How amytal changed psychopharmacy: off-label uses of sodium amytal (1920-40).

In the early 1930s, American neurologist and psychiatrist William Bleckwenn used sodium amytal to render catatonic patients responsive, so that he could engage in talk therapy. Bleckwenn found a new, 'off-label' use for this anaesthetic and anxiolytic medication in psychiatry and, in doing so, allowed for important discoveries in the diagnosis and treatment of catatonia. Pharmacological textbooks reveal a 'label', while the Index-Catalogue of the Library of the Surgeon-General's Office reveals explorations 'off label' of barbiturates. The 'off-label' use of barbiturates facilitated talk therapy, heralding an important shift in psychopharmacy. Drugs previously only used as chemical restraints became a form of treatment for specific psychiatric diseases. The current strictures against off-label prescribing are overprescriptive and close off innovative new uses.

Pioneering early Intensive Care Medicine by the 'Scandinavian Method' of treatment for severe acute barbiturate poisoning.

Between the 1920s and the mid-1950s, barbiturates were the sedative-hypnotic agents most used in clinical practice. Their ready availability and narrow therapeutic margin accounted for disturbingly high rates of acute poisoning, whether suicidal or accidental. Until the late 1940s, medical treatment was relatively ineffective, with mortality subsequently high - not only from the effects of coma, respiratory depression and cardiovascular shock with renal impairment, but also from complications of the heavy use in the 1930s and 1940s of analeptic stimulating agents. Incidence of barbiturate intoxication increased substantially following World War II and this paper details development of what became known as the 'Scandinavian Method' of treatment, which contributed substantially to the earliest establishment of intensive care units and to the practice and methods of intensive care medicine. Three names stand out for the pioneering of this treatment. Successively, psychiatrist, Aage Kirkegaard, for introducing effective anti-shock fluid therapy; anaesthetist, Eric Nilsson, for introducing anaesthesiologic principles, including manual intermittent positive pressure ventilation into management; and, psychiatrist, Carl Clemmesen, for introducing centralisation of seriously poisoned patients in a dedicated unit. Clemmesen's Intoxication Unit opened at the Bispebjerg Hospital, Copenhagen, on 1 October 1949. ICU pioneer Bjørn Ibsen suggested it was the initial ICU, while noting that it supplied Intensive Therapy for one type of disorder only (as had HCA Lassen's Blegdam Hospital unit for Denmark's 1952 to 1953 polio epidemic). Treatment for barbiturate poisoning during the 1950s in some other Scandinavian hospitals will also be considered briefly.

[On the history of barbiturates]. / Pionerer bag barbituraterne.

Throughout the history of humanity, numerous therapeutic agents have been employed for their sedative and hypnotic properties such as opium, henbane (Hyoscyamus niger) and deadly nightshade (Atropa belladonna), but also alcohol and wine. In the 19th century potassium bromide was introduced as a sedative - and antiepileptic drug and chloral hydrate as sedative-hypnotics. A new era was reached by the introduction of barbiturates. The story started with the chemist Adolf von Baeyer. His breakthrough in the synthesis of new agents as barbituric acid and indigo and his education of young chemists was of great importance for the science of organic chemistry and the development of the dye and medicine industry in the late 19th century. The next important step was the development of barbiturates. The pioneers were Josef von Mering and Emil Fischer. Using the Grimaux-method they synthesized various barbiturates. It was von Mering who got the idea of introducing ethyl groups in the inactive barbituric acid to obtain sedatives, but the synthesis was succeeded by the chemist Emil Fischer. Experiments with dogs clearly showed sedative and hypnotic effect of the barbiturates and the oral administration of barbital (Veronal) confirmed the effect in humans. Barbital was commercialized in 1903 and in 1911 phenobarbital (Luminal) was introduced in the clinic, and this drug showed hypnotic and antiepileptic effects. Thereafter a lot of new barbiturates appeared. Dangerous properties of the drugs were recognized as abuse, addiction, and poisoning. An optimum treatment of acute barbiturate intoxication was obtained by the "Scandinavian method", which was developed in the Poison Centre of the Bispebjerg Hospital in Copenhagen. The centre was established by Carl Clemmesen in 1949 and the intensive care treatment reduced the mortality of the admitted persons from 20% to less than 2%. To-day only a few barbiturates are used in connection with anaesthesia and for the treatment of epilepsy, and chemists are focusing on drugs with more selective effects.

How theories evolved concerning the mechanism of action of barbiturates.

The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ-aminobutyric acid (GABA) on GABA(A) receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABA(A) receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the ß3 GABA(A) -receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent as a GABA(A) -receptor modulator than pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABA(A) receptors (possibly including extrasynaptic receptors containing δ subunits); and reduced activity at other ion channel targets, including voltage-gated calcium channels. In recent years, substantial progress has been made in defining the structural features of GABA(A) receptors responsible for gating and allosteric modulation by drugs. Although the precise sites of action of barbiturates have not yet been defined, the second and third transmembrane domains of the ß subunit appear to be critical; binding may involve a pocket formed by ß-subunit methionine 286 as well as α-subunit methionine 236. In addition to effects on GABA(A) receptors, barbiturates block AMPA/kainate receptors, and they inhibit glutamate release through an effect on P/Q-type high-voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities. Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents.

Early drug discovery and the rise of pharmaceutical chemistry.

Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history.

Liquor made quicker: alcohol as a synthetic reagent for molecules in anesthesia.

