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Sunday, 13 July 2014

BROMAZEPAM SYNTHESIS

Bromazepam.svg

Bromazepam
Bromazepam-from-xtal-3D-balls.png
Systematic (IUPAC) name
7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
Clinical data
Trade namesLexotan, Lexotanil
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy cat.D (USA)
Legal statusSchedule IV(US)
RoutesOral
Pharmacokinetic data
Bioavailability84%
MetabolismHepatic
Half-life12-20 hours
ExcretionRenal
Identifiers
CAS number1812-30-2 Yes
ATC codeN05BA08
PubChemCID 2441
DrugBankDB01558
ChemSpider2347 Yes
UNIIX015L14V0O Yes
KEGGD01245 Yes
ChEMBLCHEMBL277062 Yes
Chemical data
FormulaC14H10BrN3O 
Mol. mass316.2

Chemical  Synthesis Of Bromazepam






Synthesis

anthranilamide + P4O10 Phosphorus pentoxide → anthranilonitrile + 2-pyridyllithium → 2-(2-Aminobenzoyl)pyridine.

Bromazepam synthesis.[60]


Bromazepam
Use: tranquilizer
 7- bromo- 1 ,3- di hydro- 5- (2- pyridinyl)- 2 H- 1 ,4- benzo diazepine- 2- one
 MW: 316.16 MF: C14H10BrN3O
 LD50: 879 mg/kg (M, p.o.);1950 mg/kg (R, p.o.)
Bromazepam Reference(s):
 US 3 100 770 (Roche; 13.8.1963; appl. 11.8.1961).
US 3 182 065 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).
US 3 182 066 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).
US 3 182 067 (Roche; 4.5.1965; appl. 9.4.1964).
Fryer, R.I. et al.: J. Pharm. Sci. (JPMSAE) 53, 264 (1964).

modified methods:
DAS 2 233 483 (Roche; appl. 7.7.1972; GB-prior. 8.7.1971, 7.10.1971).
DOS 2 252 378 (Roche; appl. 25.10.1972; CH-prior. 18.11.1971).


alternative synthesis of 2-(2-amino-5-bromobenzoyl)pyridine:
DAS 2 256 614 (Roche; appl. 17.11.1972).
DAS 1 813 241 (Roche; appl. 6.12.1968; J-prior. 8.12.1967, 9.12.1967, 12.12.1967,
25.4.1968).

combination with sulpiride:
DAS 2 342 214 (Roche; appl. 21.8.1973; CH-prior. 21.9.1972).

A white or yellowish crystalline powder. M.p. 237° to 238.5° with decomposition.
Practically insoluble in water, sparingly soluble in alcohol and in dichloromethane.

Bromazepam Dissociation Constant.

pKa2.9, 11.0.

Partition Coefficient.

Log P(octanol/water), 2.05.

Colour Test.

Formaldehyde–Sulfuric Acid—yellow.

Bromazepam Thin–layer Chromatography.

System TA—Rf 61; system TB—Rf 6; system TC—Rf 41; system TD—Rf 13; system TE—Rf 63; system TF—Rf 18; system TL—Rf 53; system TAD—Rf 47; system TAE—Rf 73; system TAF—Rf 69; system TAJ—Rf 34; system TAK—Rf 04; system TAL—Rf 63.

Bromazepam Gas Chromatography.

System GA—bromazepam RI 2665, M (3-OH-) RI 2470; system GB—bromazepam RI 2760, bromazepam-TMS RI 2702; M (3-OH-)-TMS2 RI 2650; system GG—RI 3280.
Column: DB-17 (30 m × 0.32 mm i.d., 0.25 μm film thickness). Column temperature: 150°, held for 1 min, ramp to 230°, held for 5 min, ramp to 300° held for 9 min at 10°/min. Injector and detector temperatures: 270° and 300°, respectively. Carrier gas: helium (pre–column pressure, 80 kPa). Detection: ECD. Retention time: 18.0 min. [F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.]
Column: HP5-MS (5% phenyl:95% siloxane, 30 m × 0.25 mm, 0.25 μm film thickness). Column temperature: 60° held for 1 min, ramp to 295° at 30°/min, held for 6 min. Injector temperature: 250°. Carrier gas: helium, flow rate 1 mL/min. MS detection (NCI mode). Retention time: 9.7 min. [P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129.]

Bromazepam High Performance Liquid Chromatography.

