By the end of the 1950s one in three prescriptions in America was for meprobamate, which dampened anxiety.
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Other ingredients that stayed potent after their expiration date included butalbital, methaqualone, phenacetin, meprobamate, pentobarbital, secobarbital, hydrocodone, homatropine and chlorpheniramine.
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Meprobamate binds to GABAA receptors which interrupts neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain. Meprobamate has the ability to activate currents even in the absence of GABA. This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (including alcohol). It is also a potent adenosine reuptake inhibitor.
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Symptoms of meprobamate overdose include drowsiness, headache, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock.livertox.nlm.nih.gov -Meprobamate , overview Death has been reported with ingestion of as little as 12 g of meprobamate and survival with as much as 40 g. 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.
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Related drugs include carisoprodol and tybamate (prodrugs of meprobamate), felbamate, mebutamate, and methocarbamol.
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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 doses not much above recommended.
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Marketed as a safer alternative to barbiturate anxiolytics, meprobamate (Miltown, Equanil) was commonly used to relieve anxiety in the late 1950s and 1960s. Like barbiturates, therapeutic doses produce sedation and significant overdoses may be fatal. In the US, meprobamate has generally been replaced with benzodiazepines while the drug is now withdrawn in many European countries and Canada. The muscle relaxant carisoprodol has anxiolytic effects by metabolizing to meprobamate.
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Meprobamate synthesis: Meprobamate, 2-methyl-2-propyl-1,3-propanediol 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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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. Berger, clinical director of Wallace Laboratories, 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.
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European Medicines Agency recommended suspension of marketing authorisations for meprobamate-containing medicines in the European Union in January 2012.
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Meprobamate is licensed for the short-term relief of anxiety, although whether the purported antianxiety effects of meprobamate are separable from its sedative effects is not known. 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 200- and 400-mg tablets for oral administration. It is also a component of the combination drug Equagesic (discontinued in the UK in 2002), acting as a muscle relaxant.
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In January 1960, Carter Products, Inc. and American Home Products Corporation (which marketed meprobamate as 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 about two-thirds and Carter about one-third.
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On January 19, 2012, the European Medicines Agency withdrew marketing authorization in the European Union for all medicines containing meprobamate, "due to serious side effects seen with the medicine." The Agency’s Committee for Medicinal Products for Human Use "concluded that the benefits of meprobamate do not outweigh its risks." In October 2013, Canada also withdrew marketing authorization.
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Other formulations utilized amphetamines, barbiturates, and meprobamate for their ability to potentiate analgesia by combining them with analgesics such as phenacetin and aspirin.
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While there was some tentative evidence of effectiveness when combined with meprobamate, with the medication no longer available it is not clinically important.
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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, meprobamate was listed as a controlled substance after it was discovered to cause physical and psychological dependence.
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Carisoprodol has a rapid, 30-minute onset of action, with the aforementioned effects lasting about two to six hours. It is metabolized in the liver via the cytochrome P450 oxidase isozyme CYP2C19, excreted by the kidneys and has about an eight-hour half- life. A considerable proportion of carisoprodol is metabolized to meprobamate, which is a known drug of abuse and dependence; this could account for the abuse potential of carisoprodol (meprobamate levels reach higher peak plasma levels than carisoprodol itself following administration). Meprobamate is believed to play a significant role in the effects of carisoprodol and meprobamates long half-life results in bioaccumulation following extended periods of carisoprodol administration.
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An anxiotropic agent is one that modifies anxiety, a human emotion that has homologous processes in animals. In psychopharmacology anxiotropic agents consist of two categories of psychoactive drugs: anxiolytics that reduce anxiety and may be used therapeutically, and anxiogenic compounds that increase anxiety. Most anxiolytic agents are minor tranquilizers, the founding compound of which was meprobamate, marketed in the United States as Miltown. Meprobamate was eventually eclipsed by the benzodiazepines.
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Aspirin/meprobamate (trade name Equagesic ) is a combination drug indicated for short-term pain treatment accompanied by tension or anxiety in patients with musculoskeletal disorders or tension headache.
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Monkey studies looking at the dependence liability of several sedative drugs showed that benzoctamine was a dependence- free drug, while pentobarbital, alcohol, chloroform, meprobamate, diazepam, chlordiazepoxide, and oxazolam were not.
