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BENZODIAZEPINES - HOW IT ALL STARTED
Two articles about Librium
The Librium Story
Dilip Ramchandani, MD
Director, Consultation/Liaison Service
Department of Psychiatry and Behavioral Science
Temple University Hospital
The development of the benzodiazepines was a landmark in modern psychopharmacology. Their discovery, however, was not accidental. Beginning at the turn of the century, the pharmaceutical industry, quite aware that there was profit to be made, had focused its efforts on the rapid development of "mood-altering" chemicals. The bromides and chloral hydrate had replaced the wonder drug of the 18th century, opium, on the grounds that it was too addictive. They were in turn replaced by the "safer" barbiturates in the 1930s. By the 1950s, however, the addictive potential of barbiturates was causing consternation. The advent of phenothiazines and Meprobamate (Miltown) sought to satisfy the increasing need for less addictive prescriptions to treat anxiety. Despite their tremendous success, it was apparent that the phenothiazines had too many side effects to warrant their uninhibited use in ambulatory patients, and meprobamate was often too weak. So the need for a drug with a mid-range potency between meprobamate and phenothiazines was great.
In 1954, therefore, in the New Jersey-based laboratories of Hoffmann-La Roche, Dr Leo Sternbach began to study a class of unexplored compounds, the benzheptoxdiazines, with which he had previously worked as a postdoctoral student in Poland. A chemist usually chooses one of several routes to seek new therapeutic agents, such as synthesizing drugs similar to naturally occurring medicinal products or modifying existing drugs to find compounds with greater usefulness. Another option is to develop a theory and apply compounds to test it or randomly screen chemicals for pharmacologically active and therapeutic effects.
Dr Sternbach decided to revisit compounds he had helped synthesize 20 years earlier but whose biological activity was unknown. He soon discovered that these compounds were not seven-membered rings as he had previously believed but were six-membered rings. Although he was able to derive 40 new compounds from them, all, unfortunately, proved pharmacologically inert. Finally, he decided to treat one of the derivatives with methylamine, a primary amine, and labeled the resulting white, crystalline water-soluble powder Ro 5-0690 but shelved it for later examination.
He forgot the compound until eighteen months later in 1957 when Sternbach's lab was being cleared up by an assistant. The assistant came upon this chemical and asked if it should be thrown away or be sent for screening. Sternbach thought for a moment and said it should be submitted to the pharmacological research laboratory at Roche for further evaluation.
In July of that year Sternbach received a report from Roche's head of pharmacology, Dr Lowell Randall, stating that "the substance has hypnotic, sedative, and antistrychnine effects in mice similar to meprobamate." It was also far more potent than meprobamate as a muscle relaxant in cats. Unlike the 40 inert quinazoline 3-oxide compounds that preceded it, this chemical, chlordiazepoxide, proved to be a 1,4-benzodiazepine with a seven-membered ring structure and great clinical potential.
This drug turned out to be the most active agent of the group and became known as Librium. Time was now ripe for clinical trials after more detailed pharmacological and toxicity studies had been performed. In 1958 the compound Ro 5-0690 (methaminodiazepoxide or chlordiazepoxide) was administered to geriatric patients in relatively large doses and found to be primarily sedating.
It also produced ataxia and slurred speech. As a result, interest in the drug diminished until Dr Irvin Cohen in Galveston, Texas and two other clinical investigators agreed to participate in clinical trials of the drug in their psychoneurotic patients who received office-based treatment. All three were impressed with the drug's anxiolytic action, which occurred without any accompanying clouding of consciousness or intellectual dysfunction. Toxicity was minimal, and the success of Phase III testing in thousands of patients in three settings (prison, clinic, and private office) led to its approval by the FDA in February 1960. A month later, it was marketed as Librium. The first clinical note on its therapeutic efficacy was published in the March 1960 issue of the Journal of the American Medical Association.