System HI—k 2.32; system HK—k 2.99; system HX—RI 397; system HY—RI 331; system HZ—retention time 3.0 min; system HAA—retention time 14.7 min; system HAF—retention time 6.6 min (tailing peak); system HAX—retention time 5.8 min; system HAY—retention time 5.1 min; system HBH—k 1.63; system HBI—k 0.80; system HAL—retention time 8.1 min; system HAM—not detected.
Column: RP C18 (150 × 3.9 mm i.d., 5 μm). Mobile phase: water:acetonitrile:triethylamine (700:300:4), adjusted to pH 7.4 with phosphoric acid, flow rate 2 mL/min. UV detection (λ = 240 nm). Retention time: bromazepam, 2.1 min,α-hydroxytriazolam (IS), 3.2 min. [Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775.]

Bromazepam Ultraviolet Spectrum.

Aqueous acid—239, 345 nm; aqueous alkali—237 nm (A11=920b), 348 nm; methanol—233 nm (A11=1050b), 320 nm (A11=61b).

Bromazepam Infra–red Spectrum.

Principal peaks at wavenumbers 1685, 825, 750, 802, 1315, 1230 cm−1.

Bromazepam Mass Spectrum.

Principal ions at m/z 236, 317, 315, 288, 316, 286, 208, 78; 3–hydroxybromazepam 79, 78, 52, 105, 304, 314, 316, 51.

Quantification.

Gas chromatography.

In plasma: limit of detection 5 μg/L, ECD—U. Klotz,J. Chromatogr.,1981, 222(21) B Biomed. Appl., 501–506. In plasma or blood: bromazepam and other benzodiazepines, ECD and NPD—P. Lillsunde and T. Seppala,J. Chromatogr.,1990, 533, 97–110. In hair: limit of detection, 20 pg/mg hair, MS (NCI mode)—P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129. In urine: bromazepam and other benzodiazepines, limit of detection for bromazepam 160 μg/L, ECD—F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.

Bromazepam Gas chromatography–mass spectrometry.

In tissue: limit of quantification, 50 ng/g tissue, SIM—X.X. Zhang et al.,J. Chromatogr.,1996, 677 B Biomed. Appl., 111–116. In urine: bromazepam, diazepam, and nordazepam, TOF–MS, comparison with MS and ECD—B. Aebi et al.,Forensic Sci. Int.,2002, 128, 84–89.

Bromazepam High performance liquid chromatography.

In plasma: limit of detection 5 μg/L, UV detection—H. Hirayama et al.,J. Chromatogr.,1983, 277(28) B Biomed. Appl., 414–418. In plasma: limit of detection 3 μg/L, UV detection—A. Boukhabza et al.,Analyst,1989, 114, 639–641. In plasma: limit of detection, 50 μg/L, UV detection—H. Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775. In serum: bromazepam and other benzodiazepines, UV detection—E. Tanaka et al.,J. Chromatogr.,1996,682 B Biomed Appl., 173–178 and E. Tanaka et al.,J. Chromatogr. B Biomed. Sci. Appl.,1998, 709, 324.

Bromazepam Disposition in the Body.

Well absorbed after oral administration and peak plasma concentrations are usually achieved within 2 h. About 70% of a dose is excreted in the urine in 72 h, including about 2% of the dose as unchanged bromazepam, about 27% as the glucuronide of 3–hydroxybromazepam, about 40% as the glucuronide of 2–amino–5–bromo–3–hydroxybenzoylpyridine, and less than 1% as 2-(2–amino–5–bromobenz–oyl)-pyridine.

Bromazepam Therapeutic concentration

After a single oral dose of 12 mg, administered to 10 subjects, peak plasma concentrations of 0.11 to 0.17 mg/L (mean 0.13) were attained in 1 to 4 h. Steady–state concentrations of 0.08 to 0.15 mg/L (mean 0.12) were measured during dosing of 6 subjects with 9 mg daily. [S. A. Kaplan et al.,J. Pharmacokinet. Biopharm.,1976, 4, 1–16.]
Administration of bromazepam as a slow–release formulation to 24 healthy subjects after an overnight fast resulted in peak plasma concentrations of 9.09 to 13.00 μg/L (mean 11.05 μg/L) attained in 4 to 16 h (mean 8 h); the corresponding values for a conventional–release preparation administered as 2 separate 1.5 mg doses, 12 h apart, were 8.91 to 11.50 μg/L (mean 10.21 μg/L) in 2 to 8 h (mean 8 h). [F. E. Lerner et al.,Arzneimittelforschung,2001,51, 955–958.]

