Getting the dose-response wrong: why hormesis became marginalized and the threshold model accepted.

The dose-response relationship is central to the biological and biomedical sciences. During the early decades of the twentieth century consensus emerged that the most fundamental dose-response relationship was the threshold model, upon which scientific, health and medical research/clinical practices have been based. This paper documents that the scientific community made a fundamental error on the nature of the dose response in accepting the threshold model and in rejecting the hormetic-biphasic model, principally due to conflicts with homeopathy. Not only does this paper detail the underlying factors leading to this dose response decision, but it reveals that the scientific community never validated the threshold model throughout the twentieth century. Recent findings indicate that the threshold model poorly predicts responses in the low dose zone whereas its dose response "rival", the hormesis model, has performed very well. This analysis challenges a key foundation upon which biological, biomedical and clinical science rest.

Historical blunders: how toxicology got the dose-response relationship half right.

Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses.

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

Pharmacodynamic principles of homeopathy.

Homeopathy was already known to Hippocrates and further studied by Hahnemann. However, since the discovery of the medical effects of digitalis by William Withering around 1785, and the first synthesis of an organic molecule, urea, by Friedrich Wöhler in 1828, and through the further rapid evolution of modern pharmacological chemistry and molecular biology, it has gradually been abandoned as a serious therapeutic alternative to allopathy by most practitioners of scientifically founded medicine. Because a credible scientific explanation for its mode of action has been lacking, homeopathy is regarded by many medical researchers and scientists as, at best, placebo therapy, in spite of the fact that for centuries hosts of patients have testified to its effects. It is suggested that the gulf between homeopathy and allopathy can be reconciled if one takes into consideration modern knowledge of physiology, biochemistry and the physical properties of the water used in the potentiation process. A description of the mechanisms occurring during potentiation, both inside and outside a live mammalian organism, is presented.

An integrated approach to the pharmacological evaluation of traditional materia medica.

A triple-tiered working model is projected for the pharmacological evaluation of crude drugs prescribed in traditional medical practices. Of the proposed component tests and procedures, the majority have had their usefulness already validated in natural product pharmacological research. First-level investigations (herbalist consultations/professional attestations, hippocratic screening and literature surveys) provide first-hand pharmacological information about traditional materia medica. Second-level investigation comprising bioassay-modelled tests (brine shrimp toxicity test, opiate receptor-binding studies, fertilized sea urchin egg test, platelet adenyl cyclase/phosphodiesterase assays, hexobarbital-induced sleeping time test, antimicrobial assays, isolated guinea pig ileum test and pharmacodynamic screening) are designed to extend the mode(s) of drug action suggested by the first-level procedures. Based on data from Level 1 and Level 2 findings, third-level experiments are specific tests tailored to confirm the pharmacodynamic/kinetic properties and clinical efficacy of traditional drugs. Level 2 and Level 3 tests may be combined in monitoring fractionations and subsequent isolation of unique crude drug constituents with potential application in conventional therapeutics.

[Alternative and natural science therapy forms: incompatible contrast]. / Alternative und naturwissenschaftliche Therapieformen: Unvereinbare Gegensätze.

In spite of the accomplishments of science-oriented medicine, we are still confronted with a multitude of "alternative" or "complementary" therapies which claim to heal "holistically" without adverse effects. Common to alternative treatment methods, which are several or many centuries old, is the notion that a special force ("vis vitalis", "entelechy", "spiritual bioforce", etc.) is responsible for life that, ultimately, cannot be investigated. According to this perception, which is termed "vitalism", diseases are a result of changes in the immaterial force of life. Therefore, treatments have to be directed at this central regulator ("regulatory therapy"). The medicine that is based on the natural sciences, in contrast, presumes that all expressions of life including diseases are amenable to critical and rational analysis. According to this school of thought, a causal therapy can be derived only from a detailed knowledge of the various body functions down to the molecular level and the effects of drugs on these functions. Corresponding therapeutic theories have to be verified or falsified experimentally, excluding bias as much as possible. Using such "objective" methods, a statistical assessment of the beneficial and adverse effects of a treatment may be possible ("evidence-based medicine"). In the final analysis, an incompatibility of scientific concepts is at the heart of the controversy between alternative treatment methods and the medicine based on natural sciences.

