C30). Inthe latter case, the conventional concentration of prednisolone was 10—60 wt % (10—60 M). Series I was performed on 30 rats. The effect of bipathic treatment with prednisolone was studied on animals with experimental acute inflammation. This state wasinduced by injection of 0.05 mg 1% carrageenan into the hindlimb of rats. Activatedprednisolone was administered through a probe to group 1 animals with experimentalinflammation. Group 2 animals received prednisolone in a total dose of 20 mg per rat.Group 3 animals were subjected to combined treatment with both drugs. The standard andpotentiated forms of prednisolone were administered twice (1 h before and 2 h aftercarrageenan injection). The control groups consisted of intact animals and untreated ratswith carrageenan induced inflammation. We showed that administration of prednisolone alone or in combination withactivated prednisolone is followed by the reduction of inflammatory edema of the paw.Potentiated prednisolone had no antiinflammatory activity and did not potentiate theantiinflammatory effect. However, bipathic administration of prednisolone wasaccompanied by several positive effects. Migration of peritoneal macrophages significantly decreased during inflammation.Normal doses of prednisolone did not improve macrophage migration. However,macrophage migration rapidly returned to the control level after combined treatment withstudy drugs. An electron microscopic and morphological study showed that administration of 20mg prednisolone is followed by moderate destructive changes in the liver and thymus ofanimals. However, the structure of these organs was not impaired after combinedadministration of prednisolone and activated prednisolone in the same doses. Carrageenan induced inflammation is accompanied by the increase in energyconsumption due to activation of the protective response. Prednisolone has no effect onblood ATP concentration. Bipathic administration of prednisolone is followed by a sharpdecrease in ATP content, which reduces energy supply to the inflammatory process.Combined administration of prednisolone in the toxic and ultralow dose improves enzymeactivity in blood cells, activates alkaline phosphatase in neutrophils, and has a normalizingeffect on the activities of ATPase, 5 nucleotidase, and lactate dehydrogenase. Thesechanges illustrate the restoration of energy supply to cells. As compared to “standard” prednisolone, bipathic administration was followed bya greater increase in biosynthetic activity of rat peripheral blood lymphocytes. Thisconclusion was derived from the increase in RNA level. Series II was designed to evaluate whether potentiated prednisolone (10—60 wt %)may prevent the side effect of chronic treatment with prednisolone in normal doses for 2weeks. Prednisolone in a daily dose of 50 mg/kg body weight was administered through aprobe. This dose of prednisolone produced a strong antiinflammatory effect on the modelof carrageenin induced inflammation. The potentiated substance had a variety of protectiveeffects under these conditions (Table 2.1; V.G. Zilov et al., 2000). These data indicate that the activated agent prevents metabolic disordersin lymphocytes and neutrophils and, probably, has a normalizing effect onmembrane processes after treatment with normal doses of prednisolone. A potentiated form of prednisolone also prevented the development of destructive changes in the liver, adrenal glands, and lymph nodes and gastric26
  27. 27. Chapter 2. Three types of effects of ultralow dosesTable 2.1. Protective effects of potentiated prednisolone Prednisolone Prednisolone + potentiated formSignificant increase in the number Slight increase in the number of stabof stab granulocytes granulocytes; significant decrease in the absolute number of monocytesDecrease in leukocyte count compared Leukocyte count does not differto the control from the controlNo effect on peroxide chemiluminescence Activation of peroxidation in blood plasmaTwo fold decrease in adenosine triphosphate Increase in blood ATP concentration(ATP) content in the blood above normalTwo fold decrease in alkaline phosphatase Slight decrease in alkaline phosphataselevel in neutrophilic leukocytes level in neutrophilsIncrease in lactate dehydrogenase activity Lactate dehydrogenase activity in neutrophilsin neutrophils practically does not differ from normalDecrease in ATPase activity in lymphocytes No changes in lymphocyte ATPase(nearly by 2 times) activitymucosal erosion, which is typical of long term treatment with this drug.Activated prednisolone had a normalizing effect on synthetic activity of lymphocytes, which was suppressed after long term administration of prednisolone.It was manifested in an increase in the amount of chromatin protein uncoupledDNA. Hence, functional activity of lymphocytes returned to normal under theinfluence of activated prednisolone. We conclude that during combined (bipathic) treatment, potentiatedprednisolone has protective (adaptive) activity and abolishes the effect ofprednisolone