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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/02 06:18:13」(JST)

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Brotizolam^[1] (marketed under brand name Lendormin) is a sedative-hypnotic^[2] thienodiazepine drug which is a benzodiazepine analog.^[3] It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to short-acting benzodiazepines such as triazolam.^[4] It is used in the short-term treatment of severe or debilitating insomnia. Brotizolam is an extremely potent drug and has shown anti-anxiety activity at doses as low as 0.08 to 0.1 milligrams, but the usual hypnotic dose of brotizolam is 0.125 to 0.25 milligrams,^[5] and it is rapidly eliminated with an average half-life of 4.4 hours (range 3.6 - 7.9 hours).^[5]

The drug was developed by a team led by T Nishiyama while working for Takeda Chemical Industries in 1976 in Japan.^[6]

Brotizolam is not approved for sale in the UK, United States or Canada. It is approved for sale in the Netherlands, Germany, Spain, Belgium, Austria, Portugal, Israel, Italy, Taiwan and Japan.

Indications

Insomnia. Brotizolam is prescribed for the short-term treatment, 2–4 weeks only of severe or debilitating insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Brotizolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or getting to sleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.^[7]

Premedication. Brotizolam, in a dose of 0.25 mg can be used as a premedication prior to surgery, this dose was found to be comparable in efficacy to 2 mg flunitrazepam as a premedicant prior to surgery.^[8]

Side effects

Common side effects of brotizolam are typical of hypnotic benzodiazepines and are related to CNS depression, and include somnolence, ataxia, headache, anterograde amnesia, dizziness, fatigue, impairment of motor functions, slurred speech, confusion, and clumsiness.

Less common side effects include hypotension, respiratory depression, hallucinations, nausea and vomiting, palpitations, and paradoxical reactions (i.e. aggression, anxiety, violent behavior, etc.).

Brotizolam can cause residual side effects the next day such as impaired cognitive and motor functions as well as drowsiness. Disruption of sleep patterns may also occur such as suppression of REM sleep. These side effects are more likely at higher doses (above 0.5–1 mg).^[9]

In clinical trials brotizolam 0.125 to 0.5 mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5 mg, flunitrazepam 2 mg and triazolam 0.25 mg, whilst brotizolam 0.5 mg was shown to be superior to flurazepam 30 mg, but inferior to temazepam 30 mg in some studies. Brotizolam at dosages below 0.5 mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped.^[5]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[10]

Pharmacology

Brotizolam has been shown in animal studies to be a very high potency benzodiazepine, and it may be the most potent benzodiazepine used on humans. Although further studies need to be done to confirm this.^[11] The elimination half-life of brotizolam is 3–6 hours. It is absorbed rapidly after administration; after administration it is metabolised into active metabolites, one of which is far less potent than brotizolam and the other is only present in very small amounts in the blood and thus the metabolites of brotizolam do not have any pharmacological effect in humans.^[3] Brotizolam induces impairment of motor function and has hypnotic properties.^[12]

Brotizolam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages when benzodiazepines such as brotizolam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.^[13]

Abuse

Brotizolam is a drug with a potential for abuse. Drug misuse is defined as taking the drug to achieve a 'high', or continuing to take the drug in the long term against medical advice.^[14]

Abuse of brotizolam, although not widespread, was a problem in Hong Kong back in the late 1980s and 1990s. To control benzodiazepine abuse in Hong Kong, the Government's Pharmacy and Poisons Board reclassified benzodiazepines as Dangerous Drugs in October 1990. Apart from formal prescriptions, detailed records were then required for the supply and dispensing of these drugs. These regulations were applied initially only to brotizolam, triazolam and flunitrazepam as they were the major benzodiazepines of abuse. The impact of these regulatory changes on benzodiazepine use has been studied by analyzing the sales patterns of seven benzodiazepines between 1990-1993. In 1991, the sales of flunitrazepam and triazolam fell, but the sales of five unrestricted benzodiazepines increased.^[15] Particular problems arose with the trafficking and abuse of nimetazepam and the abuse of temazepam within that same year in 1991. The regulations that were originally only applied to brotizolam, triazolam and flunitrazepam were now being extended to include all benzodiazepines by January 1992. A regulation requiring the use of proper prescriptions and detailed records for the supply and dispensing of benzodiazepines, appears to have curbed, at least partially, their abuse in Hong Kong. There is still some problems with temazepam, nimetazepam, triazolam, and brotizolam but it is not major.