[Gutiérrez Bueno (1745-1822), textbooks and a new public for chemistry in the last third of the 18th century]. / Pedro Gutiérrez Bueno (1745-1822), los libros de texto y los nuevos pùblicos de la química en el último tercio del siglo XVIII.

This paper is a part of a general research project on the role that chemistry played in the transition of materia medica to experimental pharmacology during 19th century Spain. Within this general framework, the paper deals with the main characteristics of Spanish textbooks aimed at pharmaceutical and medical students. In a former study, published in this journal, we outlined the institutional context in which these books were read, written and published. Some of these issues are developed in the present paper through analysis of the "Curso de química" written by Pedro Gutiérrez Bueno. New light is shed on the public for chemistry during the late XVIII century Spain and their role in shaping the contents and organisation of chemistry textbooks.

[Laqueur and Organon. The university laboratory and the pharmaceutical industry in the Netherlands]. / Laqueur en Organon. Het universitaire laboratorium en de farmaceutische industrie in Nederland.

Since the 1970s cooperation between universities and pharmaceutical firms is business as usual. This has not always been the case. The first alliances between academic scientists and the pharmaceutical industry can be traced back to the 1920s. Compared to the U.S. and most other European countries, the creation of networks between the Dutch academy and industry shows a rather peculiar pattern that is illustrative in clarifying how the relationships between scientists and the pharmaceutical companies were built. Dutch scientists could not ally themselves with the pharmaceutical industry, simply because no Dutch pharmaceutical company specialized in organpreparations existed prior to the 1920s. This situation forced scientists to opt for the strongest form of alliance they could create, namely to take part in the founding of a pharmaceutical company. Ernst Laqueur, a professor in pharmacology at the University of Amsterdam, was one of the three founders of Organon, the Dutch pharmaceutical firm that was founded in 1923. Based on an analysis of the early history of sex endocrinology, this paper examines the creation of networks between Laqueur and Organon. The paper concludes that the university laboratory played a crucial role in the development of Organon. Organon was dependent on Laqueurs laboratory for the provision of the required biological essay techniques in order to manufacture standardized hormone products, Moreover, Laqueur mediated all the contacts between Organon and the clinic, required for the clinical testing of hormones and the provision of raw materials for the making of hormones into chemicals and drugs.

Rebound effect of modern drugs: serious adverse event unknown by health professionals.

OBJECTIVE: Supported in the Hippocratic aphorism primum non nocere, the bioethical principle of non-maleficence pray that the medical act cause the least damage or injury to the health of the patient, leaving it to the doctor to assess the risks of a particular therapy through knowledge of possible adverse events of drugs. Among these, the rebound effect represents a common side effect to numerous classes of modern drugs, may cause serious and fatal disorders in patients. This review aims to clarify the health professionals on clinical and epidemiological aspects of rebound phenomenon. METHODS: A qualitative, exploratory and bibliographic review was held in the PubMed database using the keywords 'rebound', 'withdrawal', 'paradoxical', 'acetylsalicylic acid', 'anti-inflammatory', 'bronchodilator', 'antidepressant', 'statin', 'proton pump inhibitor' and 'bisphosphonate'. RESULTS: The rebound effect occurs after discontinuation of numerous classes of drugs that act contrary to the disease disorders, exacerbating them at levels above those prior to treatment. Regardless of the disease, the drug and duration of treatment, the phenomenon manifests itself in a small proportion of susceptible individuals. However, it may cause serious and fatal adverse events should be considered a public health problem in view of the enormous consumption of drugs by population. CONCLUSION: Bringing together a growing and unquestionable body of evidence, the physician needs to have knowledge of the consequences of the rebound effect and how to minimize it, increasing safety in the management of modern drugs. On the other hand, this rebound can be used in a curative way, broadening the spectrum of the modern therapeutics.