in the toxic dose*. The next series of experiments was performed in collaboration withProfessor Tamara Mikhailovna Vorob’eva (Head of the Laboratory of Neurophysiology and Immunology, Ukrainian Institute of Neurology andPsychiatry). When the protective effect of activated prednisolone wasestablished, the author of this monograph (professional psychiatrist) decidedto develop a new drug for the therapy of alcohol abuse and opium addiction.We asked Tamara Mikhailovna to perform an experimental study with potentiated ethanol and morphine. The animals were subjected to chronicintoxication with these substances. These experiments involved the standardneurophysiological behavioral tests, biochemical assays, and immunological* In some experiments, a potentiated form of prednisolone tended to increase the anti inflammatory activity of prednisolone. Initially, this fact received little attention. 27
  28. 28. Ultralow dosesmethods. Electrical activity of the brain and self stimulation of the “pleasurecenter” in the lateral hypothalamus were studied*. I would like to briefly describe the results of “bipathic” treatment withethanol. It was shown that ultralow dose of test substance modifies the effectof the same substance in normal dose. Activated ethanol had a strong protective(adaptive) effect against alcohol in the toxic dose. It was manifested in the “regulation” of animal behavior (e.g., conditioned responses) and normalization ofseveral parameters (electrical activity of the brain, structure of sleep,neurotransmitter balance, and blood alcohol level). It should be emphasized thatthe animals could stimulate the “pleasure center” via a stereotaxic electrode bypressing the lever. However, they refused to perform self stimulation. T. M. Vorob’eva believed that this unusual effect reflects a well balanced emotional state.Hence, pathological alcohol addiction was reduced in these animals. Furtherclinical trials with ultralow doses of alcohol showed that they have anti abstinence properties. An antialcohol drug Anti E (activated alcohol) was approved bythe Russian Ministry of Health. This drug was manufactured by the “MateriaMedica Holding” Research and Production Company beginning from 1998. Experiments of T. M. Vorob’eva and further clinical trials showed thatpotentiated morphine has a wide range of protective activity during intoxicationwith morphine or opium surrogates. However, this drug was not introduced intoclinical practice. Our studies revealed the phenomenon of bipathy in 1996 (200 yearanniversary of homeopathy). Followers of Hahnemann performed the effective,but extremely conservative studies for 2 centuries. Homeopaths believed that theprinciple of similarity is absolutely essential for the effectiveness of ultralowdoses. Initially, we shared this opinion. The results of experimental studies in themid 1990s showed that activated preparations have biological activity. However,this fact received insufficient attention of homeopaths. There was a greatdiscrepancy between homeopathic physicians and experimental biologists. Onthe one hand, homeopaths could not ignore the homeopathic doctrine. On theother hand, biologists knew a little about homeopathy and, therefore, could notintroduce the phenomenon of homeopathy into the area of rational scientificknowledge. At the same time, studies of low and ultralow doses were conductedfor a long time. At the beginning of the 1920s, a famous Russian pharmacologistN. P. Kravkov (1924) showed that blood flow variations in the rabbit ear can beinduced by vasoconstricting and vasodilating agents in low concentration (up to10—32 wt %). Further experiments of A. N. Kudrin (1991) revealed that* The results of this experiment and further studies are described in the monograph “Informational and ontological models of adaptation” (O. I. Epstein et al., 1997) and joint articles.28
  29. 29. Chapter 2. Three types of effects of ultralow dosesadministration of epinephrine in a concentration of 10—16 wt % has a similareffect on blood flow in frog mesenteric vessels. The effectiveness of phosphatasein a concentration of 10—16 wt % was demonstrated by A. M. Kuzin in 1947.The results of these experiments were published only in 1997. At the beginningof the 1950s, A. Gay and J. Boiron showed that sodium chloride at dilution C27modifies the dielectric constant of water. On the basis of these data, one vesselwith potentiated sodium chloride in the submolar concentration was correctlyselected from 100 vessels (99 vessels with placebo). In 1941, W. Boyddemonstrated that activated mercury chloride in a concentration 10—6 wt %accelerates enzymatic hydrolysis of starch. The effects of substances in ultralow concentrations on biological objected(primarily on plants) were described by various authors, including G. N.Shangin Berezovskii (1982, 1986) and L. Kolisko (1953). In the 1980s, high technology studies with ultra diluted solutions were devoted to the evaluation of their biological activity. A group of investigators underthe direction of