Review of the Pharmacological Properties and Clinical Usefulness of Muscarinic Agonists for Xerostomia in Patients with Sj??gren??s Syndrome

Abstract

The anti-xerostomia effects of muscarinic agonists (cholinomimetics) are reviewed. Cevimeline (cevimeline monohydrochloride hemihydrate) is a novel muscarinic agonist that stimulates salivary secretion in animals and humans both with normal salivary gland function and with impaired salivary secretion (xerostomia or oral dryness) as effectively as pilocarpine. Other classic and nonselective muscarinic agonists, such as arecoline, carbachol, muscarine and oxotremorine, as well as acetylcholine, failed to exhibit a sufficient salivation effect even at sublethal doses in animals.Oral administration of cevimeline 30mg to humans induces a moderate and lasting increase in salivary flow, and the effect is maintained for at least 4 to 6 hours, longer than with pilocarpine. Mean increases in salivary flow rates after cevimeline treatment were 2-fold higher than after placebo, and no evidence of tolerance of the pharmacological effect has been observed during prolonged administration for up to 12 months.The clinical efficacy of cevimeline in relieving symptoms of xerostomia, including oral dryness and difficulties in chewing, swallowing and speaking, has been demonstrated by placebo-controlled, double-blind, randomised clinical trials in the USA and Japan. In these studies, cevimeline 30mg three times daily increased salivary flow and improved the symptoms of xerostomia in a significantly higher percentage of patients compared with placebo. Some patients receiving cevimeline therapy for xerostomia experienced adverse events such as sweating, gastrointestinal symptoms (nausea, diarrhoea, abdominal pain and vomiting), dizziness and rigors; these effects were related to muscarinic activity and were generally mild and tolerable in comparison with those of pilocarpine.These findings suggest that muscarinic M3 agonists are suitable for the treatment of xerostomia. Cevimeline in particular has a long-lasting salivation effect with fewer adverse events than pilocarpine, and so is expected to be more useful for the treatment of xerostomia in patients with Sjögren's syndrome, reducing symptom severity and improving their quality of life.