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Carisoprodol, meprobamate, and related drugs such as tybamate, have the potential to produce physical dependence of the barbiturate type following periods of prolonged use. Withdrawal of the drug after extensive use may require hospitalization in medically compromised patients. In severe cases the withdrawal can mimic the symptoms of alcohol withdrawal including the potentially lethal status epilepticus. Psychological dependence has also been linked to carisoprodol use although this is much less severe than with meprobamate itself (presumably due to the slower onset of effects).
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Reports from Norway have shown carisoprodol has abuse potential as a prodrug of meprobamate and/or potentiator of hydrocodone, oxycodone, codeine, and similar drugs. In May 2008 it was taken off the market in Norway.
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The usual dose of 350 mg is unlikely to engender prominent side effects other than somnolence, and mild to significant euphoria or dysphoria, but the euphoria is generally short-lived due to the fast metabolism of carisoprodol into meprobamate and other metabolites; the euphoria derived is, according to new research, most likely due to carisoprodol's inherent, potent anxiolytic effects that are far stronger than those produced by its primary metabolite, meprobamate, which is often misblamed for the drug-seeking associated with carisoprodol, as carisoprodol itself is responsible for the significantly more intense central nervous system effects than meprobamate alone. Carisoprodol has a unique mechanism of action, qualitatively different from that of meprobamate (Miltown). The medication is well tolerated and without adverse effects in the majority of patients for whom it is indicated. In some patients, however, and/or early in therapy, carisoprodol can have the full spectrum of sedative side effects and can impair the patient's ability to operate a firearm, motor vehicles, and other machinery of various types, especially when taken with medications containing alcohol, in which case an alternative medication would be considered.
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How it works is not clear. Some of its effects are believed to occur following being converted into meprobamate. Carisoprodol was approved for medical use in the United States in 1959. Its approval in Europe was withdrawn in 2008.
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Tybamate (INN; Solacen, Tybatran, Effisax) is an anxiolytic of the carbamate family. It is a prodrug for meprobamate in the same way as the better known drug carisoprodol. It has liver enzyme inducing effects similar to those of phenobarbital but much weaker.
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2-Methyl-2-propyl-1,3-propanediol (MPP) is a simple alkyl diol which has sedative, anticonvulsant and muscle relaxant effects. It is both a synthetic precursor to, and an active metabolite of the tranquilizers meprobamate and carisoprodol, as well as other derivatives.
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The autopsy found Equagesic in his system. On October 15, 2005, Chow stated in an interview that Lee died from an allergic reaction to the tranquilizer meprobamate, the main ingredient in Equagesic, which Chow described as an ingredient commonly used in painkillers.
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Phenaglycodol (brand names Acalmid, Acalo, Alterton, Atadiol, Felixyn, Neotran, Pausital, Remin, Sedapsin, Sinforil, Stesil, Ultran) is a drug described as a tranquilizer or sedative which has anxiolytic and anticonvulsant properties. It is related structurally and pharmacologically to meprobamate, though it is not a carbamate.
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Prenderol (Diethylpropanediol) is a simple alkyl diol which has sedative, anticonvulsant and muscle relaxant effects. It is closely related in structure to meprobamate and numerous other alkyl alcohols and diols with generally comparable activity.Reyes Q., Aaurelio; Mascetti V., G.; Martinez J., Rolando. Synthesis of polyhydroxylated alcohols.
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Frank Milan Berger was a Czechoslovakian pharmacologist who discovered meprobamate, carisoprodol, and felbamate, while working at Wallace Laboratories. He also discovered the 'tranquilising' effects of mephenesin in rodents while working at a laboratory in the United Kingdom, and campaigned against the advertising of medications in the mass media.
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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. Following the trial, hydrotherapy and all types of shock treatment were subsequently halted. Meprobamate was found to help in the treatment of alcoholics by 1956.
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Only reversal of the FDA's decision, allows removing the drug from the CSD. Ethoheptazine is not listed as a controlled substance under the Controlled Substances Act, 1970 in the United States. The controlled status (Schedule IV) of Equagesic was due to the meprobamate content.PDR 1978, pp 1618 Regulation elsewhere varies.
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Phenprobamate (Gamaquil, Isotonil) is a centrally acting skeletal muscle relaxant, with additional sedative and anticonvulsant effects. Overdose is similar to barbiturates. Its mechanism of action is probably similar to meprobamate. Phenprobamate has been used in humans as an anxiolytic, and is still sometimes used in general anesthesia and for treating muscle cramps and spasticity.