Professor E. B. Burlakova (N. E. Emanuel’ Institute of Biochemical Physics, 1986) showed that antioxidants at submolar dilution (10—15M) have a stronger effect on electrical activity of the isolated snail neuron thanthose in the physiological concentration (10—3 M). Further experiments ofE. B. Burlakova et al. (1986, 1990) revealed that ultralow doses have variousbiological effects. The results of a well known study by E. Danevas and J. Benveniste (1988)were published in Nature. They showed that high and low doses have a similareffect. Until the present time, this experiment is one of the most “academic”researches in the field of ultralow doses. The authors revealed that degranulationof basophils with surface immunoglobulin E (IgE) may be induced by anti IgEat concentrations of 10—2 10—120 M. Treatment with the substance in theseconcentrations was followed by successive peaks of degranulation in 40 60%basophils. Molecules of anti IgE were absent in several dilutions, whichexceeded the Avogadro constant. However, the authors hypothesized that thismethod for preparation of homeopathic dilutions (thorough shaking of thesolution) provides transmission of biological information due to the arrangementof water molecules. Basophil degranulation was also observed in the presenceof other substances at high and low dilutions, including the specific allergen(basophils from allergic patients) and peroxidase (basophils from peroxidaseimmunized rabbits). J. Benveniste et al. evaluated the degree of basophildegranulation in the presence of phospholipase A2 from bee venom or pigpancreas, sodium ionophore monensin (up to 90% degranulation at anequivalent concentration of 10—30 M), and calcium ionophores A23187 andionomycin (10—38 M). The specific effect of high dilutions was confirmed byexperiments with ionophores. Degranulation of basophils decreased after the 29
  30. 30. Ultralow dosesremoval of the corresponding ion from the extracellular medium (E. Danevaset al., 1988). These results were reproduced in six laboratories of four universities (ParisSouth University, Toronto University, Jewish University, and Milan University)and published in Nature. However, an Editorial Article (J. Maddox, 1988) hascast doubt on the reliability of these data. In the follow up period, a similarexperiment was repeated under strict conditions. The results of this study werepublished in the Journal of the French Academy of Sciences (J. Benveniste, 1991). To bridge the gap between modern biology, medicine, and homeopathy, itwas necessary to follow simple steps. The phenomenological (narrow) view ofultralow doses should be changed to a detailed systemic evaluation of their activity.Except for several researches in the 1980s and mid 1990s, a rational study ofultralow doses was terra incognita. Until recent times, homeopathic remedies shouldmeet simple requirements of Medical Regulatory Authorities in various countries.Hence, even worldwide leaders in the production of homeopathic remedies donot have the experience of high level experimental studies with ultralow doses. In discussing the results of studies with bipathic (combined) administration of ethanol and morphine, T. M. Vorob’eva supposed that the phenomenon of bipathy is related to biological properties of ultralow doses. Theseproperties should not be associated with the homeopathic doctrine. Sheproposed to perform a detailed study of ultralow doses. Neurophysiologicalstudies of morphine in ultralow doses were performed in 1996. A large scale study showed that the systemic effect of activated morphineis qualitatively similar to that of normal dose morphine. Similarly to morphinein normal doses, potentiated morphine decreased the pain threshold, facilitatedthe acquisition of conditioned reactions in animals, and modulated theemotional state (model of self stimulation). However, morphine in ultralowdoses did not cause euphoria and addiction. These data could break the tabooof homeopathy, which was associated with the principle of similarity. Morphinein ultralow doses had a strong effect on experimental animals withoutindividualization of treatment. Tamara Mikhailovna Vorob’eva showed that ultralow doses have a specificbiological activity, which does not depend on individual treatment. It becameclear that this activity is a general property of ultralow doses. Similarly tohomeopathy, bipathy should be considered as a particular approach to the useof potentiated drugs. Morphine and other substances in ultralow doses have littleeffect, which limits the therapeutic use of these drugs. Hence, a particularapplication (homeopathy and bipathy) is of greater importance than a generalapplication. The indication for use, but not the dose, serves as a “watershed”between allopathy and homeopathy. Trials of homeopathic remedies areperformed on healthy volunteers. Homeopathic remedies can cause allergic30
