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Lack of Tolerance Observed to Hypnosedative Actions upon Repeated Treatment with the Novel Hypnosedative Zopiclone (Cyclopyrrolone) in Animal Models for Hypnosedation
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Background
Benzodiazepine (BZD) hypnosedatives are widely used for treatment of insomnia and anxiety, since last 5-6 decades. Large number of BZD analogues has been synthesized to obtain superior risk/benefit ratio since then. Most of the BZDs have similar pharmacological actions; however they lack in specificity and associated with the problem of tolerance, rebound insomnia and anxiety disorders which have necessitated the search for alternatives. Zopiclone is a newer Hypnosedative chemically unrelated to benzodiazepines; binds with high affinity to benzodiazepine receptors at the site close to rather than identical to the site occupied by BZDs. Results of the earlier studies are most contradictory since, some studies reported that Zopiclone has less potential to develop tolerance, rebound insomnia and anxiety disorders on regular use than benzodiazepines and some reported even greater potential to develop these side effects than benzodiazepines. Present study was therefore designed to investigate whether tolerance is developed to hypnosedative activity on repeated administration of Zopiclone (7.5 mg/kg) daily.
Experimental approach
For evaluation of development of tolerance to its hypnosedative actions animals were treated with respective drug i.e. control group (0.1ml NS), standard group (Lorazepam 5mg/kg p.o.) and test group (Zopiclone 7.5mg/kg p.o.) for 10 consecutive days; and on 10th day Pentobarbitone sleeping time potentiation & Elevated plus maze performance test were performed. The observations of 10th day compared with observations on day one.
Results
Zopiclone (7.5 mg/kg) on chronic administration did not develop tolerance to hypnotic activity; instead this activity was increased but it was statistically insignificant i.e. P>0.05. Similar results were observed for anxiolytic activity.
Conclusions
Zopiclone can be recommended as substitute for conventional hypnosedative for short term (1 - 4 weeks) treatment of insomnia, or alternatively, long term infrequent treatment of insomnia.
Keywords
- Ashton, H. Toxicity and adverse consequences of benzodiazepine use. Psychiatric Annals (1995) 25,158- 165.
- Blanchard JC, Boireau A, Garret C, Julou L In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sci.1979. 24: 2417-2420.
- Sanger DJ, Joly D, Zivkovic B. Behavioral effects of nonbenzodiazepine anxiolytic drugs: A comparison of CGS 9896 and zopiclone with chlordiazepoxide. J Pharmacol Exp Ther 1985; 232: 831-837.
- Julou L, Bardone MC, Blanchard JC, Garret C, Stutzmann JM. Pharmacological studies on zopiclone. Pharmacology (Basel) 1983. 27 (S2): 46-58.
- Sanger DJ.The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;18 Suppl 1:9-15; discussion 41, 43-5.
- Melton ST, Wood JM, Kirkwood CK. Eszopiclone for insomnia. Ann Pharmacother. 2005 Oct;39(10):1659- 66. Epub 2005 Aug 30.
- Najib J. Eszopiclone, a nonbenzodiazepine sedativehypnotic agent for the treatment of transient and chronic insomnia. Clin Ther. 2006 Apr;28(4):491-516.
- Wadworth AN, McTavish D. Zopiclone. A review of its pharmacological properties and therapeutic efficacy as a hypnotic. Drugs Aging. 1993 Sep-Oct;3(5):441-59.
- Bramness JG; Olsen H. “[Adverse effects of zopiclone]”. Tidsskrift for den Norske laegeforening. 1998. 118 (13): 2029–32. PMID 9656789.
- Luty S, Sellman D. “Imovane—a benzodiazepine in disguise”. N. Z. Med. J. July 1993. 106 (959): 293. PMID 8321452.
- Dandiya PC, Cullumbine H, Sellers EA. Studies on Acorus calamus. IV. Investigations on mechanism of action in mice. J Pharmacol Exp Ther. 1959 Aug; 126:334–337.
- Dandiya,P.C. and Cullumbine, H. Studies on Acorus calamus (III): some pharmacological properties of the volatile oil J.Pharmacol. Expt. Therap.125:353-359, 1959
- Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat, Pharmacol Biochem Behav 1986; 24: 525-529.
- Itoh, J. Nabeshima, T. and Kameyama, T.: Utility of an elevated plus maze for the evaluation of nootropics, scopolamine and electro convulsive shock. Psychopharmacology 1990., 101: 27-33.
- Lister, R. G. The amnesic action of benzodiazepines in man. Neurosci Biobehav Rev. 1985., 9: 87-94.
- Pellow, S., Chopin, P., File, S. E. and Briley, M. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods 1985., 14: 149–167)
- G Perrault, E Morel, DJ Sanger and B Zivkovic Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. J Pharmacol Exp Ther October 1992 263:298-303
- Ozawa M., Nakada Y., Sugimachi K., Akai T., Yamaguchi M. Interactionof the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3. Nippon. Yakuri.Zasshi., 1991,98:399-408
- A Döblea, T Cantona, C Malgourisa, JM Stutzmanna, O Piota, MC Bardonea, C Paucheta and JC Blancharda European Psychiatry Volume 10, Supplement 3, 1995, Pages 117s-128s Satellite Symposium to the AEP Congress
- Anderson, Aa. “Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice.” Sleep (1987)10 Suppl 1: 54–62.
- Begg, Ej; Robson, Ra; Frampton, Cm; Campbell, Je. “A comparison of efficacy and tolerance of the short acting sedatives midazolam and zopiclone.”. The New Zealand medical journal (Oct 1992);105 (944): 428–9.
- Dorian, P; Sellers, Em; Kaplan, H; Hamilton, C. “Evaluation of zopiclone physical dependence liability in normal volunteers.” Pharmacology. (1983) 27 Suppl 2: 228–34.
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