| Systematic (IUPAC) name | |
|---|---|
| [2-(carbamoyloxymethyl)-2-methyl-pentyl] carbamate | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682077 |
| Pregnancy cat. | D(US) |
| Legal status | Schedule IV (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Half-life | 10 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 57-53-4 |
| ATC code | N05BC01 |
| PubChem | CID 4064 |
| DrugBank | APRD01095 |
| ChemSpider | 3924 |
| UNII | 9I7LNY769Q |
| KEGG | D00376 |
| ChEMBL | CHEMBL979 |
| Chemical data | |
| Formula | C9H18N2O4 |
| Mol. mass | 218.250 g/mol |
| SMILES | eMolecules & PubChem |
|
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| Physical data | |
| Density | 1.229 g/cm³ |
| Melt. point | 105-106 °C (-54 °F) |
| Boiling point | 200-210 °C (-146 °F) |
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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 It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines.
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Meprobamate was first synthesized by Bernard John Ludwig, PhD, 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 borough of Milltown in New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining notoriety for its seemingly miraculous effects.[1]
In the mid-1940s, Dr. Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called mephenesin 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. However, there were three major drawbacks to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain, and a weak activity. [2] After moving to Wallace Laboratories in New Jersey, Dr. Berger and a chemist, Dr. Bernard Ludwig, synthesized a chemically-related tranquilizing compound, meprobamate, that was able to overcome these three drawbacks.[3] It was soon prescribed under the trade name Miltown.
A December 1955 study of 101 patients at the Mississippi State Hospital in Whitfield, Mississippi, found meprobamate useful in the alleviation of "mental symptoms." Three percent of the patients made a complete recovery, 29% were greatly improved, and 50% were somewhat better. Eighteen percent 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.[4] Meprobamate was found to help in the treatment of alcoholics by 1956.[5] By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written.[6] Dr. Berger, clinical director of Wallace Laboratories (who died on March 16, 2008, aged 94[7]), 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. Though patients reported being able to relax more easily, meprobamate did not completely alleviate their tense feelings. 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.[8] Coincidentally, carisoprodol, a prodrug of meprobamate, was initially marketed under 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.
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 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.[9]
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.[10] 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.[11]
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. 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 diazepam — better known by its original brand-name, Valium (also introduced by Roche Products).
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 completely 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[12] which interrupts neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain. It has been shown that meprobamate has the ability to activate currents even in the absence of GABA.[13] It is also a potent adenosine reuptake inhibitor (AdoRI).[14][15]
Related drugs include carisoprodol (a prodrug of meprobamate) and tybamate.
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,[16] and is not used as often as the benzodiazepines for this purpose.
Meprobamate is available in 200 mg and 400 mg 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.
Meprobamate is also found as a component of the combination drug "Stopayne" capsules
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.
Meprobamate is a Schedule IV drug (US) (S5 in South Africa) under the Convention on Psychotropic Substances. With protracted use it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that of barbiturates and alcohol.
An acute cerebral edema caused by a reaction to Equagesic, a combination of aspirin and meprobamate, is believed to have caused the death of Bruce Lee.
Meprobamate, 2-methyl-2-propyl-1,3-propandiol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules of formaldehyde and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate via successive reactions with phosgene and ammonia.
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