  31. 31. Chapter 2. Three types of effects of ultralow dosesreactions in some of these individuals. They serve as a clinical criterion for theuse of this remedy. Modern pharmaceutical products are tested on patients. Thehyperergic reaction to these pharmaceutics is considered as a side effect. Theindications for use of “standard” pharmaceutics are based on their general(physiological) properties. Previous studies of cyclophosphane, phenazepam, and haloperidol showedthat combined treatment with a medical product and potentiated substanceholds much promise. Combined administration of cyclophosphane and ultralowdose of this drug to experimental animals with melanoma, lung cancer, andcarcinosarcoma was followed by an increase in antitumor activity of thecytostatic. The antimetastatic effect of cyclophosphane increased mostsignificantly after bipathic administration (E. N. Amosova, 2003). To understand the mechanisms of bipathy we evaluated whether thisphenomenon is the prerogative of a living organism, or ultralow dose maymodify the effect of “high” dose in simple physicochemical systems. In vitroexperiments were performed to answer this question. The first study was conducted under the direction of Professor A. V. Zakharov and Senior ResearcherV. G. Shtyrlin (Candidate of Chemical Sciences) at the Kazan State University. A nuclear magnetic resonance study was performed to estimate the effectof potentiation on the kinetics of ATP hydrolysis with citrate buffer atphysiological pH. The rate of hydrolysis was measured after addition ofpotentiated ATP or potentiated buffer (Table 2.2). The rate of hydrolysis decreased slightly after addition of any componentin a bipathic form. Our further studies were performed in collaboration with Professor S. I.Petrov (Institute of Oil and Gas). Potentiated preparations of lithium chlorideand mercury nitrate were shown to modulate electroconductivity of a simpleTable 2.2. Effect of potentiated substances on hydrolysis № Type of sample Hydrolysis rate, K (sec–1)1 Reference (3.35+0.07)×10—52 Reference (3.45±0.12)×10—53 Bipathic (3.02±0.05)×10—5 (with potentiated ATP solution)4 Bipathic (2.60±007)×10—5 (with potentiated buffer solution)Note. (1, 2) Reactions with two various reference preparations; (3) addition of 10 vol % potentiatedhomeopathic solution of ATP at dilution C30; (4) addition of 10 vol % potentiated homeopathic solutionof citrate buffer at dilution C30. K, hydrolysis rate constant for ATP in aqueous solutions of the referenceand potentiated sample with citrate buffer at pH 6.7 and T 378K. 31
  32. 32. Ultralow doseselectrochemical system, which contained these electrolytes in normalconcentrations (S. I. Petrov et al., 2003). Professor M. A. Myagkova et al.(2003) revealed that activated antibodies in ultralow doses have a modulatoryeffect on the antibody antigen binding constant in EIA. Similar results wereobtained in further experiments of E. A. Dukhanina. The effect of potentiated antibodies on “standard” antibodies was studiedby means of EIA (E. A. Dukhanina). A reaction mixture consisted of antigen (sorbed in plate wells), standard antibodies(diluted in phosphate buffered saline, PBS), and potentiated dilutions. The control systemswere composed of potentiated water and PBS instead of potentiated dilutions and standardantibodies, respectively. The optical density in wells with potentiated dilutions was muchhigher than that in wells with standard antibodies and water. The average optical densityAst+dilut was estimated in four independent experiments with 10 12 samples of potentiateddilutions. This parameter varied from 0.276±0 to 0.643±0.024. The average optical densityAst+water varied from 0.210±0.046 to 0.531±0.026. These values were not the sum of opticaldensities for the reference substance and potentiated dilutions. For a quantitative study ofthe effect, the relative optical density was calculated as follows: (Ast+dilutOAst+water)×100%/Ast+water. The average value was 23.2±7.2%. These data suggest that potentiated dilutionshave a direct effect on the antigen antibody interaction. Standard antibodies and sorbedantigen in various concentrations were used for a detailed study of this phenomenon. Theconcentration of standard antibodies varied from 0.3 to 100 ng/ml. The content of standardantibodies varied from 5.7±3.0 (at 0.3 ng/ml) to 22.7±3.9% (at 100 ng/ml). Hence, decreasingthe concentration of standard antibodies was accompanied by the reduction of effect. We discovered the phenomenon of bipathy. During combined (bipathic)administration of ultralow dose and normal dose, the activated preparationalways modifies the effect of the original substance. A potentiated form in vivoand in vitro modifies the effect of the original substance. It should beemphasized that the potentiated preparation modifies not only biological, butalso fine physicochemical properties of the original substance. As regards the toxic and subtoxic dose* of a medical product, itspotentiated form has a strong protective (adaptive) effect. Sometimes thepotentiated preparation “strengthens” a therapeutic effect of the originalsubstance (e.g., antimetastatic activity of cyclophosphane). Under otherconditions the potentiated preparation has no effect on pharmacological activityof the original substance (e.g., antiinflammatory effect of prednisolone). Bipathy could become a major direction of activity in the “MateriaMedica Holding” Research and Production Company. Moreover, potentiationof well known pharmaceutics and correction of their toxicity are the urgentproblems. These approaches are developed by the world’s leading pharma* The potentiated substance can produce a complex polymodal effect on toxic doses (see Chapter 5).32