Commercial names

Name	Countries
Bondormin, Brotizolam	Israel
Dormex	Chile
Lendorm	Austria, Denmark
Lendormin	South Africa, Belgium, Germany, Hungary, Italy, Japan, Netherlands, Portugal, Taiwan
Lendormine	Switzerland
Lindormin	Mexico
Noctilan	Chile
Sintonal	Spain

Notes

^ DE Patent 2445430
^ Fink, Max; Irwin, Peter (1981). "Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic". Clinical Pharmacology and Therapeutics 30 (3): 336–42. doi:10.1038/clpt.1981.169. PMID 7273596.
^ ^a ^b Jochemsen, R; Wesselman, JG; Van Boxtel, CJ; Hermans, J; Breimer, DD (1983). "Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects". British Journal of Clinical Pharmacology 16 (Suppl 2): 291S–297S. doi:10.1111/j.1365-2125.1983.tb02303.x. PMC 1428224. PMID 6140948.
^ Mandrioli, Roberto; Mercolini, Laura; Raggi, Maria A. (2008). "Benzodiazepine Metabolism: an Analytical Perspective". Current Drug Metabolism 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
^ ^a ^b ^c Langley, MS; Clissold, SP (1988). "Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic". Drugs 35 (2): 104–22. doi:10.2165/00003495-198835020-00002. PMID 3281819.
^ US patent 4017620, Yutaka Kuwada et al, "Thienodiazepine derivatives", published 1975-08-05, issued 1977-12-04
^ Rickels, K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica 74: 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.
^ Nishiyama, Tomoki; Yamashita, Koichi; Yokoyama, Takeshi; Imoto, Akinobu; Manabe, Masanobu (2007). "Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam". Journal of Anesthesia 21 (1): 7–12. doi:10.1007/s00540-006-0445-2. PMID 17285406.
^ Nicholson, AN; Stone, BM; Pascoe, PA (1980). "Studies on sleep and performance with a triazolo-1, 4-thienodiazepine (brotizolam)". British Journal of Clinical Pharmacology 10 (1): 75–81. doi:10.1111/j.1365-2125.1980.tb00504.x. PMC 1430017. PMID 7397057.
^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, A.A.; Vennat, B.; Llorca, P.-M.; Eschalier, A. (2009). "Dépendance aux benzodiazépines : le syndrome de sevrage" [Benzodiazepine dependence: Focus on withdrawal syndrome]. Annales Pharmaceutiques Françaises (in French) 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
^ Shibuya, Takeshi; Field, Richard; Watanabe, Yasuo; Sato, Katsuhiko; Salafsky, Bernard (1984). "Structure-affinity relationships between several new benzodiazepine derivatives and 3H-diazepam receptor sites". Japanese Journal of Pharmacology 34 (4): 435–40. doi:10.1254/jjp.34.435. PMID 6144807.
^ Yasui, M; Kato, A; Kanemasa, T; Murata, S; Nishitomi, K; Koike, K; Tai, N; Shinohara, S; Tokomura, M (2005). "Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes". Nihon shinkei seishin yakurigaku zasshi 25 (3): 143–51. PMID 16045197.
^ Noguchi, Hideaki; Kitazumi, Kazuhiro; Mori, Megumi; Shiba, Toshiharu (2004). "Electroencephalographic Properties of Zaleplon, a Non-Benzodiazepine Sedative/Hypnotic, in Rats". Journal of Pharmacological Sciences 94 (3): 246–51. doi:10.1254/jphs.94.246. PMID 15037809.
^ Griffiths, RR; Johnson, MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of clinical psychiatry 66 (Suppl 9): 31–41. PMID 16336040.
^ Lee, KK; Chan, TY; Chan, AW; Lau, GS; Critchley, JA (1995). "Use and abuse of benzodiazepines in Hong Kong 1990-1993--the impact of regulatory changes". Journal of toxicology. Clinical toxicology 33 (6): 597–602. doi:10.3109/15563659509010615. PMID 8523479.

