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{{Short description|Carbamate derivative used as an }}
{{Redirect|Miltown|places with the name Milltown|Milltown (disambiguation)}} {{Redirect|Miltown|places with the name Milltown|Milltown (disambiguation)}}
{{Infobox drug
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 414648920
| verifiedrevid = 459508597
| IUPAC_name = carbamate | IUPAC_name = carbamate
| image = Meprobamate.svg | image = Meprobamate.svg
| image2 = Meprobamate ball-and-stick model.png
| width = 250
| image2 = Meprobamate3d.png


<!--Clinical data--> <!--Clinical data-->
| tradename = ''Miltown'', ''Equanil'', ''Meprospan'', ''Amepromat'', ''Quivet'', ''Zirponand'', and many others
| tradename =
| Drugs.com = {{drugs.com|monograph|meprobamate}} | Drugs.com = {{drugs.com|monograph|meprobamate}}
| MedlinePlus = a682077 | MedlinePlus = a682077
| pregnancy_AU = C
| pregnancy_US = D | pregnancy_US = D
| legal_AU = S4
| legal_BR = B1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_US = Schedule IV | legal_US = Schedule IV
| legal_CA = Schedule IV
| legal_DE = Anlage II
| legal_UK = Class C
| routes_of_administration = Oral | routes_of_administration = Oral


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<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 7225
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 57-53-4 | CAS_number = 57-53-4
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<!--Chemical data--> <!--Chemical data-->
| C=9 | H=18 | N=2 | O=4 | C=9 | H=18 | N=2 | O=4
| smiles = O=C(N)OCC(C)(CCC)COC(N)=O
| molecular_weight = 218.250 g/mol
| smiles = O=C(OCC(COC(=O)N)(C)CCC)N
| InChI = 1/C9H18N2O4/c1-3-4-9(2,5-14-7(10)12)6-15-8(11)13/h3-6H2,1-2H3,(H2,10,12)(H2,11,13)
| InChIKey = NPPQSCRMBWNHMW-UHFFFAOYAM
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H18N2O4/c1-3-4-9(2,5-14-7(10)12)6-15-8(11)13/h3-6H2,1-2H3,(H2,10,12)(H2,11,13) | StdInChI = 1S/C9H18N2O4/c1-3-4-9(2,5-14-7(10)12)6-15-8(11)13/h3-6H2,1-2H3,(H2,10,12)(H2,11,13)
Line 50: Line 55:
| StdInChIKey = NPPQSCRMBWNHMW-UHFFFAOYSA-N | StdInChIKey = NPPQSCRMBWNHMW-UHFFFAOYSA-N
| density = 1.229 | density = 1.229
| melting_point = 105-106 | melting_point = 105
| melting_high = 106
| boiling_point = 200-210
| boiling_point = 200
| boiling_notes = to 210 °C (410 °F)
}} }}

'''Meprobamate''' (marketed under the brand names '''Miltown''' by Wallace Laboratories, '''Equanil''' by Wyeth, and '''Meprospan''') is a ] derivative which is used as an ] drug. It was the best-selling ] for a time, but has largely been replaced by the ]s.
'''Meprobamate'''—marketed as '''Miltown''' by ] and '''Equanil''' by ], among others—is a ] derivative used as an ] drug. It was the best-selling ] for a time, but has largely been replaced by the ]s due to their wider ] (lower risk of toxicity at therapeutically prescribed doses) and lower incidence of serious side effects.