Ethanol was an early anesthetic, and chemists transformed it into better ones. Hypnotic/anesthetic/analgesic molecules prepared from ethanol include barbiturates, benzocaine, chloral hydrate, chloroform, diethyl ether, ethyl chloride, ethylene, etomidate, meperidine, paraldehyde, phenacetin, procaine, tribromoethanol, and urethane. Ethanol was sometimes mixed deliberately with the other anesthetics, and John Snow's inhaled amylene came from the "fusel oil" fraction of rotgut whisky.

From King Kong pills to mother's little helpers--career cycles of two families of psychotropic drugs: the barbiturates and benzodiazepines.

This article compares the careers of two families of 20th-century psychotropic drugs, the barbiturates and the benzodiazepines, in five different countries. Both families of drugs were used as so-called hypnotics and sedatives, and later as minor tranquillizers. In addition these drugs were extensively used as self-medication. The careers show a cyclical temporal course and generally encompass three phases: first, an expanding use of the drugs, accompanied by high expectations; then, rising criticism and disappointment; and finally contracting use and limited application. These phases need not have been sequential: they often overlapped. The cycle sometimes ended by the disappearance of the drug from mental health care, only to be replaced by new drugs with a profile of promise and hope. These cycles, which we term Seige cycles, are generally typical for the careers of psychotropic drugs. The analytical concept of the Seige cycle facilitates a comparative perspective on the commonalities as well as the differences between the various drug careers under consideration.

[A century of barbiturates in neurology]. / Un siglo de barbitúricos en neurologia.

INTRODUCTION AND AIMS: Until the early 20th century, pharmacological treatments for neurological disorders were scarce and inefficient; only bromides stood out as sedating and antiepileptic agents. DEVELOPMENT: The introduction of barbiturates for clinical use in 1904 heralded the beginning of a new age in the pharmacological management of certain neurological pathologies. In this study, we analyse the historical process of the discovery and use of barbiturates in the field of neurology, from the moment it was started by von Baeyer in 1864, with the synthesis of malonylurea, up to the period of the decline of barbiturate therapy in the 1960s. In 1903, von Mering and Fischer discovered the hypnotic properties of barbital and later synthesised phenobarbital (1911). In the years that followed a number of barbiturates, such as butobarbital, amobarbital, secobarbital, pentobarbital, thiopental, and so on, were gradually incorporated into the therapeutic arsenal. During this period, the different therapeutic uses of barbiturates in neurology were analysed, from their traditional use as hypnotic agents (von Husen) to the discovery of the anticonvulsant properties of phenobarbital (Hauptmann) and its use in the treatment of epilepsy. CONCLUSIONS: The barbiturates were one of the first pharmacological tools that proved to be really effective in the management of some neurological disorders. Nevertheless, problems associated with their safety (dependence phenomena and deaths from overdoses), together with the introduction of numerous psychopharmacological agents in the 1950s, ended up eclipsing the use of barbiturates, except for a few very specific cases in which they are still indicated.

Analeptic use in clinical toxicology: a historical appraisal.

BACKGROUND: The introduction and increasing popularity of the barbiturates during the first two decades of the 20th century was associated with a new life threatening toxicological problem: the barbiturate overdose. METHODS: This paper reviews the four major phases of analeptic use. As interest in the principles of physiologic antagonism between stimulants and depressants grew, analeptic agents were increasingly used to treat the obtundation and respiratory depression of barbiturate overdose. At first, naturally occurring stimulants such as camphor, strychnine, picrotoxin, and caffeine were used in desperate attempts to awaken patients. During the 1930s, and continuing at some centers into the 1960s, an increasing number of synthetic analeptics agents such as nikethamide, pentylenetetrazol, bemegride, amphetamine, and methylphenidate were enthusiastically recommended as barbiturate antidotes, often at very high doses. Unfortunately, utilizing generous amounts of multiple convulsants was not without its share of complications. Using this analeptic strategy the mortality rate after moderate to severe barbiturate overdose remained as high as 45%. Beginning in the mid-1940s a group of Scandinavian physicians pioneered a revolutionary approach to sedativehypnotic overdose that rejected the use of analeptics and relied on respiratory ventilation and supportive care. CONCLUSIONS: Although barbiturate overdose mortality decreased to less than 1% using this strategy, it would take another 20 years before this technique was universally adapted. While analeptic therapies for the treatment of drug overdose have now been abandoned, one of these analeptics, methylphenidate, currently enjoys wide use in the treatment of attention deficit hyperactivity disorder.

Breve história dos hipnoindutores: dos barbituratos aos hipnóticos de terceira geraçäo / Short history of hypnotics: from barbiturates to third-generation hypnotics

A Psicofarmacologia ainda busca hipnótico ideal. No entanto, observa-se evoluçäo desde os antigos babitúricos à nova geraçäo de hipnáticos. Entre esses dois tipos de substâncias se encontram as Benzodiazepinas (segunda geraçäo), compostos que servem de modelo farmacológico aos novos hipnóticos. Este artigo mostra algumas diferenças essenciais entre as Benzodiazepinas e hipnóticos de terceira geraçäo (Imidazopiridina e Ciclopirrolona). Os ensaios de laboratórios e clínico demonstram real avanço com os novos hipnóticos.

Historical aspects and applications of barbituric acid derivatives. A review.

This review considers the pharmacological and other applications of barbituric and 2-thiobarbituric acid derivatives. A chronological description about the discovery, structural studies and first clinical assays are given. Therapeutic expectations as anticonvulsant, antimicrobial, spasmolytic, antiinflammatory, antitumoral and some other effects of 5,5-disubstituted barbituric acids and alkylidene- or arylidenebarbituric acids are overviewed. A considerable amount of these types of compounds have been proposed as industrial dyes and pigments, photosensitizers and thermosensitive materials.