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Drugs

, Volume 35, Issue 2, pp 104–122 | Cite as

Brotizolam

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy as an Hypnotic
  • Mark S. Langley
  • Stephen P. Clissold
Drug Evaluation

Summary

Synopsis

Brotizolam is a new thienotriazolodiazepine derivative with a pharmacological profile similar to that of benzodiazepines. it is indicated for use as an hypnotic in the management of insomnia, although it also has anticonvulsant, antianxiety and muscle relaxant properties in animals.

In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies. Brotizolam is an effective hypnotic for hospital patients awaiting surgery, in whom it also reduces anxiety.

Brotizolam has an elimination half-life of about 5 hours, which is ‘intermediate’ compared with the shorter-acting hypnotic, triazolam, and longer-acting benzodiazepines. Consequently, it is able to induce sleep without producing early morning rebound insomnia, and can also maintain sleep throughout the night. Brotizolam at dosages below 0.5mg 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/kg. 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.

Thus, brotizolam is a useful hypnotic which can be used in patients who have difficulty in falling asleep and also in patients who are troubled by night-time awakenings. Used in the recommended dosage it may be particularly useful for patients in whom daytime impairment of performance is unacceptable.

Pharmacodynamic Studies

Brotizolam binds with high affinity to benzodiazepine receptor sites, and in animal studies it demonstrated anticonvulsant, antianxiety and muscle relaxant properties similar to those of nitrazepam and other benzodiazepines. In healthy volunteers and insomniacs, brotizolam 0.2 to lmg increases total sleep time and reduces total wake time by both hastening sleep onset and reducing the number and duration of nocturnal awakenings. Stage 2 sleep is increased, particularly in insomniacs. Rapid eye movement (REM) sleep was usually reduced in patients with insomnia receiving brotizolam 0.5mg at night (a dose of 0.25mg did not affect REM sleep) but was not significantly altered in healthy volunteers who received doses of 0.1 to lmg at night. Following abrupt withdrawal of brotizolam therapy, rebound insomnia has been reported in some individuals. Brotizolam at dosages of less than 0.3mg in the morning caused minimal changes in acute psychometric function tests, whereas higher dosages were associated with a more significant impairment of attention, concentration and psychomotor performance. Following nighttime doses of brotizolam up to 0.5mg minimal residual effects have been noted the next morning; however, a dose of 0.6mg caused impairment of visuomotor performance for up to 14.5 hours. Animal studies suggested that brotizolam is unlikely to produce physical dependence at normal therapeutic dosages.

Pharmacokinetic Studies

Maximum plasma concentrations of brotizolam usually occur within 2 hours of single oral 0.25 to 1mg doses, and there appears to be a linear relationship between dose and mean maximum plasma concentration for dosages up to 1.5mg. After administration of brotizolam 0.5mg orally its bio-availability was calculated to be 70%. Brotizolam rapidly distributes throughout the body and animal studies have shown that it passes into breast milk and crosses the placenta. The apparent volume of distribution of brotizolam was 0.66 L/kg after administration of 0.25mg intravenously to healthy volunteers. Brotizolam is extensively bound to human plasma proteins (89 to 95%).

Brotizolam is rapidly and almost completely metabolised in the liver by oxidation, the primary metabolites being 1-methylhydroxy and 4-hydroxy derivatives. These have some pharmacological activity, but are further metabolised to inactive conjugates of glucuronic or sulphuric acid and eliminated via the kidneys. Excretion of a single dose is complete within 4 days. Brotizolam has a short elimination half-life (about 5 hours) which is increased in elderly subjects (mean values of up to 9.8 hours have been reported). Renal insufficiency does not affect the elimination of brotizolam. In contrast, elimination half-life is longer in patients with liver cirrhosis and this was associated with decreased clearance and increased volume of distribution. Currently there is no evidence that either brotizolam or its metabolites accumulate with repeated administration.

