(±)-cis-2-Methylspiro[1,3-oxathiolane-5,3-quinuclidine] Hydrochloride, Hemihydrate (SNI-2011, Cevimeline Hydrochloride) Induces Saliva and Tear Secretions in Rats and Mice: The Role of Muscarinic Acetylcholine Receptors

Abstract

We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats and mice to evaluate its therapeutical efficacy for xerostomia and xerophthalmia in patients with Sjogren's syndrome and X-ray exposure in the head and neck. Intraduodenal administrations of SNI-2011 increased saliva secretion in a dose-dependent manner at doses ranging from 3 to 30 mg/kg in normal rats and mice, two strains of autoimmune disease mice and X-irradiated saliva secretion defective rats. The salivation elicited by SNI-2011 was completely inhibited by atropine. A similar atropine-sensitive response was observed in tear secretion. In rat submandibular/sublingual gland membranes, [3H]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot analysis revealed a single population of binding sites with a Kd of 22 pM and a maximal binding capacity of 60 fmol/mg protein. The competitive inhibition curve of the [3H]QNB binding by SNI-2011 was obtained, and its dissociation constant value calculated from IC50 was 1-2 microM. These results suggest that SNI-2011 increases saliva and tear secretions through a direct stimulation to muscarinic receptors in salivary and lacrimal glands, and they suggest that SNI-2011 should be beneficial to patients with Sjögren's syndrome and X-ray exposure in the head and neck.

Protease-Activated Receptor-2 (PAR-2)-Related Peptides Induce Tear Secretion in Rats: Involvement of PAR-2 and Non-PAR-2 Mechanisms

“…The tear secretion bioassay was performed in pentobarbital-anesthetized rats essentially according to the previously described method with minor modifications (Iga et al, 1998). Briefly, Schirmer strips that are clinically used to measure the amount of tear secreted were inserted into the inner aspect of bilateral eyelids in the rats and replaced with new strips every 2 min.…”

Cevimeline for the treatment of dry mouth in patients with Sjogren's syndrome

“…and can, therefore, increases the secretion of saliva. 13 The dominant characteristics of this drug compared to Pilocarpine are its longer lasting effect on salivation, from 1.4 to 1.8 times longer in rats, and twice as long in dogs. 17 The studies on rats have also demonstrated that cevimeline is able to induce lacrimal secretions without having to increase the intake of water with the dosage necessary for the induction of salivation.…”

Cevimeline-Induced Monophasic Salivation from the Mouse Submandibular Gland: Decreased Na+Content in Saliva Results from Specific and Early Activation of Na+/H+Exchange

“…This secretion was completely inhibited by atropine, a muscarinic AChR antagonist, and 4-diphenylacetoxy-Nmethyl-piperidine methiodide, an M3 AChR antagonist (Iwabuchi and Masuhara, 1994). The binding affinity of M3 receptors for CVL is thought to be the same as or higher than affinities for other muscarinic drugs (Iga et al, 1998). Furthermore, CVL has been shown to increase salivary secretion in both healthy subjects and patients being treated for dry mouth, including patients with Sjögren's syndrome and patients after radiotherapy for head and neck cancer (Fife et al, 2002;Chambers et al, 2007;Braga et al, 2009).…”