Yoshinori Iga, Hirohiko Arisawa, Nobuo Ogane, Yasunari Saito, Toshie
Tomizuka, Yuzo Nakagawa-Yagi, Hiroaki Masunaga, Hiroshi Yasuda and Nobuo
Miyata
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd.,
519, Shimo-ishibashi, Ishibashi-machi, Shimotsuga-gun, Tochigi 329-0512,
Japan
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 Sjogren's syndrome and X-ray exposure in the head and neck.
Keywords: SNI-2011, Muscarinic agonist, Sjogren's syndrome, Salivary
gland, Lacrimal gland