Nimetazepam

Last updated
Nimetazepam
Nimetazepam.svg
Nimetazepam ball-and-stick model.png
Clinical data
Trade names Erimin
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • X
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Metabolism Liver
Elimination half-life 14–30 hours
Excretion Kidney
Identifiers
  • 1-methyl-7-nitro-5-phenyl-3H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.016.302 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H13N3O3
Molar mass 295.298 g·mol−1
3D model (JSmol)
  • [O-][N+](C1=CC2=C(C=C1)N(C)C(CN=C2C3=CC=CC=C3)=O)=O
  • InChI=1S/C16H13N3O3/c1-18-14-8-7-12(19(21)22)9-13(14)16(17-10-15(18)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3 Yes check.svgY
  • Key:GWUSZQUVEVMBPI-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nimetazepam (marketed under brand name Erimin and Lavol) is an intermediate-acting hypnotic drug which is a benzodiazepine derivative. It was first synthesized by a team at Hoffmann-La Roche in 1964. [2] It possesses powerful hypnotic, anxiolytic, sedative, and skeletal muscle relaxant properties. Nimetazepam is also a particularly potent anticonvulsant. [3] It is marketed in 5 mg tablets known as Erimin, which is the brand name manufactured and marketed by the large Japanese corporation Sumitomo. Japan is the sole manufacturer of nimetazepam in the world. Outside of Japan, Erimin is available in much of East and Southeast Asia and was widely prescribed for the short-term treatment of severe insomnia in patients who have difficulty falling asleep or maintaining sleep. Sumitomo has ceased manufacturing Erimin since November 2015. It is still available as a generic drug or as Lavol.

Contents

Nimetazepam was widely prescribed in the 1980s and 1990s, particularly in Japan, Malaysia, Brunei, the Philippines, Thailand, Indonesia, Hong Kong and Singapore. Prescriptions for the drug have decreased dramatically since 2005 due to rampant misuse and addiction. It is primarily used as an anticonvulsant in children. It is also still used in the most severe and debilitating cases of insomnia in an inpatient setting or in short term outpatient treatment. Hypnotic benzodiazepines estazolam and nitrazepam are used more frequently than nimetazepam for this purpose. Antidepressants such as trazodone and mirtazapine or Z-drugs like zopiclone and zolpidem are first line treatment for insomnia.

Although prescriptions for nimetazepam have decreased, abuse of the drug is still significant in Brunei, Singapore, Malaysia, and the Philippines. It is commonly used in combination with methamphetamine and MDMA (Ecstasy) and opiates (especially heroin or morphine). The strict legal restrictions nimetazepam is subject to in Malaysia has made the drug scarce, but many pills sold as nimetazepam in the black market are counterfeit. Diazepam and nitrazepam are among the most commonly prescribed benzodiazepines in the region, and as a result, they are commonly diverted and sold on the black market, often as nimetazepam.

Illicit manufacturing of nimetazepam (sold as Erimin-5) is prevalent in the region. Abuse of nimetazepam continued to rise throughout the 2010s. Seizures of illicitly manufactured Erimin-5 tablets paralleled the seizures of methamphetamine seizures in Malaysia. A small seizure of 46 illicit Erimin-5 tablets were tested for their physical and chemical characteristics. The active ingredient, adulterant, major diluent, and dyes make up the chemical characteristics of a tablet. The results indicated that nimetazepam was the most common active ingredient in the vast majority of the tablets seized. Lactose was detected as a major diluent in the majority of the samples, followed by mannitol and then calcium phosphate dibasic dihydrate. Sunset yellow was found in most of the tablet samples either alone or in combination with other dyes such as tartrazine and ponceau 4R to give the tablets a peach/orange colour. Green tablets in the samples contained brilliant blue and tartrazine dyes. Diazepam, which is primarily an anxiolytic, was the active ingredient in only one tablet out of the 46. Nitrazepam, a powerful sedative-hypnotic, which is also nimetazepams parent drug, was found to be a minor compound together with a caffeine as a major compound in three of the tablets. [4]

In 2003, 94,200 Erimin-5 tablets were seized in Singapore. The Central Narcotics Bureau's (CNB) laboratory tested the tablets with results that confirmed the tablets were indeed nimetazepam.