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Midaflur (INN; EXP 338) is an extremely stable 3-imidazoline derivative with central skeletal muscle relaxant and sedative properties in humans and other species of mammals, exhibiting consistently high oral bioavailability and a long duration of action. While its pharmacodynamics remain poorly understood, midaflur resembles meprobamate and pentobarbital in terms of observed effects while being considerably more potent.
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Meprobamate—marketed as Miltown by Wallace Laboratories and Equanil by Wyeth, among others—is a carbamate derivative used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines due to their wider therapeutic index (lower risk of toxicity at therapeutically prescribed doses) and lower incidence of serious side effects.
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In recreational drug users, deaths have resulted from carelessly combining overdoses of hydrocodone and carisoprodol. Another danger of misuse of carisoprodol and opiates is the potential to aspirate while unconscious. Meprobamate and other muscle-relaxing drugs often were subjects of misuse in the 1950s and 60s. Overdose cases were reported as early as 1957, and have been reported on several occasions since then.
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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 (delirium tremens). For this reason, discontinuation is often achieved through an extended regimen of slowly decreasing doses over a period of weeks or even months. Alternatively, the patient may be switched to a longer-acting gabaergic agent such as diazepam (in a manner similar to the use of methadone therapy for opiate addiction) before attempting detitration. While an acute cerebral edema is widely believed to be the cause of actor and martial artist Bruce Lee's death in 1973, another factor which may have contributed to Lee’s death, was his decision to take Equagesic (a brand which combined meprobamate and aspirin).
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Detroit:Wayne State University; 1959. It had been developed by Frank Berger at Wallace Laboratories and was named carisoprodol. Carisoprodol was a modification of meprobamate, intended to have better muscle relaxing properties, less potential for abuse, and less risk of overdose. The substitution of one hydrogen atom with an isopropyl group on one of the carbamyl nitrogens was intended to yield a molecule with new pharmacological properties.
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"In the January 2008 issue of Drug Safety Update, a Stop press article announced the recent European review of carisoprodol for which the Committee for Medicinal Products for Human Use concluded that the risks of treatment outweigh the benefits. This review was triggered by concerns from the Norwegian Medical Agency that carisoprodol (converted to meprobamate after administration) was associated with increased risk of abuse, addiction, intoxication, and psychomotor impairment." February 2008.
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Ethoheptazine (trade name Zactane) is an opioid analgesic from the phenazepane family. It was invented in the 1950s and is related to other drugs such as proheptazine and pethidine. Ethoheptazine produces similar effects to other opioids, including analgesia, sedation, dizziness and nausea. It was sold by itself as Zactane, and is still available as a combination product with acetylsalicylic acid and meprobamate as Equagesic, which is used for the treatment of conditions where both pain and anxiety are present.
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Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of the barbiturates and acts at the barbiturate binding site (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.
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In addition, some carbamates are used in human pharmacotherapy, for example, the acetylcholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine. Other examples are meprobamate and its derivatives like carisoprodol, felbamate, mebutamate, and tybamate, a class of anxiolytic and muscle relaxant drugs widely used in the 1960s before the rise of benzodiazepines, and still used nowadays in some cases. Carbachol is primarily used for various ophthalmic purposes. The protease inhibitor darunavir for HIV treatment also contains a carbamate functional group.
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Overdose symptoms in combination with opiates are similar but are distinguished by the presentation of normal or pinpoint pupils, which are generally unresponsive to light. Carisoprodol (as with its metabolite meprobamate) is particularly dangerous in combination with alcohol. Flumazenil (the benzodiazepine antidote) is not effective in the management of carisoprodol overdose as carisoprodol acts at the barbiturate binding site. Treatment mirrors that of barbiturate overdoses and is generally supportive, including the administration of mechanical respiration and pressors as implicated (and in rare cases, bemegride).
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Wallace Laboratories, a subsidiary of Carter Products, bought the license and named their new product "Miltown" after the borough of Milltown, New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining fame for its seemingly miraculous effects. It has since been marketed under more than 100 trade names, from Amepromat through Quivet to Zirpon. 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 patients made a complete recovery, 29% were greatly improved, 50% were somewhat better, while 18% realized little change.
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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. Meprobamate was one of the first drugs to be widely advertised to the general public, with user Milton Berle promoting the drug heavily on his television show, calling himself 'Uncle Miltown'. Miltown soon became ubiquitous in 1950s American life, with 1 in 20 Americans having used it by late 1956, and popular comedians making as many jokes about the drug as they did about Elvis Presley.