==History== ==History==
] was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called ] (or myanesin) calmed laboratory rodents without actually sedating them.<ref>{{Cite book|url=https://books.google.com/books?id=aK2__vkxiP0C|title=Let them eat prozac| vauthors = Healy D |date=2003|publisher=J. Lorimer & Co|isbn=978-1550287837|location=Toronto|pages=27|oclc=52286331}}</ref> Berger subsequently referred to this “tranquilizing” effect in a now-historic article, published by the ''British Journal of Pharmacology'' in 1946.<ref>{{cite journal |last1=Frank Berger and William Bradley |title=The pharmacological properties of α:β-dihydroxy-γ-(2-methylphenoxy)-propane (myanesin) |journal=Br J Pharmacol Chemother |date=Dec 1946 |volume=1 |issue=4 |pages=265–272 |doi=10.1111/j.1476-5381.1946.tb00046.x |pmid=19108096 |pmc=1509753 }}</ref><ref name="pmid19108125">{{cite journal | vauthors = Berger FM | title = The mode of action of myanesin | journal = British Journal of Pharmacology and Chemotherapy | volume = 2 | issue = 4 | pages = 241–50 | date = December 1947 | pmid = 19108125 | pmc = 1509790 | doi = 10.1111/j.1476-5381.1947.tb00341.x }}</ref> 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 (resulting in a very low ]), and a weak activity.<ref>{{cite journal | vauthors = Ban TA | title = The role of serendipity in drug discovery | journal = Dialogues in Clinical Neuroscience | volume = 8 | issue = 3 | pages = 335–44 | date = 2006 | pmid = 17117615 | pmc = 3181823 | doi = 10.31887/DCNS.2006.8.3/tban }}</ref>
Meprobamate was first synthesized by Bernard John Ludwig, PhD, and Frank Milan Berger, MD, at ] in May 1950. Wallace Laboratories, a subsidiary of Carter Products, bought the license and named it Miltown after the borough of ] in ]. 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.<ref>{{cite book
], ], ] and ].]]
|last= Tone
In May 1950, after moving to ] in New Jersey, Berger and a chemist, Bernard John Ludwig, synthesized a chemically related tranquilizing compound, meprobamate, that overcame these three drawbacks.<ref>{{cite journal |doi=10.1021/ja01156a086 | vauthors = Ludwig BJ, Piech E |title=Some anticonvulsant agents derived from 1, 3-propanediol |journal=J Am Chem Soc |volume=73 |issue=12 |pages=5779–5781 |year=1951}}</ref> Wallace Laboratories, a subsidiary of Carter Products, bought the license and named their new product "Miltown" after the borough of ], 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.<ref>{{cite book| vauthors = Tone A |title=The Age of Anxiety: A History of America's Turbulent Affair with Tranquilizers|year=2009|publisher=Basic Books|location=New York|isbn=978-0-465-08658-0|chapter=The Fashionable Pill|url=https://books.google.com/books?id=sgkXBQAAQBAJ}}</ref> It has since been marketed under more than 100 trade names, from Amepromat through Quivet to Zirpon.<ref>{{cite web | title = Meprobamate | url = http://webbook.nist.gov/cgi/cbook.cgi?ID=57-53-4 | work = NIST Chemistry WebBook, SRD 69 | publisher = National Institute of Standards and Technology (NIST) }}</ref>
|first= Andrea
|title=The Age of Anxiety: A History of America's Turbulent Affair with Tranquilizers
|year=2009
|publisher= Basic Books
|location= New York
|isbn= 9780465086580
|chapter=The Fashionable Pill}}</ref>


A December 1955 study of 101 patients at the ] in ], 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. 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, ] and all types of ] were subsequently halted.<ref>{{cite web | vauthors = Laurence WL | url = https://www.nytimes.com/1955/12/28/archives/new-hope-arises-on-cancer-serum-isolation-of-substance-that-blocks.html | title = New Hope Arises On Cancer Serum | work = ] | date = 28 December 1955 | page = 21 }}</ref> Meprobamate was found to help in the treatment of alcoholics by 1956.<ref>{{cite news |title=ALCOHOLIC PERIL FOUND IN DRUGS; Some Tranquilizing Therapy May Be Habit-Forming, Physicians Tell Parley |page=28 |work=] |date=1956-04-01 |url=http://select.nytimes.com/gst/abstract.html?res=F00910F83F5F157A93C3A9178FD85F428585F9 |access-date=2009-01-23}}</ref> 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.<ref>{{cite news | vauthors = Dokoupil T |title=How Mother Found Her Helper |work=] |date=2009-01-22 |url=http://www.newsweek.com/id/180998 |access-date=2009-01-23}}</ref> Berger, clinical director of Wallace Laboratories, described it as a relaxant of the ], whereas other ] suppressed it. A ] 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 ] in ], at which ] addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness", in the next few years.<ref>{{cite web |url=https://www.nytimes.com/1956/10/19/archives/behavior-drugs-now-envisioned-aldous-huxley-predicts-they-will.html |title='BEHAVIOR' DRUGS NOW ENVISIONED; Aldous Huxley Predicts They Will Bring Re-Examining of Ethics and Religion |work=] |date=1956-10-19 |access-date=2009-02-01 }}</ref>
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.
<ref>{{cite journal | author = Berger FM. | title = Mode of Action of Myanesin. | journal = Br J Pharmacol. | volume = 2 | issue = 4 | pages = 241–250 | year = 1947 }}</ref>
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.<ref>{{cite journal | doi = 10.1021/ja01156a086 | author = Ludwig BJ, Piech E. | title = Some anticonvulsant agents derived from 1, 3-propanediol. | journal = J Am Chem Soc. | volume = 73 | issue = 12 | pages = 5779–5781 | year = 1951 }}</ref> It was soon prescribed under the trade name Miltown.