  33. 33. Chapter 2. Three types of effects of ultralow dosesceutical companies. Unexpectedly, our study gained a new direction. We met afamous scientist and one of the leading specialists in neuroimmunology M. B.Shtark (Academician of the Russian Academy of Medical Sciences). MarkBorisovich thoroughly examined the results of our experiments. He proposedfurther studies on simple biological models to formally confirm the presence ofbipathy. In the opinion of M. B. Shtark, the so called long term posttetanicpotentiation (LTPTP) in surviving brain slices serves as an adequate model.Ultrathin sections of the animal brain can retain functional activity for a longtime in a special nutrient medium. LTPTP is a well known electrophysiologicalphenomenon. This phenomenon has been extensively used in neurobiology formany years. Neurotropic activity of various drugs may be evaluated from theireffect on LTPTP. The phenomenon of bipathy was studied on the model ofLTPTP with antibodies to S 100 protein from nervous tissue*. In immunology, any molecule that causes the formation of complementary antibodies is designated as an antigen. Hence, we shall use the term“antibodies to S 100 antigen”. The description of our experiment may seem complicated to the readerof this book (i.e., general practitioner). Let’s consider only the main results.Antibodies to S 100 antigen (anti S100) in normal doses have an inhibitoryeffect on LTPTP. Under certain technical conditions, the potentiated substancecompletely abolished a physiological effect of anti S100 in “normal” doses. Amajor advantage of our experiment is the uniqueness of results. Anti S100 innormal doses inhibited the electrophysiological reaction (LTPTP—). However,this reaction returned to normal after combined treatment with potentiated antiS100 (LTPTP+; O. I. Epstein et al., 1999). This experiment was performed by M. A. Starostina, N. A. Borisov, andN. S. Sorokina under the supervision of M. B. Shtark (Novosibirsk Institute ofMolecular Biology and Biophysics, Siberian Division of the Russian Academyof Medical Sciences). These data are of particular importance for our scientificresearch. A complete description of this experiment is presented below (according to the monograph of V. G. Zilov et al., 2000). The study was performed on surviving slices with an artificial medium, which retainsphysiological activity for a long time. It was based on a well known electrophysiologicalphenomenon of LTPTP. During tetanic electrical stimulation in one of the regions of rathippocampal slice, the evoked postsynaptic potential is recorded in another region with aspecial electrode. This potential persists for a long time (from 40 min to several hours) andhas specific characteristics. Synaptic effectiveness (transmission) is evaluated by recordingof the potential.* An unusual name of this protein is associated with the procedure of isolation. In one of the stages, this protein is dissolved in 100% saturated solution of ammonium sulfate. 33
  34. 34. Ultralow doses The development of LTPTP is a calcium dependent process. S 100 protein is acalcium binding protein, which has an important role in synaptic processes. The antiserumto S 100 protein inhibits these processes, including LTPTP. However, the synaptic effect was abolished after bipathic (combined) administrationof antiserum in normal dose and potentiated form C6 (10—12 wt %). A homeopathic doseof the substance (i.e., immunological preparation) blocked the action of an effective dose. It is important that this experiment involved an electrophysiological method, whichallowed us to repeat the measurements under standard conditions. This series was performed to compare the effects of antibodies toneurospecific protein S 100 and potentiated sample of the same antibodies. Theinfluence of combined (“bipathic”) treatment with these antibodies was studiedon the model of LTPTP in the hippocampus of animals. Experiments were performed on hippocampal slices from Wistar ratsweighing 180 299 g. Transverse hippocampal sections (400 m in width) wereplaced in a temperature controlled chamber at 35 37oC (Fig. 2.1). FlowYamamoto medium (Fig. 2.2) was aerated by carbogen (95% O2 and 5% CO2). 1 3 4 10 8 7 2 9 5 5 6Fig. 2.1. Scheme of an experimental chamber to study LTPTP in survivinghippocampal slices.The incubation medium is delivered from reservoir 1, passes successively through polyvinyl tubes 2,tap 3 (regulation and maintenance of the flow rate at 250 ml/min), and dropper 4 (prevention of airbubble formation in the system), and enters compartment 6 (heat capacity fluid). The constanttemperature of this fluid was maintained using thermostat 5. The incubation medium was deliveredthrough tube spirals in compartment 6, heated to a certain temperature, and entered chamber 7 (510 ml in volume). The medium outflowed from chamber 7 through water jet pump 8. Incubationchamber 7 was closed with cap 10. The fluid in chamber 7 was heated and aerated with carbogen,which contributed to water evaporation and carbon dioxide exchange between the medium and air.Cap 10 had the only hole above chamber 9 for the release of water vapor and CO2 that moistenedthe above chamber space and prevented a change in pH.34
