Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240？min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline. 1. Introduction The functions of the salivary glands are controlled by the autonomic nervous system and influenced by the sensory nervous system. When parasympathetic impulses dominate, salivary flow is greatly enhanced and the saliva has a low protein content. Studies of animal and human innervation have revealed that parasympathetic nerve fibers are present around acinar cells, ducts, and blood vessels in the major salivary glands [1]. A research has also shown that beside the classic transmitters noradrenaline and acetylcholine, neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP) (Figure 1) are present in the nerve fibers of the autonomic nervous system as well as in the auriculotemporal nerve, facial nerve, and cervical dorsal root fibers [2]. These neuropeptides are known to cause salivation in rats [2–7]. In recent years, the mechanisms of actions of drugs that used to treat xerostomia have been elucidated pharmacologically from the viewpoint of salivary neuropeptide levels. Anethole trithione and pilocarpine have been shown to elevate SP and CGRP levels in human saliva [8–11]. Figure 1: Structures of substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP). Cevimeline hydrochloride hydrate (cevimeline)
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