Meprobamate was one of the first drugs to be widely advertised to the general public, with user ] promoting the drug heavily on his television show, calling himself 'Uncle Miltown'.<ref>{{Cite book|title=The age of anxiety : a history of America's turbulent affair with tranquilizers|author=Tone, Andrea|date=2009|publisher=Basic Books|isbn=9780786727476|location=New York|oclc=302287405}}</ref> Miltown soon became ubiquitous in 1950s American life, with 1 in 20 Americans having used it by late 1956,<ref>{{Cite news|url=https://www.cbc.ca/radio/ondrugs/miltown-a-game-changing-drug-you-ve-probably-never-heard-of-1.4237946|title=Miltown: a game-changing drug you've probably never heard of |work=CBC Radio|access-date=2018-09-22|language=en-US}}</ref> and popular comedians making as many jokes about the drug as they did about ].<ref>{{Cite book|title=Psychopharmacology for Mental Health Professionals: An Integrative Approach| vauthors = Ingersoll E, Rak C |publisher=Cengage Learning|year=2015|isbn=9781305537231|pages=129}}</ref>
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. ] and all types of ] were halted.<ref>''New Hope Arises On Cancer Serum'', New York Times, December 28, 1955, Page 21.</ref> Meprobamate was found to help in the treatment of alcoholics by 1956.<ref>{{cite news |last = Author unknown |title = ALCOHOLIC PERIL FOUND IN DRUGS; Some Tranquilizing Therapy May Be Habit-Forming, Physicians Tell Parley |page = 28 |publisher = New York Times |date = 1956-04-01 |url = http://select.nytimes.com/gst/abstract.html?res=F00910F83F5F157A93C3A9178FD85F428585F9 |accessdate = 2009-01-23}}</ref> 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.<ref>{{cite news |last = Dokoupil |first = Tony |title = How Mother Found Her Helper |publisher = Newsweek |date = 2009-01-22 |url = http://www.newsweek.com/id/180998 |accessdate = 2009-01-23}}</ref>
Dr. Berger, clinical director of Wallace Laboratories (who died on March 16, 2008, aged 94<ref>{{cite news |url=http://www.nytimes.com/2008/03/21/health/research/21berger.html?partner=permalink&exprod=permalink|title=Frank Berger, 94, Miltown Creator, Dies - New York Times |date=2008-03-21 |publisher=New York Times |accessdate=2009-02-01 |last=Carey |first=Benedict}}</ref>), described it as a relaxant of the ], whereas other
] suppressed it. A ] 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 ], at which ] addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness," in the next few years.<ref>
{{cite web
|url=http://select.nytimes.com/gst/abstract.html?res=F10C15FD395916738FDDA00994D8415B8689F1D3 |title='BEHAVIOR' DRUGS NOW ENVISIONED; Aldous Huxley Predicts They Will Bring Re-Examining of Ethics and Religion |publisher=New York Times |date=1956-10-19 |accessdate=2009-02-01 |last= |first=}}</ref>
Coincidentally, ], a prodrug of meprobamate, was initially marketed under the trade name of "Soma," which was also a fictional drug in Aldous Huxley's ]. Latterly carisoprodol was marketed as a skeletal muscle relaxant under the name of "Carisoma." It was never as popular as the rival products ] or ], and is principally known for having inspired the "Ashworth Scale" to rate the degree of spasticity.{{Citation needed|date=November 2008}}