Hormesis: Toxicological foundations and role in aging research.

The field of toxicology adopted the threshold dose response in the early decades of the 20th century. The model was rapidly incorporated into governmental regulatory assessment procedures and became a central feature of chemical evaluation and assessment. The toxicological community never validated the capacity of this model to make accurate predictions throughout the remainder of the 20th century. A series of recent investigations have demonstrated that the threshold and linear dose response model failed to make accurate predictions in the low dose zone. Such findings demonstrate a profound failure by the toxicology community on the central pillar of its discipline and one with profound public health, medical and economic implications. Ironically, the hormetic dose response, which was rejected by the toxicology community during the early decades of the 20th century, accurately predicted responses in the low dose zone in the same three large-scale validation assessments. Within the past two decades hormetic dose responses have been frequently reported in the experimental biogerontology literature, associated with endpoints associated enhancing healthy aging and longevity. The low dose stimulatory response of the hormetic dose response model represents the quantification of enhanced biological performance in the experimental facilitation of aging quality via multiple endpoints and mechanisms and in the extension of lifespan in such animal models research.

Fundamentação científica do princípio de cura homeopático na farmacologia moderna / Scientific basis of the homeopathic healing principle in modern pharmacology

INTRODUÇÃO: O modelo homeopático de tratamento utiliza o ‘princípio dos semelhantes’ como método terapêutico, administrando medicamentos que causam determinados sintomas em indivíduos sadios para tratar sintomas semelhantes em indivíduos doentes (similia similibus curantur), com o intuito de despertar uma reação secundária e curativa do organismo contra os seus próprios distúrbios. Essa reação secundária (vital, homeostática ou paradoxal) do organismo está embasada no ‘efeito rebote’ dos fármacos modernos, evento adverso observado após a descontinuação de diversas classes de drogas que utilizam o ‘princípio dos contrários’ (contraria contrariis curantur) como método terapêutico...

INTRODUCTION: Homeopathy employs the so-called ‘principle of similars’as therapeutic method, which consists in administering medicines thatcause certain symptoms in healthy individuals to treat similar symptomsin sick individuals (similia similibus curantur) to arouse a secondaryand healing reaction by the body against its own disorders. Thissecondary (vital, homeostatic or paradoxical) reaction of the body isbased on the ‘rebound effect’ of modern drugs, a type of adverseevent that occurs following discontinuation of several classes of drugsprescribed according to the ‘principle of contraries’ (contraria contrariiscurantur)....

Scientific basis of the homeopathic healing principle in modern harmacology

BACKGROUND: Homeopathy employs the so-called ‘principle of similars’ as therapeutic method - which consists in administering medicines that cause certain symptoms in healthy individuals to treat similar symptoms in sick individuals (similia similibus curantur) - to induce a secondary and healing reaction by the body against its own disorders. This secondary (vital, homeostatic or paradoxical) reaction of the body is based on the ‘rebound effect’ of modern drugs, a type of adverse event that occurs following discontinuation of several classes of drugs prescribed according to the ‘principle of contraries’ (contraria contrariis curantur). AIM: The present review sought to scientifically substantiate the homeopathic healing principle vis-à-vis experimental and clinical pharmacology through a systematic study of the rebound effect of modern drugs or paradoxical reaction of the body. METHODS: Employing as reference studies and revisions on the subject published since 1998, we updated the data adding recent studies included in database PubMed. RESULTS: The rebound effect occurs after discontinuation of several classes of drugs with action contrary to the symptoms of diseases, exacerbating them to levels above the ones before treatment. [...]. Following the homeopathic premises, modern drugs might also be used according to the principle oftherapeutic similitude, thus employing the rebound effect (paradoxical reaction) with curative intent. CONCLUSIONS: Evidenced by hundreds of studies that attest to the similarityof concepts and manifestations, the rebound effect of modern drugs scientifically substantiates the principle of homeopathic cure. Although the rebound phenomenon is anadverse event studied by modern pharmacology, it is not known by health care professionals, thus depriving doctors of knowledge indispensable for safe management of drugs.