Pharmacokinetics

Taken orally, Nimetazepam has very good bioavailability with nearly 100% being absorbed from the gut. It is among the most rapidly absorbed and quickest acting oral benzodiazepines, and hypnotic effects are typically felt within 15–30 minutes after oral ingestion. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.5–0.7 hours and the terminal half-life from 8 to 26.5 hours (mean 17.25 hours).[ citation needed ] It is the N-methylated analogue of nitrazepam (Mogadon, Alodorm), to which it is partially metabolized. nitrazepam has a long elimination half-life, so effects of repeated dosage tend to be cumulative.

Recreational use

There is a risk of misuse and dependence in both patients and non-medical users of Nimetazepam. The pharmacological properties of Nimetazepam such as high affinity binding, high potency, being short to intermediate – acting and having a rapid onset of action increase the abuse potential of Nimetazepam. The physical dependence and withdrawal syndrome of Nimetazepam also adds to the addictive nature of Nimetazepam.

Nimetazepam has a particular reputation in South East Asia for recreational use, at around USD 7 per tab, and is particularly popular among persons addicted to amphetamines or opioids. [5] [6] In addition, Nimetazepam has an anti-depressant and muscle relaxant effect. [7] Nimetazepam also has withdrawal suppression effect and lower drug seeking versus nitrazepam in rhesus monkey (Macaca Mulatta). [8] which might help stimulant addicts to overcome withdrawal symptoms.

Drug misuse

Nimetazepam has a reputation for being particularly subject to abuse (known as 'Happy 5', sold as an ecstasy replacement without a hangover). Although is still a significant drug of abuse in some Asian countries such as Japan and Malaysia, Nimetazepam is subject to legal restrictions in Malaysia, and due to its scarcity, many tablets sold on the black market are in fact counterfeits containing other benzodiazepines such as diazepam or nitrazepam instead. [9] [10] [11]

In the United States, Nimetazepam is categorized Schedule IV FDA and DEA.

Nimetazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971. [12]

In Singapore, Nimetazepam is a physician prescribed drug, and is regulated under the Misuse of Drugs Act. [13] The illegal possession or consumption of Nimetazepam is punishable by up to 10 years of imprisonment, a fine of 20,000 Singapore dollars, or both. Importing or exporting nimetazepam is punishable by up to 20 years of imprisonment and/or caning.

In Hong Kong, Nimetazepam is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Nimetazepam can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. [14]

Similarly in Taiwan and Indonesia Nimetazepam is also regulated as a controlled prescribed substance.

In Victoria Australia, nimetazepam is regulated under Schedule 11 of "Drugs, Poisons and Controlled substances act 1981". It is deemed to fall under the category of "7-NITRO-1,4-BENZODIAZEPINES not included elsewhere in this Part". . [15]

Toxicity

In a rat study Nimetazepam showed greater damage to the fetus, as did nitrazepam when compared against other benzodiazepines, all at a dosage of 100 mg/kg. Diazepam however showed relatively weak fetal toxicities. [16] The same fetotoxicity of nitrazepam could not be observed in mice and is likely due to the particular metabolism of the drug in the rat. [17]

In a rat study nimetazepam showed slight enlargement of the liver and adrenals and atrophy of the testes and ovaries were found in high dose groups of both drugs at the 4th and 12th week, however, in histopathological examination, there were no change in the liver, adrenals and ovaries. Degenerative changes of seminiferous epithelium in the testes were observed, but these atrophic change returned to normal by withdrawal of the drugs for 12 weeks. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Flunitrazepam</span> Benzodiazepine sedative

Flunitrazepam, sold under the brand name Rohypnol among others, is a benzodiazepine used to treat severe insomnia and assist with anesthesia. As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Temazepam</span> Insomnia medication

Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic effects begin in less than 30 minutes and can last for up to eight hours. Prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam, clonazepam, and lorazepam have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs and atypical antidepressants as first line treatment for insomnia.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.