  35. 35. Chapter 2. Three types of effects of ultralow dosesFig. 2.2. General view of an experimental device to study LTPTP in survivinghippocampal slices: chamber with a flow system, micromanipulators that carrycathode followers, preamplifiers, and stimulating and reference electrodes. Positionof electrodes is shown in Fig. 2.3.Evoked postsynaptic potentials (EPSP) were recorded after 40 60 minincubation. A stimulatory electrolytically sharpened bipolar wolfram electrodewas introduced into the zone of mossy fibers. A reference glass electrode (tipthickness 3 4 m, resistance 2 5 mO) was filled with 2.5 M NaCl and placed inCA3 region (initial segments of apical dendrites; Fig. 2.3). Testing was performed with single rectangular pulses (duration 200 msec)delivered at intervals of not less than 5 min. The amplitude of test stimuli varied СА1 СА2 СА3 !!!!!!!!!! !!!!! ! ! !! ! СА4 DF 1 2Fig. 2.3. Scheme for the position of a reference (1) and stimulating electrode (2)to study the dynamics of LTPTP in surviving hippocampal slices. CA1 4, fields ofthe Ammon’s horn (hippocampus); DF, dentate fascia. 35
  36. 36. Ultralow dosesfrom 10 to 30 V. EPSP were recorded on a 12 digit analog to digital converter(Digidata, Axon Instruments Inc.). The results were analyzed on a computerwith pClamp 6 (Axon Instruments Inc.) and Microcal Origin softwares. To induce LTPTP, the amplitude of a test stimulus was selected so thatthe response corresponded to 50% of the maximum value. Tetanization wasproduced by three consecutive series of stimulation at 200 Hz. The length ofeach series was 1 sec. Stimulation was applied at 2 sec intervals. The procedureof tetanization was repeated after 10 min. EPSP were recorded for at least 40min after the first tetanization, which allowed us to make a conclusion aboutthe induction or absence of LTPTP. A significant increase in the amplitude ofEPSP (by 1.5 2 times), which persisted for at least 20 min after the secondtetanization, served as a criterion for the induction of potentiation. The effect of antibodies to S 100 protein was studied as follows.Tetanization was induced in one or two slices of each series. Furtherexperiments with slices of this series were performed only after the induction ofLTPTP. All slices were maintained in the incubation medium after addition ofa specified amount of antibodies or reference solutions. The initial latency ofeffect was considered to be 20 min (according to D. Levis and T. Teyler). Theeffect of antiserum to neurospecific protein S 100 on the induction of LTPTPin rat hippocampal slices was described previously (D. Levis et al., 1986). Thenthe period of incubation was selected experimentally. After study of eachdilution, the chamber was repeatedly washed with distilled water and ethylalcohol and completely dried with compressed air. The indication of LTPTP is characterized by a significant increase in theamplitude of EPSP in synapses of mossy fibers in the hippocampal dentatefascia in response to the test stimulus after tetanization (Fig. 2.4). Twenty minute incubation with antiserum to neurospecific protein S 100(anti S100, final dilution 1:50) completely inhibited the induction of LTPTP mV 5 1 0 2 0 5 10 15 20 Time, μsecFig. 2.4. Dynamics of EPSP in CA3 region of the Ammon’s horn during extracellularrecording. Amplitude of the test stimulus is 20 V. (1) Before and (2) 10 min aftertetanization.36
  37. 37. Chapter 2. Three types of effects of ultralow doses(Fig. 2.5), which is consistent with the results of previous experiments. Highdilution of antiserum in our experiments is related to differences in the titer ofantibodies at various laboratories. Nonimmune rabbit antiserum at the same dilution had no effect onLTPTP induction in rat hippocampal slices (Fig. 2.6). Incubation of slices withethanol at a concentration present in potentiated preparations (similar dilution)did not impair the induction of LTPTP in slices (Fig. 2.7). To study the combined effect of test samples, anti S100 and itspotentiated form were added simultaneously to the incubation medium. Thistreatment completely blocked the induction of LTPTP in slices. It should beemphasized that combined administration of these substances did not abolish mV 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7Fig. 2.5. Effect of anti S100 on the induction of LTPTP in hippocampal slices.Ordinate, amplitude of EPSP. (1) Before treatment with anti S100; (2 5) over 20min after treatment with anti S100 (5 7 min interval); and (6, 7) 7 and 12 min afterthe second tetanization, respectively. Amplitude of the test stimulus is 30 V. 1.0 0.8 0.6 0.4 0.2 0.0 1 2 3 4 5 6Fig. 2.6. Induction of LTPTP in the presence of nonimmune rabbit serum. Dilution1:50. Ordinate: average amplitude of EPSP. (1) After 10 min incubation in nonimmune serum; (2, 3) 5 and 10 min the first tetanization, respectively; and (4 6)over 20 min after the second tetanization. Amplitude of the test stimulus is 12 V. 37
