[A current view on the history of atypical antipsychotics]. / Sovremennyi vzgliad na istoriiu atipichnykh antipsikhoticheskikh sredstv.

Based on the analysis of the original literature, the author for the first time systemizes the data on the story of atypical antipsychotic drugs. The history of introduction of the first atypical neuroleptics - clozapine and sulpiride, which launched the dichotomic development of psychopharmacology of atypical antipsychotics, is described. Historical facts on the introduction into practice of different sulpiride- and clozapine-like neuroleptics as well as the relationship of their history with the elaboration of dopamine and serotonin hypotheses of mechanisms of action of antipsychotics are presented. The author analyzes the efficacy and tolerability of treatment with different atypical neuroleptics. An importance of evidence-based medicine principles in the history of atypical antipsychotics is described. A significance of the history of some atypical and typical (pericyazine) neuroleptics in the evolution of conceptions on the validity of evidence-based medicine in psychiatry is evaluated. Main stages in the history of typical and atypical antipsychotics are determined.

Neurosyphilis, malaria, and the discovery of antipsychotic agents.

Four of the most disabling human diseases are syphilis, malaria, schizophrenia, and manic-depressive illness. The history of the development of treatments for these seemingly unrelated disorders intersects at several points. Treatment of tertiary cerebral syphilis (general paresis) by inducing fever with malaria led to a Nobel Prize. Although attempts to synthesize quinine, a plant product effective against malaria, failed, these efforts encouraged industrial organic chemists to synthesize many useful substances, including dyes, antibiotics, and antihistamines. The aniline-derived dye methylene blue was a member of a new class of polycyclic chemicals, the phenothiazines. Efforts to modify phenothiazines to find an antimalarial agent also failed but led to novel antiemetic-sedative antihistamines, including promethazine, promazine, and eventually chlorpromazine--the first effective treatment for schizophrenia and mania. Chlorpromazine has antipsychotic and antimanic properties, and it revolutionized the therapeutics of psychotic illnesses.

History of the discovery and clinical introduction of chlorpromazine.

BACKGROUND: The historical process of discovery and clinical introduction of chlorpromazine, one of the greatest advances of 20th century medicine and history of psychiatry, is analyzed. METHODS: In this review, we have studied the original works of pioneers in the discovery and clinical use of chlorpromazine, as well as the contributions of prestigious researchers (historians, pharmacologists, psychiatrists, etc.) about this topic. RESULTS: The discovery of phenothiazines, the first family of antipsychotic agents has its origin in the development of German dye industry, at the end of the 19th century (Graebe, Liebermann, Bernthsen). Up to 1940 they were employed as antiseptics, antihelminthics and antimalarials (Ehrlich, Schulemann, Gilman). Finally, in the context of research on antihistaminic substances in France after World War II (Bovet, Halpern, Ducrot) the chlorpromazine was synthesized at Rhône-Poulenc Laboratories (Charpentier, Courvoisier, Koetschet) in December 1950. Its introduction in anaesthesiology, in the antishock area (lytic cocktails) and "artificial hibernation" techniques, is reviewed (Laborit), and its further psychiatric clinical introduction in 1952, with initial discrepancies between the Parisian Val-de-Grâce (Laborit, Hamon, Paraire) and Sainte-Anne (Delay, Deniker) hospital groups. The first North-American publications on chlorpromazine took place in 1954 (Lehmann, Winkelman, Bower). The introduction of chlorpromazine in the USA (SKF) was more difficult due to their strong psychoanalytic tradition. The consolidation of the neuroleptic therapy took place in 1955, thanks to a series of scientific events, which confirmed the antipsychotic efficacy of the chlorpromazine. CONCLUSIONS: The discovery of the antipsychotic properties of chlorpromazine in the 1950s was a fundamental event for the practice of psychiatry and for the genesis of the so-called "psychopharmacological revolution."

Cincuenta años de clorpromazina / Fifty years of chlorpromazine

Se analiza el descubrimiento del núcleo químico fenotiazínico, a partir de ciertos colorantes emparentados químicamente, en el contexto de la síntesis de la quinina a finales del siglo XIX. Las fenotiazinas fueron empleadas como antimaláricos inicialmente por Paul Ehrlich y, más tarde, como antihistamínicos por Daniel Bovet. Henry Laborit y Pierre Huguenard utilizan las fenotiazinas en anestesia para contrarrestar los efectos del "shock quirúrgico", lo que les conduce al hallazgo de la prometazina y de la clorpromazina, siendo ésta la primera sustancia, reconocida por Jean Delay y Pierre Deniker, que exibe propiedades antipsicóticas eficaces en el tratamiento de la esquizofrenia. Este espectacular hallazgo convierte en obsoletas la hibernación artificial, la cura gangliopléjica y las técnicas mediante la cura de sueño, el electroshock, la terapia cardiazólica o insulínica, o la lobotomía quirúrgica, y marca oficialmente el nacimiento de una nueva ciencia: la psicofarmacología. En sus orígenes fundacionales, se considera a la clorpromazina como el agente de la "lobotomía química" y la "insulina del sistema nervioso central" (AU)

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

Dyes, antipsychotic drugs, and antimicrobial activity. Fragments of a development, with special reference to the influence of Paul Ehrlich.

The history of phenothiazines, from methylene blue via chlorpromazine to recently synthesized isomeric derivatives of various neuroleptics, is reviewed in the light of their antimicrobial activity and Paul Ehrlich's receptor concept. The latter is clearly in line with most modern theories concerning drug action of stereo-isomeric compounds.

The early history of psychotherapeutic drugs.

The four most frequently used groups of drugs in psychiatric therapy are: neuroleptics, antidepressants, anxiolytics, and lithium salts. Their introduction came largely during the past 3 decades. This review summarizes the history of the research that led to their discovery and to the present concept of their modes of action.

[Neuroplegia: results of an interdisciplinary approach to its physiopathology]. / La neuroplégie: résultats d'une approche interdisciplinaire de la physio-pathologie

Neuroplegia was born from a physiopathological study of states of shock and research on inhibition of the autonomic reaction to aggression. Over the last 25 years, the experimental facts have become accumulated in favour of the first theory of H. Laborit, i.e. that this so-called defence reaction defended our lives only through conservation of motor activity in the environment. When this motor activity is inefficacious or useless, the neuroendocrine reaction may lead, during the acute phase, to states of shock and to chronic psychosomatic pathology. On this general theme, inhibition of this reaction by neuroplegic drugs, among which the phenothiazine derivatives have played a very important role, has led in numerous surgical and medical disciplines, to basic research and therapeutic consequences. Thus, in anesthetics, it was at the origin of potentialised anesthesia, then neuroleptanalgesia. In general intensive care, it is used in various ways in the study and treatment of states of shock. In psychiatry, it has initiated neuro-psychopharmacology and the neuro-physiological and biochemical study of the nervous system in its response to the psycho-social environment. It has found its place in anesthesia and in obstetric pathology. But above all, has led pharmacologists to the study of metabolic and biochemical activities. The result of an interdisciplinary approach, neuroplegia has on the contrary, often been the origin of an interdisciplinary development of our physiological and physiopathological knowledge. Today this development seems to better understand its mode of action at various levels of organisation of living systems. One may thus say that neuroplegia, apart from its therapeutic interest, has been a good working instrument and led to better understanding of numerous biological disciplines.