<span class="mw-page-title-main">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<span class="mw-page-title-main">Flurazepam</span> Hypnotic medication

Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

Thailand's Psychotropic Substances Act is a law designed to regulate certain mind-altering drugs. According to the Office of the Narcotics Control Board, "The Act directly resulted from the Convention on Psychotropic Substances 1971 of which Thailand is a party." The Act divides psychotropic drugs into four Schedules. Offenses involving Schedule I and II drugs carry heavier penalties than those involving Schedule III and IV drugs. Note that this statute does not regulate most opioids, cocaine, or some amphetamines. The vast majority of narcotic painkillers, along with cocaine and most amphetamines are regulated under the Narcotics Act.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Pinazepam</span> Benzodiazepine drug

Pinazepam is a benzodiazepine drug. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Camazepam</span> Chemical compound

Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Fludiazepam</span> Chemical compound

Fludiazepam, marketed under the brand name Erispan (エリスパン) is a potent benzodiazepine and 2ʹ-fluoro derivative of diazepam, originally developed by Hoffmann-La Roche in the 1960s. It is marketed in Japan and Taiwan. It exerts its pharmacological properties via enhancement of GABAergic inhibition. Fludiazepam has 4 times more binding affinity for benzodiazepine receptors than diazepam. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Fludiazepam has been used recreationally.

<span class="mw-page-title-main">Etizolam</span> Benzodiazepine analog drug

Etizolam is a thienodiazepine derivative which is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.

<span class="mw-page-title-main">Brotizolam</span> Benzodiazepine

Brotizolam is a sedative-hypnotic thienotriazolodiazepine drug which is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to other short-acting hypnotic benzodiazepines such as triazolam or midazolam. It is used in the short-term treatment of severe insomnia. Brotizolam is a highly potent and short-acting hypnotic, with a typical dose ranging from 0.125 to 0.25 milligrams, which is rapidly eliminated with an average half-life of 4.4 hours.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Flutoprazepam</span> Benzodiazepam

Flutoprazepam (Restas) is a drug which is a benzodiazepine. It was patented in Japan by Sumitomo in 1972 and its medical use remains mostly confined to that country. Its muscle relaxant properties are approximately equivalent to those of diazepam - however, it has more powerful sedative, hypnotic, anxiolytic and anticonvulsant effects and is around four times more potent by weight compared to diazepam. It is longer acting than diazepam due to its long-acting active metabolites, which contribute significantly to its effects. Its principal active metabolite is n-desalkylflurazepam, also known as norflurazepam, which is also a principal metabolite of flurazepam.

<span class="mw-page-title-main">Menitrazepam</span> Chemical compound

Menitrazepam is a drug which is a benzodiazepine derivative. It is similar in structure to tetrazepam and nimetazepam, with the 7-chloro group of tetrazepam replaced by nitro. It is a hypnotic agent used in the treatment of insomnia, and therefore has strong sedative, anticonvulsant, muscle relaxant, and anxiolytic actions like those of other hypnotic benzodiazepines. Menitrazepam is a good oral hypnotic agent, however, delay in the time for peak plasma levels to reach their maximum brings into question the benefit of menitrazepam for the treatment of insomnia when compared to other hypnotics. Typically, the sleep inducing properties of hypnotics occur within 0.5 hours. In some cases, as with temazepam and nitrazepam, strong hypnotic effects can be felt 15 to 20 minutes after oral ingestion.

<span class="mw-page-title-main">Benzodiazepine overdose</span> Medical condition

Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. The most common symptoms of overdose include central nervous system (CNS) depression, impaired balance, ataxia, and slurred speech. Severe symptoms include coma and respiratory depression. Supportive care is the mainstay of treatment of benzodiazepine overdose. There is an antidote, flumazenil, but its use is controversial.

<span class="mw-page-title-main">Benzodiazepine use disorder</span> Illicit use of benzodiazepine drugs

Benzodiazepine use disorder (BUD), also called misuse or abuse, is the use of benzodiazepines without a prescription and/or for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.