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 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. 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.<ref>{{cite web | vauthors = Ranzal E |url= https://select.nytimes.com/gst/abstract.html?res=FB091EF83A5C16738DDDA10A94D9405B808AF1D3 |title=TRUST SUIT NAMES 2 DRUG CONCERNS; Makers of Tranquilizers Are Accused |work=] |access-date=2009-02-01 |date=1960-01-28}}</ref>
order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it.<ref>
{{cite web
|url=http://select.nytimes.com/gst/abstract.html?res=FB091EF83A5C16738DDDA10A94D9405B808AF1D3
|title=TRUST SUIT NAMES 2 DRUG CONCERNS; Makers of Tranquilizers Are Accused
|publisher=New York Times
|accessdate=2009-02-01
|date=1960-1-28
|last=Ranzal
|first=Edward
}}
</ref>


In April 1965 meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a ] instead. The U.S. Pharmacopoeia published the ruling. At the same time the ] disclosed that meprobamate could be addictive at dosage levels not much above recommended.<ref> In April 1965, meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a ], instead. The '']'' published the ruling. At the same time, the '']'' disclosed that meprobamate could be addictive at doses not much above recommended.<ref>{{cite web |url=https://www.nytimes.com/1965/04/22/archives/miltown-off-list-of-tranquilizers-but-it-will-continue-to-be-used-a.html |title=MILTOWN OFF LIST OF TRANQUILIZERS; But It Will Continue to Be Used as a Sedative |work=] |access-date=2009-02-01 |date=1965-04-22}}</ref> In December 1967, meprobamate was placed under abuse control amendments to the ]. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.<ref>{{cite web |url=https://www.nytimes.com/1967/12/06/archives/tranquilizer-is-put-under-us-curbs-sideeffects-noted.html |title=Tranquilizer Is Put Under U.S. Curbs; Side-Effects Noted |work=] |access-date=2009-02-01 |date=1967-12-06}}</ref>
{{cite web
|url=http://select.nytimes.com/gst/abstract.html?res=F10A1EFD345C147A93C0AB178FD85F418685F9
|title=MILTOWN OFF LIST OF TRANQUILIZERS; But It Will Continue to Be Used as a Sedative
|publisher=New York Times
|accessdate=2009-02-01
|date=1965-4-22
|last=
|first=
}}
</ref> In December 1967 meprobamate was placed under abuse control amendments to the ]. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.<ref>
{{cite web
|url=http://select.nytimes.com/gst/abstract.html?res=F6081FFD3A5B1A7B93C4A91789D95F438685F9
|title=Tranquilizer Is Put Under U.S. Curbs; Side-Effects Noted
|publisher=New York Times
|accessdate=2009-02-01
|date=1967-12-6
|last=
|first=
}}
</ref>


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.
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{{By whom|date=August 2010}} to be the forerunner of the modern-era ] 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, ] (synthesized by the Swiss firm, Hoffman LaRoche and marketed as Librium when introduced in 1960), gave rise to the drug ] — better known by its original brand-name, Valium (also introduced 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 ]. The medical role of barbiturates today is virtually restricted to the emergency treatment of some forms of (usually epileptic) seizures in infants and as an induction agent for general anesthesia.{{Citation needed|date=August 2010}}-->


On January 19, 2012, the ] withdrew marketing authorization in the ] 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."<ref>{{cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/meprobamate_107/WC500120737.pdf |title=Questions and answers on the suspension of the marketing uthorisations for oral meprobamate-containing medicines |access-date=2012-01-20 |date=2012-01-19}}</ref> In October 2013, Canada also withdrew marketing authorization.<ref>{{cite web | work = Health Canada | url = http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/35311a-eng.php | title = 282 MEP (meprobamate-containing medicine) - Market Withdrawal, Effective October 28, 2013 - For Health Professionals | date = 25 August 2021 }}</ref>
==Pharmacology==
Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of the ]s (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against ]s, but can exacerbate generalized ]s.