Toxicity

In a 68–year–old woman who was found unconscious and barely breathing, bromazepam intoxication was discovered to be the cause (a serum level of 6 mg/L was detected); normal functions were restored 12 days after the ingestion. [J. Rudolf et al.,Dtsch. Med. Wochenschr.,1998, 123, 832–834.]
A 42–year–old woman ingested 420 mg bromazepam in a suicide attempt and survived despite being found unconscious outdoors in a state of semi–undress and suffering from hypothermia. About 12 h after the ingestion the blood concentration of bromazepam was 7.7 mg/L. [K. Michaud et al.,Forensic Sci. Int.,2001, 124, 112–114.]

Bromazepam Half–life.

Plasma half–life, 8 to 19 h (mean 12).

Bromazepam Volume of distribution.

About 0.9 L/kg.

Bromazepam Protein binding.

In plasma, 70%.

Bromazepam Dose.

Usually 3 to 18 mg daily; up to a maximum of 60 mg daily in divided doses has been given to hospitalised patients.
tags-synthesis of drugs,method of preparation of Bromazepam,molecular weight Bromazepam, molecular formula of  Bromazepam,structure of Bromazepam,A1%1 cm Bromazepam

Bromazepam (marketed under several brand names, including Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil,Bromaze, Somalium and Lexotanil)[1] is a benzodiazepine derivative drug, patented by Roche in 1963[2] and developed clinically in the 1970s.[3][4] It has mainly an anti-anxiety agent with similar side effects to diazepam (Valium). In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.[5] Bromazepam is contraindicated and should be used with caution in women who are pregnant, the elderly, patients with a history of alcohol or other substance abuse disorders and children. Prolonged use of bromazepam causes tolerance and may lead to both physical and psychological dependence on the drug, and as a result, it is a medication which is controlled by international law.

Indications

Side-effects

Bromazepam causes similar side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation,ataxia, memory impairment, and dizziness.[8] Impairments to memory functions are common with bromazepam and include a reducedworking memory and reduced ability to process environmental information.[9][10][11] A 1975 experiment on healthy, male college students exploring the effects of four different drugs on learning capacity observed that taking Bromazepam alone at 6 mg 3 times daily for 2 weeks impaired learning capacities significantly. In combination with alcohol impairments in learning capacity became even more pronounced.[12] Impaired memory, visual information processing and sensory data and impaired psychomotor performance.[13][14][15] Deterioration of cognition including attention capacity and impaired co-ordinative skills.[16][17] Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.[18] Impaired reactive and attention performance, which can impair driving skills.[19]
Drowsiness and decrease in libido.[20][21] On occasion, benzodiazepines can induce extreme alterations in memory such asanterograde amnesia and amnesic automatism, which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum.[22]
Very rarely, dystonia can develop.[23]
Up to 30% treated on a long-term basis develop a form of dependence, i.e. these patients cannot stop the medication without experiencing physical and/or psychological benzodiazepine withdrawal symptoms.
Leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer Roche recommends regular laboratory examinations to be performed routinely.
Ambulatory patients should be warned that bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.

Tolerance, dependence and withdrawal

Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological dependence and/or physical dependence.[24][25] A withdrawal study demonstrated both psychological dependence and physical dependence on bromazepam including marked rebound anxiety after 4 weeks chronic use. Those whose dose was gradually reduced experienced no withdrawal.[26]
Patients treated with bromazepam for generalised anxiety disorder were found to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms when abruptly withdrawn bromazepam.[27] Abrupt or over rapid withdrawal from bromazepam after chronic use even at therapeutic prescribed doses can lead to a severe withdrawal syndrome including status epilepticus and a condition resembling delerium tremens.[28][29][30]
Animal studies have shown that chronic administration of diazepam or bromazepam causes a decrease in spontaneous locomotor activity, decreased turnover of noradrenalineand dopamine and serotonin, increased activity of tyrosine hydroxylase and increased levels of the catecholamines. During withdrawal of bromazepam or diazepam a fall in tryptophan, serotonin levels occurs as part of the benzodiazepine withdrawal syndrome.[31] Changes in the levels of these chemicals in the brain can cause headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia.[32][33]

Contraindications and special precautions

Benzodiazepines require special precaution if used in elderly, pregnant, child, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[34]