Therapeutic Trials

In non-comparative trials of up to 26 weeks’ duration, brotizolam 0.125 to 0.5mg was found to be an effective and well tolerated hypnotic. A number of double-blind trials compared the efficacy of brotizolam with placebo in outpatients with insomnia, and usually doses of 0.25 and 0.5mg significantly reduced the time taken to fall asleep, reduced nocturnal awakenings and improved sleep quality. Nightly doses of brotizolam 0.125mg adequately increased the duration and quality of sleep in elderly patients.

In short term comparative studies, brotizolam dosages of 0.125 and 0.25mg at night were found to be equal or superior to nitrazepam 2.5 and 5mg in improving the sleep performance of general practice outpatients, hospital inpatients and geriatric patients. No clinically significant differences were documented in double-blind clinical trials comparing brotizolam 0.25mg with flurazepam 15mg, flunitrazepam 2mg or triazolam 0.25mg. However, in one study brotizolam 0.5mg was significantly better than flurazepam 30mg in improving the sleep of hospital inpatients with insomnia.

As an hypnotic for patients the night before surgery brotizolam was generally more effective than flunitrazepam 2mg and, in 1 study, was preferred by a greater proportion of patients. Brotizolam 0.5mg administered 2 hours prior to surgery significantly reduced the dose of thiopentone (297 vs 319mg, p < 0.02) required to produce the same level of anaesthesia, compared with placebo.

Preliminary studies suggest that brotizolam may be a useful hypnotic for subjects with disrupted sleep cycles (intercontinental travellers, shift or night workers, etc.) and further investigations in this setting are warranted.

Side Effects

Brotizolam has generally been well tolerated in clinical trials to date and discontinuation of therapy has rarely been necessary. Its side effect profile is similar to that of the shorter acting benzodiazepines, with drowsiness, dizziness and headache being the most frequently reported adverse experiences. Isolated instances of tinnitus, visual disturbances, difficulty in concentrating, dry mouth and nausea have been documented. Brotizolam did not affect cardiovascular or respiratory function and there have been no significant adverse biochemical or haematological reactions.

In some patients withdrawal of brotizolam has led to a degree of rebound insomnia on the first night without treatment, but usually the symptoms were not severe. Similar symptoms were noted after discontinuation of nitrazepam.

Dosage and Administration

The recommended oral dosage of brotizolam is 0.25mg taken before retiring, although this may be increased to 0.5mg in selected patients. Elderly patients should initially receive 0.125mg. No reduction of dose is necessary for patients with renal insufficiency.

Elimination of brotizolam is significantly impaired in patients with liver cirrhosis and so it should be avoided or used with extreme caution in these circumstances. As with other hypnotic drugs, patients should be cautioned about the possible effects of taking other depressant drugs and alcohol.