==Pharmacology==
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 ] and ]. Meprobamate binds to ]<ref name="pmid9067327">{{cite journal |author=Rho JM, Donevan SD, Rogawski MA |title=Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate |journal=J. Pharmacol. Exp. Ther. |volume=280 |issue=3 |pages=1383–91 |year=1997 |month=March |pmid=9067327 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9067327}}</ref> which interrupts neuronal communication in the ] and ], 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.<ref>{{cite journal |author=Rho JM, Donevan SD, Rogawski MA |title=Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate |journal=J. Pharmacol. Exp. Ther. |volume=280 |issue=3 |pages=1383–91 |year=1997 |month=March |pmid=9067327}}</ref> It is also a potent ] (AdoRI).<ref name="pmid6468504">{{cite journal | doi = 10.1016/0014-2999(84)90174-2 | author = Phillis JW, Delong RE. | title = A purinergic component in the central actions of meprobamate. | journal = Eur J Pharmacol. | volume = 101 | issue = 3-4 | pages = 295–297 | year = 1984 | pmid = 6468504 }}</ref><ref name="pmid4085561">{{cite journal | doi = 10.1016/0014-2999(85)90149-9 | author = DeLong RE, Phillis JW, Barraco RA. | title = A possible role of endogenous adenosine in the sedative action of meprobamate. | journal = Eur J Pharmacol. | volume = 118 | issue = 3 | pages = 359–362 | year = 1985 | pmid = 4085561 }}</ref>
Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of ]s and acts at the barbiturate binding site (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against ]s, but can exacerbate generalized ]s.


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 ] and ]. Meprobamate binds to ]<ref name="pmid9067327">{{cite journal | vauthors = Rho JM, Donevan SD, Rogawski MA | title = Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 280 | issue = 3 | pages = 1383–91 | date = March 1997 | pmid = 9067327 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9067327 }}</ref><ref name="pmid26872987">{{cite journal | vauthors = Kumar M, Dillon GH | title = Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors | journal = European Journal of Pharmacology | volume = 775 | pages = 149–58 | date = March 2016 | pmid = 26872987 | pmc = 4806799 | doi = 10.1016/j.ejphar.2016.02.031 }}</ref> which interrupts ] in the ] and ], causing sedation and altered perception of pain. Meprobamate has the ability to activate currents even in the absence of GABA.<ref name="pmid9067327"/> This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (including ]). It is also a potent ].<ref name="pmid6468504">{{cite journal | vauthors = Phillis JW, Delong RE | title = A purinergic component in the central actions of meprobamate | journal = European Journal of Pharmacology | volume = 101 | issue = 3–4 | pages = 295–7 | date = June 1984 | pmid = 6468504 | doi = 10.1016/0014-2999(84)90174-2 }}</ref><ref name="pmid4085561">{{cite journal | vauthors = DeLong RE, Phillis JW, Barraco RA | title = A possible role of endogenous adenosine in the sedative action of meprobamate | journal = European Journal of Pharmacology | volume = 118 | issue = 3 | pages = 359–62 | date = December 1985 | pmid = 4085561 | doi = 10.1016/0014-2999(85)90149-9 }}</ref> Related drugs include ] and ] (]s of meprobamate), ], ], ], and ].
Related drugs include ] (a ] of meprobamate) and ].


==Indications== ==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,<ref>{{Cite book Meprobamate is licensed{{Where|date=October 2020|talk=I'm almost certain it's still prescribed in South Africa under the name Equanil.}} 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,<ref>{{Cite book |edition=11 |publisher=McGraw-Hill Professional |isbn=978-0-07-142280-2 | vauthors = Brunton L, Lazo J, Parker K |title=Goodman And Gilman's The Pharmacological Basis of Therapeutics |date=2005-10-28|url=https://books.google.com/books?id=PtWdBgnQdjMC }}</ref> and is not used as often as the benzodiazepines for this purpose.
| edition = 11
| publisher = McGraw-Hill Professional
| isbn = 0071422803
| last = Brunton
| first = Laurence
| coauthors = John Lazo, Keith Parker
| title = Goodman And Gilman's The Pharmacological Basis of Therapeutics
| date = 2005-10-28
|url=http://www.amazon.com/Goodman-Gilmans-Pharmacological-Basis-Therapeutics/dp/0071422803/
}}</ref> and is not used as often as the benzodiazepines for this purpose.