References

Greenblatt, DJ; Locniskar, A; Shader, RI (1983). "Pilot pharmacokinetic study of brotizolam, a thienodiazepine hypnotic, using electron-capture gas-liquid chromatography". Sleep 6 (1): 72–6. PMID 6844800.
Langley, MS; Clissold, SP (1988). "Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic". Drugs 35 (2): 104–22. doi:10.2165/00003495-198835020-00002. PMID 3281819.
Bechtel, WD (1983). "Pharmacokinetics and metabolism of brotizolam in humans". British Journal of Clinical Pharmacology 16 (Suppl 2): 279S–283S. doi:10.1111/j.1365-2125.1983.tb02301.x. PMC 1428235. PMID 6661373.
Jochemsen, Roeline; Wesselman, J. G. J.; Hermans, J.; van Boxtel, C. J.; Breimer, D. D. (1983). "Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration". British Journal of Clinical Pharmacology 16 (Suppl 2): 285S–290S. doi:10.1111/j.1365-2125.1983.tb02302.x. PMC 1428208. PMID 6661374.

External links

Inchem.org - Brotizolam

English Journal

Severe hypoglycaemia from repaglinide-brotizolam drug interaction: a case report and literature review.

Khamaisi M.SourceInstitute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center and RBappaportFaculty of Medicine-Technion, Haifa, Israel.
Diabetic medicine : a journal of the British Diabetic Association.Diabet Med.2012 Mar 13. doi: 10.1111/j.1464-5491.2012.03631.x. [Epub ahead of print]
PMID 22414218

Development and validation of a liquid chromatography method with electrospray ionization tandem mass spectrometry for the determination of brotizolam residues in beef and commercial whole milk.

Cho HJ, Jo K, Yi H, Cho SM, Abd El-Aty AM, Kim MK, Han SB, Oh JH, Kwon CH, Shim JH, Shin HC.SourceDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul, 143-701, Republic of Korea.
Biomedical chromatography : BMC.Biomed Chromatogr.2011 Sep;25(9):1061-6. doi: 10.1002/bmc.1579. Epub 2011 Mar 14.
In this work, a liquid chromatography-tandem mass spectrometric detection technique was developed and validated for the determination of brotizolam residues in beef muscle and commercial whole milk. This procedure involves the extraction of the analyte from the samples via liquid-solid extraction, a
PMID 21400549

Japanese Journal

遅発性呼吸抑制を呈したベンゾジアゼピン大量服薬患者の１例

荻野隆史,福江靖,岸大次郎 [他],小平明弘,山田拓郎,萩原周一,大嶋清宏,飯野佑一
北関東医学 63(4), 365-368, 2013
症例は37歳, 男性. 主訴は意識障害. 既往歴は双極性うつ病で精神科通院中であった. 家族との会話中に突然興奮状態となりベンゾジアゼピン系薬剤を大量服薬したため当院に救急搬送された. 内服した薬剤は, ロヒプノール (1) 60錠, レンドルミン (0.25) 30錠, デパス (0.5) 14錠, レスリン (25) 14錠であった. 来院時所見ではバイタル等は問題なかったが, 入院後経過は服 …
NAID 130003384360