Keywords

Clinical Pharmacology Triazolam Total Sleep Time Flunitrazepam Nitrazepam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Ahmad F, Rittmeyer G, Goetzke E, Köster J. Brotizolam as a pre-operative hypnotic. British Journal of Clinical Pharmacology 16: 419S-423S, 1983CrossRefGoogle Scholar
  2. Bechtel WD. Pharmacokinetics and metabolism of brotizolam in humans. British Journal of Clinical Pharmacology 16: 279S-283S, 1983CrossRefGoogle Scholar
  3. Bechtel WD. Radioreceptor assay of brotizolam in human plasma. Fresenins Zeitschrift für Analytische Chemie 317: 714–715, 1984CrossRefGoogle Scholar
  4. Bechtel WD, Ensinger HA, Mierau J. Biochemical studies with the new thienotriazolodiazepine brotizolam. Arzneimittel-Forschung 36: 534–540, 1986aPubMedGoogle Scholar
  5. Bechtel WD, Goetzke E. Elimination of brotizolam in elderly patients after multiple doses. European Journal of Clinical Pharmacology 31: 243–245, 1986PubMedCrossRefGoogle Scholar
  6. Bechtel WD, Mierau J, Brandt K, Förster HJ, Pook KH. Metabolic fate of [14C]-brotizolam in the rat, dog, monkey and man. Arzneimittel-Forschung 36: 578–586, 1986bPubMedGoogle Scholar
  7. Bechtel WD, Mierau J, Richter I, Stiasni M. Blood level, distribution, excretion and metabolite pattern of [l4C]-brotizolam in the rat, dog and rhesus monkey. Arzneimittel-Forschung 36: 568–574, 1986cPubMedGoogle Scholar
  8. Bechtel WD, van Weyjen RGA, van den Ende A. Blood level, excretion and metabolite pattern of [14C]-brotizolam in humans. Arzneimittel-Forschung 36: 575–578, 1986dPubMedGoogle Scholar
  9. Bechtel WD, Weber KH. Brotizolam radio-immunoassay: development, evaluation and application to human plasma samples. Journal of Pharmaceutical Sciences 74: 1265–1269, 1985PubMedCrossRefGoogle Scholar
  10. Böke-Kuhn K, Dannenberg P, Kuhn FJ, Lehr E. Antiemotional and anticonvulsant activity of brotizolam and its effects on motor performance in animals. Arzneimittel-Forschung 36: 528–531, 1986PubMedGoogle Scholar
  11. Cohn MA. The effects of brotizolam, a new hypnotic, on cardiac and respiratory function in volunteers/Respiration 45: 281–285, 1984Google Scholar
  12. Danneberg P, Böke-Kuhu, Bechtel WD, Lehr E. Pharmacological action of some known and possible metabolites of brotizolam. Arzneitmittel-Forschung 36: 587–591, 1986Google Scholar
  13. Dominguez RA, Goldstein BJ, Jacobson AF, Steinbook RM. Hypnotic efficacy of a modified triazolodiazepine, brotizolam. Clinical Pharmacology and Therapeutics 37: 674–679, 1985PubMedCrossRefGoogle Scholar
  14. Evers J, Renner E, Bechtel WD. Pharmacokinetics of brotizolam in renal failure. British Journal of Clinical Pharmacology 16: 309S–313S, 1983PubMedCrossRefGoogle Scholar
  15. Ferrara N, Valentini P, Sestito M, DePrisco F, Veniero AM, et al. Comparison between brotizolam and nitrazepam in geriatric patients: randomized and cross-over double-blind clinical study. Current Therapeutic Research 3.7: 295–308, 1985Google Scholar
  16. Fink M, Irwin P. Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic. Clinical Pharmacology and Therapeutics 30: 336–342, 1981PubMedCrossRefGoogle Scholar
  17. Fritz-Osner A, Arias-Ortiz JL, Dorantes JF, Rabago-Sanchez J, Rodriguez-Tenorio A, et al. Brotizolam and chronic insomnia: a multi-centre study. British Journal of Clinical Pharmacology 16: 413S–414S, 1983PubMedCrossRefGoogle Scholar
  18. Goetzke E, Findeisen P, Welbers IB. Efficacy and tolerance: comparative studies with brotizolam and flunitrazepam. British Journal of Clinical Pharmacology 16: 397S–402S, 1983aPubMedCrossRefGoogle Scholar