In 1963 Valium was introduced as a more potent tranquilizer. The third benzodiazepine, Serax, was introduced in June 1965. Despite the initial abandonment of chlordiazepoxide as a mere sedative, it became apparent, with persistent investigation, that drugs of its class reduced anxiety, complications of acute alcoholism, convulsive states, and muscular tension. Their use became universal, and newer varieties of benzodiazepines proliferated. At last count, there were 39 benzodiazepines available for a variety of clinical uses.
Librium: how it was almost not discovered
Professor Gerald Kerkut
Emeritus Professor of Neuroscience
University of Southampton
Benzodiazepines affect the GABA receptors, but unlike barbiturates, which take effect primarily at the level of the brain stem, they affect the subcortical nuclei. This implies that they have a tranquillising function with only minor influence on the cognitive functions and level of consciousness. They do not work primarily as sedatives, but they reduce the strength of incoming sensory stimuli: the effect is that the world around you seems to become more tranquil. The area of prescription is thus primarily as an anxiolytic.
Although it was initially thought that benzodiazepines were not addictive, they have since been shown to create dependence. The withdrawal symptoms are a consequence of their effect. If the chemical tranquillity around you is stopped by termination of use, you experience the situation as uneasy, which results in anxiety, etc. However, these are precisely the symptoms for which these drugs are prescribed, so that a vicious circle of dependence soon results.
The benzodiazepine drugs made millions and millions of dollars for the drug company Hoffman-La Roche; they were one of the best sellers; the winners in the drug lottery. And they could so easily have been thrown away in the lab clear out.
You win some; you lose some.
Dr Leo H Sternbach - Biographical Note
Dr Leo Sternbach
Leo H Sternbach was born in Abbazia, Austria on 7 May 1908 and spent his childhood in Austria and Poland. Educated during the First World War he also worked in his father's pharmacy. After receiving his degree in pharmacy from Jagiellonian University in Krakow, he enrolled in a PhD program in organic chemistry and studied potential dyes and synthesised several substances known as 'heptoxdiazines'. As a result of intensifying anti-Semitism, he left Poland and went to Vienna, where he worked with Pauli and Fränkel, and then to Zürich to work with Ruzicka at the Swiss Federal Institute. After beginning work with Hoffmann-La Roche in Basel and marrying Herta Kreuzer. Fearful of Nazi invasion, in 1941 Hoffman-La Roche shipped its Jewish scientists, including Leo Sternbach, from Switzerland to the United States, where Sternbach continued work with the company in Nutley, New Jersey and began a search for new tranquillisers. Sternbach recalls that he was instructed to terminate his study of benzodiazepines but continued the research unofficially, which led to his significant discoveries of Librium, Valium, and other related drugs. Leo Sternbach also discovered the first commercially feasible synthesis of the vitamin biotin, the synthesis of the antispasmodics Quarzan and Librax (Librium + clidinium bromide) used to treat peptic ulcers as well as the benzodiazepines Dalmane and Klonopin (1976). He holds more than 230 patents.
Hoffman-La Roche, Basel, Switzerland
1940-1941 Research Chemist
Hoffman-La Roche, Nutley, New Jersey
1941-1959 Group Chief
1959-1965 Senior Group Chief
1965-1967 Section Chief
1966-1973 Director of Medicinal Chemistry
Leo Sternbach, The Father of Mother's Little Helpers, U.S. News, December 27, 1999.
Mother's Little Helper, ABC News, December 17, 2000.
Keeping an open mind, Alec Jenner: the man who helped to create Valium
Side-effects of Librium, 1960, Drs I.M. Ingram, Gerald C. Timbury.
Withdrawal Reactions from Chlordiazepoxide (Librium), Leo E. Hollister, Francis P. Motzenbecker & Roger O. Dean, 1961.
Menstrual Irregularities Associated with the Use of Chlordiazepoxide (Librium), >M. James Whitelaw, MD, 1961.
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