ブロチゾラム口腔内崩壊錠における製剤特性の検討

井上裕,荒木淳一,成澤杏奈 [他]
ジェネリック研究 : 日本ジェネリック医薬品学会機関誌 5(1), 65-70, 2011-12
NAID 40019167833

向精神薬と転倒·転落の関係に関する研究

重山昌人,田口真穂,前山直樹,柚原初美,安里昌順,長田成巨,可知敏明,藤田康平
医療薬学 37(1), 49-55, 2011
… to have ahigh risk of causing falls.When drugs of the BZ family were classified according to tmax,the mean frequency of falls differedbetween short tmax drugs and the long tmax drugs (P <0.05).This suggests that we should avoid combining shorttmax drugs (flunitrazepam,brotizolam,and triazolam) with other medication as well as the combined use of short tmaxhypnotics and drugs having potent muscle relaxant activity (bromazepam,diazepam,etizolam etc.) unless there is good justificationfor doing this.Our study showed that quazepam and rilmazafone …
NAID 130004502652

Related Pictures

★リンクテーブル★

リンク元

「ブロチゾラム」

Brotizolam
Systematic (IUPAC) name
	2-Bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy; category	?;
Legal status	US: Schedule IV;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	48-95%
Metabolism	Hepatic
Biological half-life	4.4 hours (range, 2.6–6.9 h)
Excretion	Renal
Identifiers
CAS Registry Number	57801-81-7
ATC code	N05CD09
PubChem	CID: 2451
DrugBank	DB09017
ChemSpider	2357
UNII	5XZM1R3DKF
KEGG	D01744
ChEMBL	CHEMBL32479
Chemical data
Formula	C15H10BrClN4S
Molecular mass	393.7 g/mol
	SMILES ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(Br)S4 ;
	InChI InChI=1S/C15H10BrClN4S/c1-8-19-20-13-7-18-14(9-4-2-3-5-11(9)17)10-6-12(16)22-15(10)21(8)13/h2-6H,7H2,1H3 ; Key:UMSGKTJDUHERQW-UHFFFAOYSA-N ;
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　　[★]

英: brotizolam
商: アムネゾン、グッドミン、ゼストロミン、ソレントミン、ネストローム、ノクスタール、ブロゾーム、ブロチゾラム、ブロチゾラムM、ブロチゾラムOD、ブロチゾラン、ブロメトン、レドルパー、レンデム、レンデムD、レンドルミン、レンドルミンD、ロンフルマン

抗不安薬、睡眠薬

ベンゾジアゼピン系睡眠薬(短時間型)

特徴

自然な眠りに近いスムーズな入眠。
高齢者への副作用が比較的少ない。

構造

作用機序

中枢神経系の代表的抑制性伝達物質であるGABAを介して情動をつかさどる視床下部や大脳辺縁系を抑制する(ラット)。
その結果、自律神経系その他の部位からの余剰刺激は遮断され、催眠、鎮静、抗不安等の中枢神経作用を現す。

薬理作用

動態

適応

不眠症、麻酔前投薬

注意

禁忌

重症筋無力症：［重症筋無力症を悪化させるおそれがある。］
急性狭隅角緑内障：［眼内圧を上昇させるおそれがある。］

原則禁忌

（次の患者には投与しないことを原則とするが、特に必要とする場合には慎重に投与すること）

肺性心、肺気腫、気管支喘息及び脳血管障害の急性期等で呼吸機能が高度に低下している場合［炭酸ガスナルコーシスを起こすおそれがある。］

副作用

臨床試験及び再審査終了時の調査症例6,548例中、副作用が報告されたのは256例（3.91％）であった。主な副作用は、残眠感・眠気144件（2.20％）、ふらつき66件（1.01％）、頭重感50件（0.76％）、だるさ48件（0.73％）、めまい25件（0.38％）、頭痛8件（0.12％）、けん怠感7件（0.11％）等であった。また、臨床検査値においては特に一定の傾向を示す変動は認められていない。(レンドルミン錠)

添付文書

レンドルミン錠

http://www.info.pmda.go.jp/go/pack/1124009F1223_1_05/

[1] DE Patent 2445430

[2] Fink, Max; Irwin, Peter (1981). "Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic". Clinical Pharmacology and Therapeutics 30 (3): 336–42. doi:10.1038/clpt.1981.169. PMID 7273596.