  38. 38. Ultralow doses 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 5Fig. 2.7. Induction of LTPTP after addition of 40 ml 40% ethanol. Volume of anexperimental chamber is 10 m. Ordinate: average amplitude of EPSP. (1, 2) 20 minincubation in Yamamoto medium after addition of ethanol; (3) 10 min after thefirst tetanization; and (4, 5) 10 and 30 min after the second tetanization,respectively. Amplitude of the test stimulus is 15 V.the effect of anti S100. Similar results were obtained after 10 min preincubationof the slice with potentiated anti S100, further addition of anti S100, and 20min incubation in a solution of both substances. The effect of anti S100 was abolished after 20 min preincubation of slicesin a solution of potentiated anti S100 (concentration 10 12) and 20 minincubation in a solution of native and potentiated antiserum. Hence, theinduction of LTPTP in slices was similar to that in control samples not exposedto antibodies (Figs. 2.8 and 2.9). It could be suggested that the effect of native anti S100 is abolished due to longterm incubation of the slice with an ethanol containing solution of the potentiated form,which results in modulation of the membrane state and/or impairment of antibody antigenbinding. The next series was performed to test this hypothesis. Preincubation was performedin an ethanol solution, whose concentration did not differ from that in potentiated antiS100. Other manipulations were similar to those in the previous series. Under theseconditions, anti S100 retained the ability to block the induction of LTPTP. These data show that nonimmune serum and 40% ethanol did not prevent theinduction of LTPTP. The inhibition of LTPTP was observed only in anti S100 solutions.Preincubation with potentiated anti S100 for 20 min abolished the inhibition of LTPTP byanti S100. This procedure did not prevent a normal reaction of the hippocampal CA3region, which had a potentiating effect on synaptic effectiveness. A study of the model of LTPTP provides strong evidence for thephenomenon of bipathy. The experiment had unexpected consequences. Indiscussing the results of this research, we hypothesized that activated antibodiesexhibit inexplicable “pro antigenic” activity. T. M. Vorob’eva and M. B. Shtarkdid not exclude this possibility. However, it was necessary to confirm ourhypothesis. Studies with potentiated antibodies to various neurotropic38
  39. 39. Chapter 2. Three types of effects of ultralow dosesmV a1.00.80.6 Fig. 2.8. “Bipathic effect”. (a) Induction of LTPTP in the0.4 presence of anti S100 (final dilution 1:50): (1 3) incubation in Yamamoto0.2 medium with anti S100 for 20 min, interstimulus interval 5 7 min; (4 6)0.0 10 min after the first tetanization, 3 1 2 3 4 5 6 7 8 4 min intervals; and (7, 8) 10 and 25 min after the second tetanization,mV b respectively. Amplitude of the test1.4 stimulus is 12 V. (b) Induction of LTPTP in the1.2 presence of potentiated anti S100 at1.0 a concentration of 10–12 (40 mmol): (1 3) incubation in Yamamoto0.8 medium with potentiated anti S100 (10 12) for 20 min, interstimulus0.6 interval 5 7 min; (4 6) over 10 min0.4 after the first tetanization, 3 4 min intervals; and (7 11) over 30 min0.2 after the second tetanization, 5 7 min intervals. Amplitude of the test0.0 1 2 3 4 5 6 7 8 9 10 11 stimulus is 20 V. (c) Induction of LTPTP in the premV c sence of anti S100 at a concentra tion of 10—12 (40 mmol) and dilution2.0 1:50: (1 3) incubation in Yamamoto medium with potentiated anti S100 at a concentration of 10–12 for 201.5 min, interstimulus interval 10 min; (4 6) incubation with potentiated1.0 anti S100 for 20 min, 5 7 min intervals; (7 10) over 10 min after first tetanization, 2 3 min intervals;0.5 and (11 21) over 40 min after the second tetanization, 3 5 min0.0 intervals. Amplitude of the test 5 10 15 20 stimulus is 10 V.substances, including morphine, delta sleep inducing peptide, histamine, andserotonin, were performed in Kharkov and Novosibirsk. These investigationssupported our hypothesis. Under various conditions, potentiated antibodies andantigen had “codirectional” activity. It became obvious that this is a newimmunological phenomenon. In standard immunological reactions, binding ofantibodies to the complementary antigen is followed by the inhibition of its 39
