Although 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.
용도
Treatment of
cancer.
일반 설명
Cevimeline (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 Sj?gren 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.