Fundamentação científica do princípio de cura homeopático na farmacologia moderna / Scientific basis of the principle of homeopathic cure in modern pharmacology

Introdução: O modelo homeopático de tratamento utiliza o ‘princípio dos semelhantes’ como método terapêutico, administrando medicamentos que causam determinados sintomas em indivíduos sadios para tratar sintomas semelhantes em indivíduos doentes (similia similibus curantur), com o intuito de despertar uma reação secundária e curativa do organismo contra os seus próprios distúrbios. Essa reação secundária (vital, homeostática ou paradoxal) do organismo está embasada no ‘efeito rebote’ dos fármacos modernos, evento adverso observado após a descontinuação de diversas classes de drogas que utilizam o ‘princípio dos contrários’ (contraria contrariis curantur) como métodoterapêutico. Objetivo: Esta revisão visa fundamentar cientificamente o princípio de cura homeopático perante a farmacologia clínica e experimental, através do estudo sistemático do efeito rebote dos fármacos modernos ou reação paradoxal do organismo. Métodos: Empregando como fonte de referência os estudos e revisões sobre o tema que vimos publicando desde 1998, atualizamos os dados acrescentando pesquisas recentes citadasna base de dados PubMed. Resultados: O efeito rebote ocorre após a descontinuação de inúmeras classes de fármacos com ação terapêutica contrária aos sintomas das doenças, exacerbando-os a níveis superiores aos anteriores do tratamento. Independente da doença, da droga, da dose e da duração do tratamento, o fenômeno rebote se manifesta numa pequena proporção de indivíduos suscetíveis. Seguindo as premissas homeopáticas, osfármacos modernos também podem ser utilizados segundo o princípio da similitude terapêutica, empregando o efeito rebote (reação paradoxal) de forma curativa Conclusões: [...] Embora o fenômeno rebote seja um evento adversoestudado pela farmacologia moderna, ele não é conhecido pelos profissionais da saúde, privando a classe médica de um saber indispensável ao manejo seguro dos fármacos. (AU)

Introduction: Homeopathy employs the so-called ‘principle of similars’ as therapeutic method, which consists in administering medicines that cause certain symptoms in healthy individuals to treat similar symptoms in sick individuals (similia similibus curantur)to arouse a secondary and healing reaction by the body against its own disorders. This secondary (vital, homeostatic or paradoxical) reaction of the body is based on the ‘rebound effect’ of modern drugs, a type of adverse event that occurs following discontinuation of several classes of drugs prescribed according to the ‘principle of contraries’ (contraria contrariis curantur). Aim: The present review sought to scientifically substantiate the homeopathic healing principle vis-à-vis experimental and clinical pharmacology through a systematic study of the rebound effect of modern drugs or paradoxical reaction of the body. Methods: Employing as reference the studies and revisions on the subject that we have published since 1998, we updated the data adding recent studies cited in database PubMed. Results: The rebound effect occurs after discontinuation of several classes of drugs with contrary action to the symptoms of diseases, exacerbating them to levels above the ones present before treatment. Regardless of disease, drug, dose and duration of treatment, the rebound phenomenon manifests in a small proportion of susceptible individuals.[...] Conclusions: Evidenced in hundreds of studies that attest to the similarity of concepts and manifestations, the rebound effect of modern drugs scientifically substantiates the principle of homeopathic cure. Although the rebound phenomenon is an adverse event studied by modern pharmacology, it is not known by healthcare professionals, thus depriving doctors of knowledge indispensable for a safe management of drugs. (AU)