  40. 40. Ultralow doses V, mV 0.7 0.6 0.4 0.2 0.0 1 2 3 4 5 6 7Fig. 2.9. “Bipathic effect: induction of LTPTP under “bipathic” conditions: (1, 2)20 min preincubation with potentiated anti S100 (10 –12); (3, 4) incubation withnative anti S100; (5) after the first tetanization; and (6, 7) 5 and 10 min after thesecond tetanization, respectively.activity. By contrast, antibodies in ultralow doses modify the activity of thisantigen. We asked T. M. Vorob’eva to perform the next series of experiments.Several pairs of potentiated antibodies and antigen (S 100 protein andantibodies to S 100 protein; morphine and antibodies to morphine; delta sleepinducing peptide and antibodies to delta sleep inducing peptide; etc.) werestudied on the model of behavior and brain self stimulation. It was shown thatpsychotropic activity of antibodies in ultralow doses is higher than that ofantigen in ultralow doses. It should be emphasized that during this period the author of thismonograph was not familiar with immunology. Similarly to the phenomenonof bipathy, we assumed that there is a mediator between activated antibodiesand antigens (endogenous molecules, i.e., S 100 protein) in the organism. I.P. Ashmarin and I. S. Freidlin hypothesized that the so called naturalantibodies have regulatory functions (I. P. Ashmarin et al., 1989). Thishypothesis developed the theory of a famous immunologist Pierre Grabarabout the physiological role of autoantibodies (P. N. Grabar, 1969). Undernormal conditions, nearly all molecules in the organism have “predetermined”antibodies in very low physiological concentrations. These antibodies exhibitaffinity for the corresponding antigens and stabilize, but not inhibit theiractivity. We suggested that natural antibodies serve as a target for activatedantibodies in the organism. The effect of antibodies in ultralow doses inmediated by a change in physiological functions of predetermined antibodies(“regulation of regulator”). Scientific collaboration between the Institute of Molecular Biology andBiophysics (Siberian Division of the Russian Academy of Medical Sciences),40
  41. 41. Chapter 2. Three types of effects of ultralow dosesUkrainian Institute of Neurology and Psychiatry, and “Materia MedicaHolding” Research and Production Company resulted in the development ofthree medical products with activated antibodies of a new class (Proprotein 100,Anar, and Tenoten). An antialcohol drug Proprotein 100 contains antibodies toS 100 at dilution C1000. This is the first drug of a new pharmacological class.Tenoten and Tenoten for children were synthesized from activated antibodies toS 100 protein in other doses. They have a wide range of pharmacologicalactivity. Anar is a drug for the therapy of opium withdrawal syndrome, whichcontains ultralow doses of antibodies to morphine. The discovery of a new immunological phenomenon in 1998 wasaccidental. However, this discovery was associated with the results of previousstudies with ultralow doses. The phenomenon of bipathy was historicallypreceded by isopathy. However, it was impossible to foresee new properties ofpotentiated antibodies. Before 1998, there was only one historic “junction”between ultralow doses and immunology. J. Benveniste showed that anti IgEantiserum causes degranulation of basophils (E. Danevas et al., 1099). It couldbe suggested that treatment with anti IgE in ultralow and normal dose causesthe same physiological phenomenon. However, new properties of activatedantibodies were not revealed due to technical reasons. These studies should beperformed on another experimental model (i.e., monospecific antibodies).Moreover, the phenomenon of bipathy should form the basis for a newideology. After “accidental contact” with immunology, we studied the basicprinciples of this relatively young and rapidly developing area of biology andmedicine. It was unexpected that homeopathy and immunology have commonroots. Biologically, homeopathy is based on individual sensitivity. The immunesystem maintains the individual and genetically determined integrity in anorganism. The knowledge of homeopathy and results of studying the biologicalactivity of ultralow doses provide new insight into physiological functions of theimmune system (see Chapter 4). It became evident that preparations of antibodies should bedeveloped only by qualified pharmacologists. Rational scientists express skepticism about ultralow doses. We are grateful to E. D. Gol’dberg (Academicianof the Russian Academy of Medical Sciences) and A. M. Dygai (Academicianof the Russian Academy of Medical Sciences) from the Institute of Pharmacology (Tomsk Institute of Pharmacology, Siberian Division of the RussianAcademy of Medical Sciences). Despite dogmatic statements, our collaborativestudies of ultralow doses were initiated 9 years ago. The Tomsk Institute ofPharmacology is equipped with specialized laboratories for a variety of pharmacological investigations. The collaborative study yielded high value results. Agroup of medical products from activated antibodies was developed. 41

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