Special populations[

  • Bromazepam may affect driving and ability to operate machinery.[36]

Interactions

Cimetidine, fluvoxamine and propranolol causes a marked increase in the elimination half-life of bromazepam leading to increased accumulation of bromazepam.[39][40][41]

Pharmacology


50 Pills of Lexotanil (containing 6 mg of Bromezepam apiece) as sold byHoffmann-La Roche in Germany
Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam,nitrazepam, flurazepam, and clorazepate.[42] Its molecular structure is composed of a diazepine connected to a benzene ring and apyridine ring, the benzene ring having a bromine atom attached to it.[43] It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.
Bromazepam binds to the GABA receptor GABAA, causing a conformational change and increasing the inhibitory effects of GABA. Bromazepam is a long-acting benzodiazepine and is lipophilic and metabolised hepatically via oxidative pathways.[44] It does not possess any antidepressant or antipsychotic qualities.[45]
After night time administration of bromazepam a highly significant reduction of gastric acid secretion occurs during sleep followed by a highly significant rebound in gastric acid production the following day.[46]
Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.[47]

Pharmacokinetics

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the Cytochrome P450 family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that CYP3A4, a member of the Cytochrome P450 family, was not the responsible enzyme since itraconazole, a known inhibitor of CYP3A4, did not affect its metabolism.[48] In 1995, J. van Harten at Solvay Duphar B.V.'s Department of Clinical Pharmacology inWeesp reported that fluvoxamine, which is a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6, does inhibit its metabolism.[41]
The active metabolite of bromazepam is hydroxybromazepam, which has a half-life approximately equal to that of bromazepam.[citation needed]

Overdose

Main article: Benzodiazepine overdose
Bromazepam is commonly involved in drug overdoses.[49] A severe bromazepam benzodiazepine overdose may result in an alpha pattern coma type.[50] The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs.[51] Bromazepam is the most common benzodiazepine involved in intentional overdoses in France.[52] Bromazepam has also been responsible for accidental poisonings in companion animals. A review of benzodiazepine poisonings in cats and dogs from 1991-1994 found bromazepam to be responsible for significantly more poisonings than any other benzodiazepine.[53]

Drug misuse

See also: Benzodiazepine drug misuse
Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam.[54] In France car accidents involving psychotropic drugs in combination found benzodiazepines, mainly diazepam, nordiazepam, and bromazepam, to be the most common drug, almost twice that of the next-most-common drug cannabis.[55] Bromazepam has also been used for serious criminal offences including robbery, homicide, and sexual assault.[56][57][58]

Legal status

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[59]

Synthesis

anthranilamide + P4O10 Phosphorus pentoxide → anthranilonitrile + 2-pyridyllithium → 2-(2-Aminobenzoyl)pyridine.

Bromazepam synthesis.[60]