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N.J. 1976). In that case the Government challenged both sales of bulk drug chemical and manufacturing licenses each with both bulk-sales restrictions and limitations to marketing the drug in a specific combination with another drug (for example, Ciba's patented hydrochlorothiazide plus Carter's meprobamate). The Government had two principal legal theories: (1) each agreement was a "contract, combination, or conspiracy" in violation of Sherman Act § 1; (2) the "network" of agreements amounted to a hub-and-spoke conspiracy. The district court found: > The proof in this case has shown a series of supply agreements which limit, > in varying degrees, the range of uses to which the purchaser was entitled to > put the vended material.
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In the mid-1940s, Frank 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 calmed laboratory rodents without actually sedating them. Berger subsequently referred to this sedating or “tranquilizing” effect in a now-historic article, published by the British Journal of Pharmacology in 1946. However, three major drawbacks existed 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. In May 1950, after moving to Carter Products in New Jersey, Berger and a chemist, Bernard John Ludwig, synthesized a chemically related tranquilizing compound, meprobamate, that overcame these three drawbacks.
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"For any of you who have ever lain awake at night asking: Where, oh where is the statistical center of New Jersey, there really is an answer. Nenninger Lane, East Brunswick.... Over the last several decades, New Jersey’s statistical center has gradually crept its way south and west along the New Jersey Turnpike as growth in the southern and western portions of the state has outpaced the north.... Ten years ago, it was at an intersection in Milltown, about a tenth of a mile from the Turnpike and a few paces south of a Home Depot." The groundbreaking anxiolytic and sedative drug Miltown (meprobamate) developed by Carter Products, which became available to the public in the mid-1950s, was named for the borough.via Los Angeles Times.
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The medical justification for these combination drugs was that the CNS stimulant elevates mood and suppresses appetite, while the CNS depressant mitigates many of the adverse effects of the CNS stimulant without simultaneously reducing its therapeutic benefits. Typically the CNS stimulant within these combination drugs was racemic amphetamine, dextroamphetamine, or methamphetamine as various single or mixed salts, and phenmetrazine hydrochloride (Preludin) was also marketed albeit less frequently. Typically the CNS depressant within these combination drugs was a single barbiturate salt, especially pentobarbital sodium and sodium amobarbital (Amytal), although meprobamate (Miltown), a minor tranquilizer, and methaqualone hydrochloride (Quaalude), a non-barbiturate sedative were also sometimes used. Some less common combination drug formulations included a CNS stimulant combined with multiple vitamins and minerals, a first generation antipsychotic (Eskatrol was popular), or a first generation antihistamine (Obocell-TF).
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By 1943, neuromuscular blocking drugs became established as muscle relaxants in the practice of anesthesia and surgery. The U.S. Food and Drug Administration (FDA) approved the use of carisoprodol in 1959, metaxalone in August 1962, and cyclobenzaprine in August 1977. Other skeletal muscle relaxants of that type used around the world come from a number of drug categories and other drugs used primarily for this indication include orphenadrine (anticholinergic), chlorzoxazone, tizanidine (clonidine relative), diazepam, tetrazepam and other benzodiazepines, mephenoxalone, methocarbamol, dantrolene, baclofen, Drugs once but no longer or very rarely used to relax skeletal muscles include meprobamate, barbiturates, methaqualone, glutethimide and the like; some subcategories of opioids have muscle relaxant properties, and some are marketed in combination drugs with skeletal and/or smooth muscle relaxants such as whole opium products, some ketobemidone, piritramide and fentanyl preparations and Equagesic.
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The next morning, Mott awakes massively hung over, only to find that he and Sandra have had sex while extremely intoxicated, effectively causing her to overcome her fear. Mott spends the next year and a half in prison, represented by a single, one- paragraph letter from Mott to Sandra, in which he describes prison as comparable to working for a major corporation, except “here they don’t let you out at night.” Released early from prison for good behavior, Mott, now addicted to tranquilizer pills (“Miltowns”, also known as Meprobamate) returns to New York. He wanders around the city, finding that his family’s former apartment has become a small brothel, and visiting Pappas, who now works for the Reverend Gurrey. Pappas has gotten Gurrey to back his scheme of a “Christian Aeronautical Mission” which involves using hot air balloons to drop Bibles behind the Iron Curtain.
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