Cevimeline hydrochloride hemihydrate

개요Although it was initially developed as a cognition enhancer, cevimeline was launched in the US for the treatment of dry mouth symptoms (xerostomia) in patients with Sjogren’s syndrome. Cevimeline is a racemic mixture of cis-oxathiolanes that can be obtained with a three step synthesis starting from quinuclidin-3-one followed by separation from its 9-12- fold less potent trans-diastereomer, This conformationally rigid analog of acetylcholine is a dual muscarinic M1/M3 agonist, selective versus M2, M4 and M5 receptors. It is the fifth M, agonist that has failed in clinical trials against Alzheimer’s disease. On the contrary, the sialagogic effects of cevimeline caused by its stimulation of M3 receptors in salivary and lacrimal glands were demonstrated in randomized double-blind placebo-controlled clinical trials (30 mg t.i.d. oral dose). Cevimeline (l-3 mg/kg i.v.) was as potent in dogs as pilocarpine (0.1-0.3 mg/kg i.v.), the only prior drug efficacious against xerostomia associated with Sjogren’s syndrome, but the effects of cevimeline lasted around 2-fold longer. No cardiovascular side effects were reported with cevimeline, unlike pilocarpine which has a 40-fold higher affinrty for the M2 receptor. Cevimeline seems to bind extensively to tissues (volume of distribution 6 L/kg in man) since it was found to be less than 20% bound to human plasma proteins. It is metabolized into the cis and transsulfoxide, a glucuronide conjugate and the N-oxide.

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일반 설명Cevimeline (Evoxac) iscis-2 -methylspiro {1-azabicyclo [2.2.2] octane-3, 5' -[1,3]oxathiolane} hydrochloride, hydrate (2:1). Cevimeline has amolecular weight of 244.79 and is a white to off white crystallinepowder. It is freely soluble in alcohol, chloroform, andwater. Cevimeline is a cholinergic agonist which binds to theM3 muscarinic receptor subtype, which results in an increasesecretion of exocrine glands, such as salivary and sweatglands. Because of these effects, it was approved for use in thetreatment of dry mouth associated with Sjgren syndrome. Bystimulating the salivary muscarinic receptors cevimeline promotessecretion thereby alleviating dry-mouth in these patients.Cevimeline is metabolized by the isozymes CYP2D6and CYP3A3 and CYP3A4. It has a half-life of 5 hours.