See also

References

  1. Jump up^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-10-31.
  2. Jump up^ US patent 3100770, Rodney Ian Friar, "5-PYRIDYL-1,4-Benzodiazepine Compounds", published 1961-11-7, issued 1963-13-7
  3. Jump up^ "Bromazepam, a new anxiolytic: a comparative study with diazepam in general practice. Royal College of General Practitioners Medicines Surveillance Organisation". J R Coll Gen Pract 34 (266): 509–12. September 1984. PMC 1959670. PMID 6147412.
  4. Jump up^ Fontaine, R; Annable, L; Beaudry, P; Mercier, P; Chouinard, G (1985). "Efficacy and withdrawal of two potent benzodiazepines: bromazepam and lorazepam". Psychopharmacology bulletin 21 (1): 91–2. ISSN 0048-5764. PMID 2858908.
  5. Jump up^ "Bromazepam". Pharmaceutical Benefits Scheme (PBS). Australian Government - Department of Health. Retrieved 23 March 2014.
  6. Jump up^ Guelfi JD, Lancrenon S, Millet V (1993). "[Comparative double-blind study of bromazepam versus prazepam in non-psychotic anxiety]". Encephale (in French) 19 (5): 547–52.PMID 8306923.
  7. Jump up^ Chalmers, P; Horton, Jn (Apr 1984). "Oral bromazepam in premedication. A comparison with diazepam.". Anaesthesia 39 (4): 370–2. doi:10.1111/j.1365-2044.1984.tb07280.x.ISSN 0003-2409. PMID 6143514.
  8. Jump up^ "LECTOPAM®". RxMed. RxMed. Retrieved 23 March 2014.
  9. Jump up^ Münte TF, Gehde E, Johannes S, Seewald M, Heinze HJ (1996). "Effects of alprazolam and bromazepam on visual search and verbal recognition memory in humans: a study with event-related brain potentials". Neuropsychobiology 34 (1): 49–56. doi:10.1159/000119291. PMID 8884760.
  10. Jump up^ Montenegro M, Veiga H, Deslandes A, et al. (June 2005). "[Neuromodulatory effects of caffeine and bromazepam on visual event-related potential (P300): a comparative study.]". Arq Neuropsiquiatr 63 (2B): 410–5. doi:10.1590/S0004-282X2005000300009. PMID 16059590.
  11. Jump up^ Cunha M, Portela C, Bastos VH, et al. (December 2008). "Responsiveness of sensorimotor cortex during pharmacological intervention with bromazepam". Neurosci. Lett. 448 (1): 33–6. doi:10.1016/j.neulet.2008.10.024. PMID 18938214.
  12. Jump up^ Liljequist R; Linnoila M; Mattila MJ; Saario I; Seppälä T (October 1975). "Effect of two weeks' treatment with thioridazine, chlorpromazine, sulpiride and bromazepam, alone or in combination with alcohol, on learning and memory in man". Psychopharmacologia 44 (2): 205–8. doi:10.1007/BF00421011. PMID 710.
  13. Jump up^ Stacher G; Bauer P; Brunner H; Grünberger J (January 1976). "Gastric acid secretion, serum-gastrin levels and psychomotor function under the influence of placebo, insulin-hypoglycemia, and/or bromazepam". Int J Clin Pharmacol Biopharm 13 (1): 1–10. PMID 2560.
  14. Jump up^ Bourin M, Auget JL, Colombel MC, Larousse C (1989). "Effects of single oral doses of bromazepam, buspirone and clobazam on performance tasks and memory". Neuropsychobiology22 (3): 141–5. doi:10.1159/000118609. PMID 2577220.
  15. Jump up^ Puga F, Sampaio I, Veiga H, et al. (December 2007). "The effects of bromazepam on the early stage of visual information processing (P100)". Arq Neuropsiquiatr 65 (4A): 955–9.doi:10.1590/s0004-282x2007000600006. PMID 18094853.
  16. Jump up^ Saario I (April 1976). "Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol". Ann Clin Res 8 (2): 117–23.PMID 7178.
  17. Jump up^ Jansen, AA; Verbaten, MN; Slangen, JL (1988). "Acute effects of bromazepam on signal detection performance, digit symbol substitution test and smooth pursuit eye movements.".Neuropsychobiology 20 (2): 91–5. doi:10.1159/000118481. PMID 2908134.
  18. Jump up^ Patat A, Foulhoux P (July 1985). "Effect on postural sway of various benzodiazepine tranquillizers". Br J Clin Pharmacol 20 (1): 9–16. doi:10.1111/j.1365-2125.1985.tb02792.x.PMC 1400619. PMID 2862898.
  19. Jump up^ Seppälä T; Saario I; Mattila MJ (1976). "Two weeks' treatment with chlorpromazine, thioridazine, sulpiride, or bromazepam: actions and interactions with alcohol on psychomotor skills related to driving". Mod Probl Pharmacopsychiatry 11: 85–90. PMID 9581.