Meprobamate is available in 200&nbsp;mg and 400&nbsp;mg tablets for oral administration. Meprobamate is also a component of the combination drug ] (discontinued in the UK in 2002) acting as a ]. Meprobamate is available in 200- and 400-mg tablets for oral administration. It is also a component of the combination drug ] (discontinued in the UK in 2002), acting as a ].


Meprobamate is also found as a component of the combination drug "Stopayne" capsules Meprobamate, like barbiturates, possesses an analgesic/anesthetic potential. It is also found as a component of the combination analgesic Stopayne capsules ] (acetaminophen), ] and ] phosphate].


] ]


==Side effects and overdose==
==Overdose==
{{Anchor|Adverse effects}}
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 ], requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration of ] should be considered even after 4 or more hours or if levels are rising.

Symptoms of meprobamate overdose include drowsiness, headache, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock.<ref>{{cite web | url = https://livertox.nlm.nih.gov/Meprobamate.htm | archive-url = https://web.archive.org/web/20150906060856/https://livertox.nlm.nih.gov/Meprobamate.htm | archive-date = 2015-09-06 | title = Meprobamate | work = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury | publisher = U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health & Human Services }}</ref> 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 ], requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration of ] should be considered even after 4 or more hours or if levels are rising.<ref name="pmid608316">{{cite journal | vauthors = Allen MD, Greenblatt DJ, Noel BJ | title = Meprobamate overdosage: a continuing problem | journal = Clinical Toxicology | volume = 11 | issue = 5 | pages = 501–15 | date = December 1977 | pmid = 608316 | doi = 10.3109/15563657708988216 }}</ref>


==Health issues== ==Health issues==
Meprobamate is a ] drug (US) (S5 in South Africa) under the ]. With protracted use it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that of ] and ]. Meprobamate is a ] drug (US) (S5 in South Africa) <ref>{{cite web | title = medicineprices.org.za | date = July 2023 | url = https://medicineprices.org.za/#search:Equanil }}</ref> under the ]. With protracted use, it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that of ] and ] (]). 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 ] agent such as ] (in a manner similar to the use of ] therapy for opiate addiction) before attempting tapering.


While an acute ] is widely believed to be the initial cause of actor and martial artist ]'s death in 1973, another factor which may have compounded and thereby contributed to Lee's death, was his decision to take Equagesic (a brand which combined meprobamate and aspirin).<ref>{{cite web | vauthors = Molloy T | date = 20 July 2018 | title = How Did Bruce Lee Die? New Book Has a Sad, Strange Explanation (Podcast) | url = https://www.thewrap.com/how-did-bruce-lee-die-new-book-has-a-sad-strange-explanation-podcast/ | work = The Wrap }}</ref>
An acute cerebral edema caused by a reaction to ], a combination of ] and meprobamate, is believed to have caused the death of ].


"In the January 2008 issue of Drug Safety Update, a stop press article announced the recent European review of ] 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.<ref>{{cite web | title = Carisoprodol and meprobamate: risks outweigh benefits | date = February 2008 | url = http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON084737 | work = Gov.UK }}</ref>
==Chemistry==
Meprobamate, 2-methyl-2-propyl-1,3-propandiol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules of ] and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the di] via successive reactions with ] and ].
]
*F.M. Berger, B.J. Ludwig, {{US Patent|2724720}} (1955).
*F.A. Fries, K. Moenkemeyer, {{Cite patent|CH|373026}} (1963).
*{{Cite doi|10.1021/ja01156a086}}


The European Medicines Agency recommended suspension of marketing authorisations for meprobamate-containing medicines in the European Union in January 2012.
==References==

==Synthesis==
]

Meprobamate, 2-methyl-2-propyl-1,3-propanediol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules of ] and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the di] via successive reactions with ] and ].

== See also ==
* ]
* ]
* ]
* ]
* ]

== References ==
{{Reflist|2}} {{Reflist|2}}


==External links== == External links ==
* . * .
* . * .
* (French). *
*


{{Anxiolytics}} {{Anxiolytics}}
{{GABAA receptor positive modulators}}
{{GABAergics}}
{{Ionotropic glutamate receptor modulators}}


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