Cevimeline

Useful for a narrow job and honest about it. The same receptor activation that restores saliva also makes about one patient in five sweat and one in seven nauseous, so this is a trade rather than a fix. The widely repeated description of it as an M1/M3-selective agonist does not survive contact with the binding data; the selectivity is a story about tissue, not about affinity.

The predictable problems are the drug working everywhere it is not wanted, because muscarinic receptors are not confined to salivary glands. Pooled label data give excessive sweating in about 19 percent of patients against about 2 percent on placebo, nausea in about 14 percent and rhinitis in about 11 percent, all direct consequences of muscarinic activation at sweat glands, gut smooth muscle and nasal secretory tissue.

Because muscarinic agonism constricts the pupil and can raise airway resistance, the label contraindicates cevimeline in uncontrolled asthma, acute iritis and narrow-angle glaucoma, cautions in controlled asthma and COPD, and warns that impaired night vision can affect driving. Cevimeline is cleared by CYP2D6 and CYP3A4, so inhibitors of either raise exposure and poor CYP2D6 metabolisers carry a higher risk of adverse effects. In the 75-patient Sjogren's trial, 14 participants withdrew for adverse events, most often nausea, and the 60 mg three times daily arm produced more gastrointestinal trouble than the 30 mg arm without more benefit ^[1].

Cevimeline came out of muscarinic agonist chemistry at the Israel Institute for Biological Research, where it was called AF102B and was developed as a candidate treatment for Alzheimer's disease; a single-blind placebo-controlled study in probable Alzheimer's reported effects on ADAS and ADAS-cognitive scores at 40 and 60 mg three times daily ^[3]. The Alzheimer's programme never produced an approved drug. The peripheral effect that limited it, salivation, became the indication instead: the FDA approved Evoxac on 11 January 2000 for the symptoms of dry mouth in Sjogren's syndrome, on the strength of two randomised placebo-controlled trials ^{[1] [2]}.

Regarded in rheumatology and oral medicine as one of two systemic options for Sjogren's dry mouth, alongside pilocarpine, and generally reached for when pilocarpine is not tolerated. Reviews of Sjogren's treatment place both in the same symptomatic tier and note that neither touches the underlying autoimmune process ^[6]. Outside that indication it is largely forgotten, and its original identity as an Alzheimer's candidate is rarely mentioned even in cholinergic reviews.