  20. Jump up^ Horseau, C; Brion, S (May 1982). "Clinical trial of bromazepam. Thirty-four cases (author's transl)". La Nouvelle presse médicale 11 (22): 1741–3. ISSN 0301-1518. PMID 6124948.
  21. Jump up^ Perret, J; Zagala, A; Gaio, Jm; Hommel, M; Meaulle, F; Pellat, J; Pollak, P (May 1982). "Bromazepam in anxiety. Clinical evaluation (author's transl)". La Nouvelle presse médicale 11(22): 1722–4. ISSN 0301-1518. PMID 6124942.
  22. Jump up^ Rager, P; Bénézech, M (Jan 1986). "Memory gaps and hypercomplex automatisms after a single oral dose of benzodiazepines: clinical and medico-legal aspects". Annales medico-psychologiques 144 (1): 102–9. ISSN 0003-4487. PMID 2876672.
  23. Jump up^ Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ (1992). "Bromazepam-induced dystonia". Biomed. Pharmacother. 46 (8): 375–6. doi:10.1016/0753-3322(92)90306-R. PMID 1292648.
  24. Jump up^ Rastogi RB; Lapierre YD; Singhal RL (1978). "Some neurochemical correlates of "rebound" phenomenon observed during withdrawal after long-term exposure to 1, 4-benzodiazepines".Prog Neuropsychopharmacol 2 (1): 43–54. doi:10.1016/0364-7722(78)90021-8. PMID 31644.
  25. Jump up^ Laux G (May 1979). "[A case of Lexotanil dependence. Case report on tranquilizer abuse]". Nervenarzt 50 (5): 326–7. PMID 37451.
  26. Jump up^ Fontaine, R; Chouinard, G; Annable, L (Jul 1984). "Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment.". The American Journal of Psychiatry 141(7): 848–52. ISSN 0002-953X. PMID 6145363.
  27. Jump up^ Chouinard G; Labonte A; Fontaine R; Annable L (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Prog Neuropsychopharmacol Biol Psychiatry 7 (4–6): 669–73. doi:10.1016/0278-5846(83)90043-X. PMID 6141609.
  28. Jump up^ Böning, J (May 1981). "Bromazepam withdrawal delirium - a psychopharmacological contribution to clinical withdrawal syndromes (author's transl)". Der Nervenarzt 52 (5): 293–7.ISSN 0028-2804. PMID 6113557.
  29. Jump up^ Thomas P, Lebrun C, Chatel M (1993). "De novo absence status epilepticus as a benzodiazepine withdrawal syndrome". Epilepsia 34 (2): 355–8. doi:10.1111/j.1528-1157.1993.tb02421.x. PMID 8384109.
  30. Jump up^ Fukuda M, Nakajima N, Tomita M (January 1999). "Generalized tonic-clonic seizures following withdrawal of therapeutic dose of bromazepam". Pharmacopsychiatry 32 (1): 42–3.doi:10.1055/s-2007-979188. PMID 10071183.
  31. Jump up^ Agarwal RA, Lapierre YD, Rastogi RB, Singhal RL (May 1977). "Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam". Br. J. Pharmacol. 60 (1): 3–9. doi:10.1111/j.1476-5381.1977.tb16740.x. PMC 1667179. PMID 18243.
  32. Jump up^ Professor Heather Ashton (2002). "Benzodiazepines: How They Work and How to Withdraw".
  33. Jump up^ O'Connor, RD (1993). "Benzodiazepine dependence--a treatment perspective and an advocacy for control". NIDA research monograph 131: 266–9. PMID 8105385.
  34. Jump up^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
  35. Jump up^ Ochs, HR, Greenblatt, DJ, Friedman, H, Burstein, ES, Locniskar, A, Harmatz, JS, Shader, RI. (May 1987). "Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol". Clinical Pharmacology & Therapeutics 41 (5): 562–70. doi:10.1038/clpt.1987.72. PMID 2882883.
  36. Jump up^ Hobi, V; Kielholz, P; Dubach, Uc (Oct 1981). "The effect of bromazepam on fitness to drive (author's transl)". MMW, Munchener medizinische Wochenschrift 123 (42): 1585–8.ISSN 0341-3098. PMID 6118830.
  37. Jump up^ Hoffman LaRoche Pharmaceuticals (3 April 2008). "NAME OF THE MEDICINE LEXOTAN" (PDF). Australia: roche-australia.com. Archived from the original on 19 July 2008. Retrieved 16 December 2008.
  38. Jump up^ Martens PR (June 1994). "A sudden infant death like syndrome possibly induced by a benzodiazepine in breast-feeding". Eur J Emerg Med 1 (2): 86–7. doi:10.1097/00063110-199406000-00008. PMID 9422145.
  39. Jump up^ Ochs HR, Greenblatt DJ, Friedman H, et al. (May 1987). "Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol". Clin. Pharmacol. Ther. 41 (5): 562–70. doi:10.1038/clpt.1987.72. PMID 2882883.