[pmid6140948-3] Jochemsen, R; Wesselman, JG; Van Boxtel, CJ; Hermans, J; Breimer, DD (1983). "Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects". British Journal of Clinical Pharmacology 16 (Suppl 2): 291S–297S. doi:10.1111/j.1365-2125.1983.tb02303.x. PMC 1428224. PMID 6140948.

[4] Mandrioli, Roberto; Mercolini, Laura; Raggi, Maria A. (2008). "Benzodiazepine Metabolism: an Analytical Perspective". Current Drug Metabolism 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.

[pmid3281819-5] Langley, MS; Clissold, SP (1988). "Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic". Drugs 35 (2): 104–22. doi:10.2165/00003495-198835020-00002. PMID 3281819.

[6] US patent 4017620, Yutaka Kuwada et al, "Thienodiazepine derivatives", published 1975-08-05, issued 1977-12-04

[7] Rickels, K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica 74: 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.

[8] Nishiyama, Tomoki; Yamashita, Koichi; Yokoyama, Takeshi; Imoto, Akinobu; Manabe, Masanobu (2007). "Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam". Journal of Anesthesia 21 (1): 7–12. doi:10.1007/s00540-006-0445-2. PMID 17285406.

[9] Nicholson, AN; Stone, BM; Pascoe, PA (1980). "Studies on sleep and performance with a triazolo-1, 4-thienodiazepine (brotizolam)". British Journal of Clinical Pharmacology 10 (1): 75–81. doi:10.1111/j.1365-2125.1980.tb00504.x. PMC 1430017. PMID 7397057.

[10] Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, A.A.; Vennat, B.; Llorca, P.-M.; Eschalier, A. (2009). "Dépendance aux benzodiazépines : le syndrome de sevrage" [Benzodiazepine dependence: Focus on withdrawal syndrome]. Annales Pharmaceutiques Françaises (in French) 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.

[11] Shibuya, Takeshi; Field, Richard; Watanabe, Yasuo; Sato, Katsuhiko; Salafsky, Bernard (1984). "Structure-affinity relationships between several new benzodiazepine derivatives and 3H-diazepam receptor sites". Japanese Journal of Pharmacology 34 (4): 435–40. doi:10.1254/jjp.34.435. PMID 6144807.

[12] Yasui, M; Kato, A; Kanemasa, T; Murata, S; Nishitomi, K; Koike, K; Tai, N; Shinohara, S; Tokomura, M (2005). "Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes". Nihon shinkei seishin yakurigaku zasshi 25 (3): 143–51. PMID 16045197.

[13] Noguchi, Hideaki; Kitazumi, Kazuhiro; Mori, Megumi; Shiba, Toshiharu (2004). "Electroencephalographic Properties of Zaleplon, a Non-Benzodiazepine Sedative/Hypnotic, in Rats". Journal of Pharmacological Sciences 94 (3): 246–51. doi:10.1254/jphs.94.246. PMID 15037809.

[14] Griffiths, RR; Johnson, MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of clinical psychiatry 66 (Suppl 9): 31–41. PMID 16336040.

[15] Lee, KK; Chan, TY; Chan, AW; Lau, GS; Critchley, JA (1995). "Use and abuse of benzodiazepines in Hong Kong 1990-1993--the impact of regulatory changes". Journal of toxicology. Clinical toxicology 33 (6): 597–602. doi:10.3109/15563659509010615. PMID 8523479.

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案内

案内

brotizolam