Clinical Drug Investigation

, Volume 22, Issue 2, pp 67–73 | Cite as

Review of the Pharmacological Properties and Clinical Usefulness of Muscarinic Agonists for Xerostomia in Patients with Sjögren’s Syndrome

  • Hiroshi Yasuda
  • Hiroshi Niki
Review Article


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.


Pilocarpine Salivary Flow Salivary Secretion Muscarinic Agonist Salivary Flow Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors sincerely acknowledge the help of their colleagues for their collaboration on this project.


  1. 1.
    Navazesh M, Ship II. Xerostomia: diagnosis and treatment. Am J Otolaryngol 1983; 4: 283–92PubMedCrossRefGoogle Scholar
  2. 2.
    Sreebny LM, Valdini A. Xerostomia: a neglected symptom. Arch Intern Med 1987; 147: 1333–7PubMedCrossRefGoogle Scholar
  3. 3.
    Bjerrum K, Prause JU. Primary Sjogren’s syndrome: a subjective description of the disease. Clin Exp Rheumatol 1990; 8: 283–8PubMedGoogle Scholar
  4. 4.
    Diagnosis of Sjögren’s syndrome. Lancet 1992; 340: 150–1Google Scholar
  5. 5.
    Talal N. Sjögren’s syndrome: historical overview and clinical spectrum of disease. Rheum Dis Clin North Am 1992; 18: 507–15PubMedGoogle Scholar
  6. 6.
    Dreizen S, Brown LR, Handler S, et al. Radiation-induced xerostomia in cancer patients: effect of salivary and serum electrolytes. Cancer 1976; 38: 273–8PubMedCrossRefGoogle Scholar
  7. 7.
    Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med 1999; 159: 174–81PubMedCrossRefGoogle Scholar
  8. 8.
    Fox RI, Michelson P. Approaches to the treatment of Sjögren’s syndrome. J Rheumatol Suppl 2000; 61: 15–21Google Scholar
  9. 9.
    Wiseman LR, Faulds D. Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs 1995; 49: 143–55PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher A, Brandeis R, Pittel Z, et al. Cis-2-methyl-spiro (l, 3-oxathiolane)-quinuclidine (AF102B), a new Ml agonist attenuates cognitive dysfunctions in AF64A-treated rats. Neurosci Lett 1989; 102: 325–31PubMedCrossRefGoogle Scholar
  11. 11.
    Iwabuchi Y, Masuhara T. Sialogogic activities of SNI-2011 compared with those of pilocarpine and McN-A-343 in rat salivary glands: identification of a potential therapeutic agent for treatment of Sjögren’s syndrome. Gen Pharmacol 1994; 25: 123–9PubMedCrossRefGoogle Scholar
  12. 12.
    Masunaga H, Ogawa H, Uematsu Y, et al. Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs. Eur J Pharmacol 1997; 339: 1–9PubMedCrossRefGoogle Scholar
  13. 13.
    Iga Y, Arisawa H, Ogane N, et al. Cevimeline hydrochloride induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors. Jpn J Pharmacol. 1998; 78: 373–80PubMedCrossRefGoogle Scholar
  14. 14.
    Kashiwazaki S, Ichikawa Y, Touzyou T, et al. Optimal dose of SNI-2011 for xerostomia in Sjögren’s syndrome patients [in Japanese]. Med Consul New Rem 2001; 38: 333–47Google Scholar
  15. 15.
    Ichikawa Y, Kashiwazaki S, Hara M, et al. Double-blind, controlled study of SNI-2011 for xerostomia in Sjögren’s syndrome patients: Phase III trial [in Japanese]. Med Consul New Rem 2001; 38: 349–68Google Scholar
  16. 16.
    Nitsch RM, Deng M, Tennis M, et al. The selective M1 agonist AF-102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000; 48: 913–8PubMedCrossRefGoogle Scholar
  17. 17.
    Ohtani Y, Ishii Y, Murasaki M, et al. Phase I study of FNS508: single and multiple dose studies [in Japanese]. J Clin Therap Med 1990; 6: 1551–76Google Scholar
  18. 18.
    Kashiwazaki S, Okano Y, Miyawaki M. Pharmacokinetics and salivation effect of SNI-2011 in Sjögren’s syndrome patients [in Japanese]. Med Consul New Rem 2001; 38: 393–405Google Scholar
  19. 19.
    Ishikawa Y, Skowronski MT, Ishida H. Persistent increase in the amount of aquaporin-5 in the apical plasma membrane of rat parotid acinar cells induced by a muscarinic agonist SNI-2011. FEBS Lett 2000; 477: 253–7PubMedCrossRefGoogle Scholar
  20. 20.
    Ishikawa Y, Ishida H. Aquaporin water channel in salivary glands. Jpn J Pharmacol 2000; 83: 95–101PubMedCrossRefGoogle Scholar
  21. 21.
    Matui M, Motomura D, Karasawa H, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000; 97: 9579–84CrossRefGoogle Scholar
  22. 22.
    Ichikawa Y, Kashiwazaki S, Hara M, et al. Long-term treatment trial of SNI-2011 for xerostomia in Sjögren’s syndrome patients [in Japanese]. Med Consul New Rem 2001; 38: 369–91Google Scholar
  23. 23.
    Oxholm P, Prause JU, Schiodt M. Rational drug therapy: recommendations for the treatment of patients with Sjögren’s syndrome. Drugs 1998; 56: 345–53PubMedCrossRefGoogle Scholar
  24. 24.
    Washio T, Arisawa H, Kohsaka K, et al. Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull 2001; 24: 1263–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Customer Satisfaction and Pharmaceutical DepartmentsSnow Brand Co. LtdTokyoJapan

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