  40. Jump up^ Perucca E, Gatti G, Spina E (September 1994). "Clinical pharmacokinetics of fluvoxamine". Clin Pharmacokinet 27 (3): 175–90. doi:10.2165/00003088-199427030-00002.PMID 7988100.
  41. ^ Jump up to:a b van Harten J (1995). "Overview of the pharmacokinetics of fluvoxamine". Clin Pharmacokinet 29 (Suppl 1): 1–9. doi:10.2165/00003088-199500291-00003. PMID 8846617.
  42. Jump up^ Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.
  43. Jump up^ Bromazepam Eutimia.com - Salud Mental. © 1999-2002.
  44. Jump up^ Oelschläger H. (4 July 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.
  45. Jump up^ Amphoux, G; Agussol, P; Girard, J (May 1982). "The action of bromazepam on anxiety (author's transl)". La Nouvelle presse médicale 11 (22): 1738–40. ISSN 0301-1518.PMID 6124947.
  46. Jump up^ Stacher G; Stärker D (February 1974). "Inhibitory effect of bromazepam on basal and betazole-stimulated gastric acid secretion in man". Gut 15 (2): 116–20.doi:10.1136/gut.15.2.116. PMC 1412901. PMID 4820635.
  47. Jump up^ Fink M; Weinfeld RE; Schwartz MA; Conney AH (August 1976). "Blood levels and electroencephalographic effects of diazepam and bromazepam". Clin Pharmacol Ther 20 (2): 184–91.PMID 7375.
  48. Jump up^ Oda M, Kotegawa T, Tsutsumi K, Ohtani Y, Kuwatani K, Nakano S. "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers."European Journal of Clinical Pharmacology. 2003 Nov;59(8-9):615-9. Epub 2003 Sep 27. PMID 14517708 English Fulltext (registration required) Japanese Fulltext (PDF, no registration)
  49. Jump up^ Gandolfi E, Andrade Mda G (December 2006). "[Drug-related toxic events in the state of São Paulo, Brazil]". Rev Saude Publica (in Portuguese) 40 (6): 1056–64. PMID 17173163.
  50. Jump up^ Pasinato, E; Franciosi, A; De, Vanna, M (Apr 1983). ""Alpha pattern coma" after poisoning with flunitrazepam and bromazepam. Case description". Minerva psichiatrica 24 (2): 69–74.ISSN 0374-9320. PMID 6140613.
  51. Jump up^ Marrache F, Mégarbane B, Pirnay S, Rhaoui A, Thuong M (October 2004). "Difficulties in assessing brain death in a case of benzodiazepine poisoning with persistent cerebral blood flow". Hum Exp Toxicol 23 (10): 503–5. doi:10.1191/0960327104ht478cr. PMID 15553176.
  52. Jump up^ Staikowsky F, Theil F, Candella S (July 2005). "[Trends in the pharmaceutical profile of intentional drug overdoses seen in the emergency room]". Presse Med (in French) 34 (12): 842–6.PMID 16097205.
  53. Jump up^ Bertini, S; Buronfosse F; Pineau X; Berny P; Lorgue G. (Dec 1995). "Benzodiazepine poisoning in companion animals.". Vet Hum Toxicol 37 (6): 559–62. PMID 8588297. Retrieved 31 March 2014.
  54. Jump up^ Woods, Jh (Mar 1984). "Progress report on the stimulant-depressant abuse liability evaluation project". NIDA research monograph 49: 59–62. ISSN 1046-9516. PMID 6148695.
  55. Jump up^ Staub C, Lacalle H, Fryc O (1994). "[Presence of psychotropic drugs in the blood of drivers responsible for car accidents, and who consumed alcohol at the same time]". Soz Praventivmed (in French) 39 (3): 143–9. PMID 8048274.
  56. Jump up^ Brinkmann, B; Fechner, G; Püschel, K (Dec 1984). "Identification of mechanical asphyxiation in cases of attempted masking of the homicide". Forensic Science International 26 (4): 235–45. doi:10.1016/0379-0738(84)90028-8. ISSN 0379-0738. PMID 6519613.
  57. Jump up^ de Boisjolly JM, Rougé-Maillart C, Roy PM, Roussel B, Turcant A, Delhumeau A (August 2003). "[Chemical submission]". Presse Med (in French) 32 (26): 1216–8. PMID 14506459.
  58. Jump up^ Djezzar S, Questel F, Burin E, Dally S (October 2008). "Chemical submission: results of 4-year French inquiry" (PDF). Int. J. Legal Med. 123 (3): 213–9. doi:10.1007/s00414-008-0291-x. PMID 18925406.
  59. Jump up^ List of psychotropic substances under international control (PDF). International Narcotics Control Board.
  60. Jump up^ http://drugsynthesis.blogspot.co.uk/2012/01/laboratory-synthesis-of-bromazepam.html

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