Mebrobamate

Meprobamate (marketed under the brand names Miltown by Wallace Laboratories, Equanil by Wyeth, and Meprospan) is a carbamate derivative which is used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines.

History
Meprobamate was first synthesized by Bernard John Ludwig and Frank Milan Berger, MD, at Carter Products in May 1950. Wallace Laboratories, a subsidiary of Carter Products, bought the license and named it Miltown after the village Miltown in New Jersey. Launched in 1955, it rapidly became a best seller and famous in the popular media as "Happy Pills". In the mid-1940s, Dr. Berger was working in a laboratory of a British drug company, when he noticed that a chemical with which he was working had a sedative effect in small laboratory animals (rodents). Dr Berger subsequently referred to this sedating or “tranquilizing” effect in a now-historic article, published by The British Journal of Pharmacology in 1946. After moving Wallace Laboratories in New Jersey, Dr. Berger and a chemist, Bernard Ludwig, synthesized a chemically-related tranquilizing compound, meprobamate, which was introduced under the trade name Miltown, the village near their lab at Wallace.

A December 1955 study of 101 patients at the Mississippi State Hospital in Whitfield, Mississippi, found meprobamate useful in the alleviation of mental symptoms. 3% of the patients made a complete recovery, 29% were greatly improved, and 50% were somewhat better. 18% realized little change. Self-destructive patients became cooperative and calmer, and experienced a resumption of logical thinking. In 50% of the cases relaxation brought about more favorable sleep habits. Hydrotherapy and all types of shock treatment were halted. Meprobamate was found to help in the treatment of alcoholics by 1956. Dr. Berger, clinical director of Wallace Laboratories (who died on March 16, 2008, aged 94 ), described it as a relaxant of the central nervous system, whereas other tranquilizers suppressed it. A University of Michigan study found that meprobamate affected driving skills. Patients reported being able to relax more even though they continued to feel tense (needs clarification). The disclosures came at a special scientific meeting at the Barbizon Plaza Hotel in New York City, at which Aldous Huxley addressed an evening session. He predicted the development of many chemicals capable of changing the quality of human consciousness, in the next few years.

Coincidentally, carisoprodol, a prodrug of meprobamate, was initially marketed under the trade the trade name of "Soma", which was also a fictional drug in Aldous Huxley's Brave New World. Latterly carisoprodol was marketed as a skeletal muscle relaxant under the name of "Carisoma." It was never as popular as the rival products baclofen or dantrolene, and is principally known for having inspired the "Ashworth Scale" to rate the degree of spasticity.

Miltown was sometimes referred to incorrectly as chlorpromazine. One such instance of this was a review by author Frank Slaughter of the book, A Man Against Insanity, by Paul de Kruif. In January 1960 Carter Products, Inc., makers of Miltown and American Home Products Corporation, which marketed Equanil, were charged with having conspired to monopolize the market in mild tranquilizers. It was revealed that in 1948 the sale of meprobamate earned $40,000,000 for the defendants. Of this amount American Home Products accounted for approximately 2/3 and Carter about 1/3. The U.S. Government sought an order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it.

In April 1965 meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a sedative instead. The U.S. Pharmacopoeia published the ruling. At the same time the Medical Letter disclosed that meprobamate could be addictive at dosage levels not much above recommended. In December 1967 meprobamate was placed under abuse control amendments to the Food, Drug and Cosmetic Act. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.

Production continued throughout the 1960s but by 1970 it was listed as a controlled substance after it was discovered to cause physical and psychological dependence. Nevertheless, its place in the history of pharmacology and therapeutics is cemented, as the drug is considered to be the forerunner of the modern-era benzodiazepine class of anti-anxiety and sedative/hypnotic drugs (as the pharmacological actions of the benzodiazepines on the central nervous system mimic those of meprobamate). The first member of the benzodiazepine class, chlordiazepoxide (synthesized by the Swiss firm, Hoffman LaRoche and marketed as Librium when introduced in 1960), gave rise to the drug still commonly used today — diazepam — better known by its original brand-name, Valium (also introduced and still marketed by Roche Products). The significance of meprobamate and the benzodiazepines lies in the fact that these drugs, despite being habit-forming, essentially replaced the widely-used and potentially-lethal class of sedatives, the barbiturates. The medical role of barbiturates today is virtually restricted to the emergency treatment of some forms of (usually epileptic) seizures in infants.

Pharmacology
Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of the barbiturates (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against absence seizures, but can exacerbate generalized tonic-clonic seizures.

Meprobamate's mechanism of action is not known. It has been shown in animal studies to have effects at multiple sites in the central nervous system, including the thalamus and limbic system. Meprobamate binds to GABAA receptors which interrupt neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain.

Related drugs include carisoprodol (a prodrug of meprobamate) and tybamate.

Indications
Meprobamate is licensed for the short-term relief of anxiety, although it is not known whether the purported anti-anxiety effects of meprobamate are separable from its sedative effects. Its effectiveness as a selective agent for the treatment of anxiety has not been proven in humans, and is not used as often as the benzodiazepines for this purpose.

Meprobamate is available in 200mg and 400mg tablets for oral administration. Meprobamate is also a component of the combination drug Equagesic (discontinued in the UK in 2002) acting as a muscle relaxant.



Overdose
Symptoms of meprobamate overdose include: drowsiness, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock. Death has been reported with ingestion of as little as 12g of meprobamate and survival with as much as 40g. In an overdose, meprobamate tablets may form a gastric bezoar, requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration of activated charcoal should be considered even after 4 or more hours or if levels are rising.

Health Issues
Meprobamate is a Schedule IV drug under the Convention on Psychotropic Substances.