  19. Goetzke E, Fineisen P, Welbers IB. Comparative study on the efficacy of and the tolerance to the triazolodiazepines, triazolam and brotizolam. British Journal of Clinical Pharmacology 16: 407S-412S, 1983bCrossRefGoogle Scholar
  20. Greenblatt DJ, Locniskar A, Shader RI. Pilot pharmacokinetic study of brotizolam, a thienodiazepine hypnotic, using electron-capture gas-liquid chromatography. Sleep 6: 72–76, 1983PubMedGoogle Scholar
  21. Grünberger J, Saletu B, Linzmayer L, Kalk A, Berner P. Pharmacodynamic investigations with We 941, a new triazolodiazepine, by means of psychometric analyses. Current Therapeutic Research 24: 427–440, 1978Google Scholar
  22. Hanaoka K, Tagami M, Inada Y, Yamamura H, Bechtel WD, et al. Clinical-pharmacological study of brotizolam (We 941) — phase 1 clinical trial. Japanese Journal of Clinical Pharmacology and Therapeutics 14: 365–377, 1983CrossRefGoogle Scholar
  23. Hare SA, Sonnenfeld ED. A controlled trial of brotizolam versus flunitrazepam as a hypnotic. South African Medical Journal 64: 277–278, 1983PubMedGoogle Scholar
  24. Hartse KM, Thornby JI, Karacan I, Williams RL. Effects of brotizolam, flurazepam and placebo upon nocturnal auditory arousal thresholds. British Journal of Clinical Pharmacology 16: 355S-364S, 1983CrossRefGoogle Scholar
  25. Ishiko J, Inagaki C, Takaori S. Inhibitory effects of brotizolam, a new thienodiazepine, on limbic prebrain and neostriatial dopaminergic systems in vivo and in vitro. Neuropharmacology 22: 221–226, 1983PubMedCrossRefGoogle Scholar
  26. Itil TM, Michael ST, Seaman P, Kunitz A, Bowers P, et al. Effects of brotizolam on patients with sleep disturbance, and on their daytime performance: a double-blind control study. Psychopharmacology Bulletin 19: 752–757, 1983Google Scholar
  27. Jacobson AF, Dominguez RA, Goldstein BJ, Steinbook RM. Efficacy of brotizolam in geriatric patients with insomnia. Current Therapeutic Research 39: 528–539, 1986Google Scholar
  28. Jochemsen R, Joeres RP, Wesselman JGJ, Richter E, Breimer DD. Pharmacokinetics of oral brotizolam in patients with liver cirrhosis. British Journal of Clinical Pharmacology 16: 315S–322S, 1983aPubMedCrossRefGoogle Scholar
  29. Jochemsen R, Naudi KL, Corless D, Wesselman JGJ, Breimer DD. Pharmacokinetics of brotizolam in the elderly. British Journal of Clinical Pharmacology 16: 299S–307S, 1983bPubMedCrossRefGoogle Scholar
  30. Jochemsen R, van Rijn PA, Hazelzet TGM, Breimer DD. Assay of midazolam and brotizolam in plasma by a gas Chromatographic and a radioreceptor technique. Pharmaceutisch Week-blad Scientific Edition 5: 308–312, 1983cCrossRefGoogle Scholar
  31. Jochemsen R, Wesselman JGJ, Hermans J, van Boxtel CJ, Breimer DD. Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration. British Journal of Clinical Pharmacology 16: 285S-290S, 1983dCrossRefGoogle Scholar
  32. Jochemsen R, Wesselman JGJ, van Boxtel CJ, Hermans J, Breimer DD. Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects. British Journal of Clinical Pharmacology 16: 291S-297S, 1983eCrossRefGoogle Scholar
  33. Johns MW. Sleep and hypnotic drugs. Drugs 9: 448–478, 1975PubMedCrossRefGoogle Scholar
  34. Kales A, Soldatos CR, Bixler EO, Kales JD. Early morning insomnia with rapidly eliminated benzodiazepines. Science 220: 95–97, 1983PubMedCrossRefGoogle Scholar
  35. Kimishima K, Tanabe K, Kinoshita Y, Tokuyoshi K, Houri D, et al. Effects of brotizolam, a new thienotriazolodiazepine derivative, on the central nervous system. Japanese Journal of Pharmacology 36: 461–475, 1984PubMedCrossRefGoogle Scholar