<span class="mw-page-title-main">Diclazepam</span> Benzodiazepine medication

Diclazepam (Ro5-3448), also known as chlorodiazepam and 2'-chloro-diazepam, is a benzodiazepine and functional analog of diazepam. It was first synthesized by Leo Sternbach and his team at Hoffman-La Roche in 1960. It is not currently approved for use as a medication, but rather sold as an unscheduled substance. Efficacy and safety have not been tested in humans.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ USpatent 3109843,Reeder E, Sternbach LH,"Process for preparing 5-phenyl-1,2-dihydro-3H-1,4-benzodiazepines",issued 1963-11-05, assigned to Hoffmann-La Roche
  3. ↑ Fukinaga M, Ishizawa K, Kamei C (November 1998). "Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action". Pharmacology. 57 (5): 233–41. doi:10.1159/000028247. PMID   9742288. S2CID   25773207.
  4. ↑ Kunalan, V (2012). "Forensic Drug Profiling of Erimin-5 Using TLC and GC-MS". Malaysian Journal of Forensic Sciences. 3: 1–14 – via ResearchGate.
  5. ↑ Chong YK, Kaprawi MM, Chan KB (2004). "The Quantitation of Nimetazepam in Erimin-5 Tablets and Powders by Reverse-Phase HPLC". Microgram Journal. 2 (1–4): 27–33. Archived from the original on 2011-08-10. Retrieved 2011-12-07.
  6. ↑ Devaney M, Reid G, Baldwin S (2005). "Situational analysis of illicit drug issues and responses in the Asia-Pacific region" (pdf). ANCD Research Paper 12. Canberra: Australian National Council on Drugs.
  7. ↑ Sakai S, Kitagawa S, Yamamoto H (March 1972). "Pharmacological studies on 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (S-1530)". Arzneimittel-Forschung. 22 (3): 534–9. PMID   5067925.
  8. ↑ Yanagita T, Takahashi S, Oinuma N. "Drug Dependence Liability of nimetazepam evaluated in the Rhesus Monkey".{{cite journal}}: Cite journal requires |journal= (help)
  9. ↑ Abdullah AF, Abraham AA, Sulaiman M, Kunalan V (2012). "Forensic Drug Profiling of Erimin-5 Using TLC and GC-MS". Malaysian Journal of Forensic Sciences. 3 (1): 12–15.
  10. ↑ Binti Abdul Rahim, Rusdiyah. "Profiling of Illicit Erimin 5 Tablet Seized in Malaysia". A Research Project Report Submitted to the Department of Chemistry, Faculty of Science, University of Malaya.
  11. ↑ "Erimin 5 Tablets In Singapore". The Centre for Forensic Science, HSA, Singapore. 2006.
  12. ↑ "List of psychotropic substances under international control" (PDF). Green List Annex to the annual statistical report on psychotropic substances (form P) (23rd ed.). International Narcotics Control Board. August 2003. Archived from the original (PDF) on 2012-08-31. Retrieved 2011-12-06.
  13. ↑ "Misuse of drugs act, chapter 185". Archived from the original on 2012-02-15. Retrieved 2011-09-08.
  14. ↑ "Bilingual Laws Information System". The Government of the Hong Kong Special Administrative Region of the People's Republic of China.
  15. ↑ "Victorian Legislation and Parliamentary Documents". The State Government Victoria.
  16. ↑ Saito H, Kobayashi H, Takeno S, Sakai T (December 1984). "Fetal toxicity of benzodiazepines in rats". Research Communications in Chemical Pathology and Pharmacology. 46 (3): 437–47. PMID   6151222.
  17. ↑ Takeno S, Hirano Y, Kitamura A, Sakai T (August 1993). "Comparative developmental toxicity and metabolism of nitrazepam in rats and mice". Toxicology and Applied Pharmacology. 121 (2): 233–8. Bibcode:1993ToxAP.121..233T. doi:10.1006/taap.1993.1150. PMID   8346540.
  18. ↑ Yamamoto T, Kato T, Wada H, Kerata Y (1972). "Chronic Toxicity of 1-Methyl-7-Nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Nimetazepam)in Rats". Chronic Toxicity.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.