  36. Kraft TB, Venema J, Cornelissen PJG. Brotizolam in psychiatric insomnia: a controlled comparison with flurazepam in hospital patients. Journal for Drug Therapy and Research 9: 29–32, 1984Google Scholar
  37. Kreuger H, Müller-Limmroth W. Residual effects of flurazepam and brotizolam on psychomotor performance. British Journal of Clinical Pharmacology 16: 347S–351S, 1983CrossRefGoogle Scholar
  38. Kubicki ST. Electroencephalographic assessment of dosage and sleep profile of a hypnotic triazolothienodiazepine. Zeitschrift für EEG-EMG 10: 95–100, 1979Google Scholar
  39. Lohmann H, von Delbrück O, Findeisen P. Comparative studies on the efficacy of brotizolam and nitrazepam: a multi-centre study. British Journal of Clinical Pharmacology 16: 403S–406S, 1983PubMedCrossRefGoogle Scholar
  40. Mamelak M, Csima A, Price V. Effects of brotizolam on the sleep of chronic insomniacs. British Journal of Clinical Pharmacology 16: 377S–382S, 1983PubMedCrossRefGoogle Scholar
  41. Nicholson AN, Pascoe PA, Roehrs T, Roth T, Spencer MB, et al. Sustained performance with short evening and morning sleeps. Aviation, Space, and Environmental Medicine 56: 105–114, 1985PubMedGoogle Scholar
  42. Nicholson AN, Pascoe PA, Spencer MB, Stone BM, Roehrs MB, et al. Sleep after transmeridian flights. Lancet 2: 1205–1208, 1986PubMedCrossRefGoogle Scholar
  43. Nicholson AN, Stone BM, Pascoe PA. Studies on sleep and performance with a triazolo-l,4-thienodiazepine (brotizolam). British Journal of Clinical Pharmacology 10: 75–81, 1980PubMedCrossRefGoogle Scholar
  44. Nicholson AN, Stone BM, Pascoe PA. Hypnotic efficacy in middle-age. Journal of Clinical Psychopharmacology 2: 118–121, 1982PubMedCrossRefGoogle Scholar
  45. Owen RT, Tyrer P. Benzodiazepine dependence: a review of the evidence. Drugs 25: 385–398, 1983PubMedCrossRefGoogle Scholar
  46. Rickels K, Morris RJ, Mauriello R, Rosenfeld H, Chung HR, et al. Brotizolam, a triazolothienodiazepine in insomnia. Clinical Pharmacology and Therapeutics 40: 293–299, 1986PubMedCrossRefGoogle Scholar
  47. Roehrs T, Zorick F, Koshorek GL, Wittig R, Roth T. Effects of acute administration of brotizolam in subjects with disturbed sleep. British Journal of Clinical Pharmacology 16: 371S–376S, 1983PubMedCrossRefGoogle Scholar
  48. Saletu B, Grünberger J, Linzmayer L. Quantitative pharmaco-EEG and performance after administration of brotizolam to healthy volunteers. British Journal of Clinical Pharmacology 16: 333S-345S, 1983CrossRefGoogle Scholar
  49. Saletu B, Grünberger J, Stöllberger I. Confirmation of pharmaco-EEG predictions concerning pharmacodynamic properties of an anxiolytic sedative by sleep studies. Advances in Biological Psychiatry 6: 126–142, 1981Google Scholar
  50. Sanchez-Martinez J, Landa-Palos J. A new thienodiazepine, brotizolam, for the treatment of insomnia. Journal of International Medical Research 10: 118–121, 1982PubMedGoogle Scholar
  51. Sato K, Liu HJ, Saruhasa T, Shibuya T. Pharmacological studies on brotizolam (We 941) a thienotriazolodiazepine derivative. Journal of Tokyo Medical College 43: 661–672, 1985Google Scholar
  52. Scavone JM, Greenblatt DJ, Harmatz JS, Shader RL Kinetic and dynamic interaction of brotizolam and ethanol. British Journal of Clinical Pharmacology 21: 197–204, 1986PubMedCrossRefGoogle Scholar
  53. Serra C, Rossi A, Ruocco A, Serra LL. Brotizolam vs nitrazepam in the management of agripnia. Clinical Trials Journal 22: 448–454, 1985Google Scholar
  54. Stockhaus K. Physical dependence capacity of brotizolam in rhesus monkeys. 2nd communication: primary dependence and barbital substitution. Arzneimittel-Forschung 36: 601–605, 1986PubMedGoogle Scholar
  55. Stockhaus K, Bechtel WD. Physical dependence capacity of brotizolam in rhesus monkeys. 1st communication: primary dependence studies. Arzneimittel-Forschung 36: 597–600, 1986PubMedGoogle Scholar
  56. Sybrecht GW. Influence of brotizolam on the ventilatory and mouth-occlusion pressure response to hypercapnia in patients with chronic obstructive pulmonary disease. British Journal of Clinical Pharmacology 16: 425S–430S, 1983PubMedCrossRefGoogle Scholar
  57. Ueki S, Watanabe S, Yamamoto T, Shibata S, Shibata K. Behavioral effects of brotizolam, a new thienotriazolodiazepine derivative. Japanese Journal of Pharmacology 35: 287–299, 1984PubMedCrossRefGoogle Scholar
  58. Uzzan B, Warot D, Chermot P, Dantlo B, Bornstein S, et al. Hypnotic activity of brotizolam: a study in general practice. British Journal of Clinical Pharmacology 16: 417S–418S, 1983PubMedCrossRefGoogle Scholar
  59. Valencia-Tello MA. Estudio clinica de una nueva tienodiacepinabrotizolam como medication preanestésica. Investigation Médica Internacional 9: 117–123, 1982Google Scholar
  60. Vela-Bueno A, Oliveros JC, Dobladez-Blanco B, Arrigain-Ijurra S, Soldatos CR, et al. Brotizolam: a sleep laboratory evaluation. European Journal of Clinical Pharmacology 25: 53–56, 1983PubMedCrossRefGoogle Scholar
  61. Velasco M, Velasco F, Cepeda C, Romo R, Pérez-Toledo MA. Effect of a new thienodiazepine (We 941) on sleep patterns of normal and insomniac subjects. Neuropharmacology 20: 461–468, 1981PubMedCrossRefGoogle Scholar
  62. Viukari M, Vartio T, Verho E. Low doses of brotizolam and nitrazepam as hypnotics in the elderly. Neuropsychobiology 12: 130–133, 1984PubMedCrossRefGoogle Scholar
  63. von Delbrück O, Geotzke E, Nagel C, Tolerance studies with brotizolam in hospitalized patients. British Journal of Clinical Pharmacology 16: 385S–389S, 1983aCrossRefGoogle Scholar
  64. von Delbrück O, Nagel C, Lichterfeld A. Efficacy and acceptability of brotizolam in the elderly. British Journal of Clinical Pharmacology 16: 391S–395S, 1983bCrossRefGoogle Scholar
  65. Weber KH, Kuhn FJ, Böke-Kuhn K, Lehr E, Dannenberg PB, et al. Pharmacological and neurochemical properties of 1,4-diazepines with two annealated heterocycles (‘hetrazepines’). European Journal of Pharmacology 109: 19–31, 1985PubMedCrossRefGoogle Scholar
  66. Wheatley D. Studies in general practice with brotizolam. British Journal of Clinical Pharmacology 16: 415S-416S, 1983CrossRefGoogle Scholar
  67. Wheatley D. Brotizolam: a new short-acting hypnotic. International Clinical Psychopharmacology 1: 36–44, 1986PubMedCrossRefGoogle Scholar
  68. Yoshida T, Oiwa Y, Kobayashi S, Matsumura R, Kokei H. Absorption, distribution and excretion of [l4C]-brotizolam. Japanese Pharmacology and Therapeutics 13: 76–88, 1985Google Scholar
  69. Zorick F, Kribbs N, Roehrs T, Roth T. Polysomnographic and MMPI characteristics of patients with insomnia. In Hind-marsh et al. (Eds) Sleep, benzodiazepines and performance, pp. 2–10, Springer-Verlag, 1984Google Scholar

Copyright information

© ADIS Press Limited 1988

Authors and Affiliations

  • Mark S. Langley
    • 1
  • Stephen P. Clissold
    • 1
  1. 1.ADIS Drug Information ServicesManchester and AucklandEngland

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