Disease relevance of CI 979

• Dose-related clinical signs of muscarinic stimulation, such as sialorrhoea and dacryorrhoea, were observed predominantly in rats given 10 and 30 mg/kg body weight CI-979 by gavage, and corresponded with the high plasma drug concentrations [1].
• To explain the differential toxicity generated by each means of administration, toxicokinetics of the muscarinic agonist CI-979 were investigated [1].
• In a single-dose tolerance study in young, healthy human volunteers, CI-979/RU35926 was well tolerated at doses of 0.002-1.0 mg with cholinergic symptoms such as hypersalivation and sweating, observed at 2-4 mg [2].
• Comparable incidences of corneal opacities were induced by both means of administration, but lesions appeared more rapidly and were generally of greater severity when CI-979 was given in the diet [1].
• In contrast, hydronephrosis, pyelonephritis, and inflammation and necrosis of the kidney, urinary bladder, urethra and urinary papilla were linked to sustained, albeit lower plasma drug concentrations attained by dietary administration of CI-979 at 10 and 50 mg/kg body weight [1].

Psychiatry related information on CI 979

• Safety and tolerability of CI-979 in patients with Alzheimer's disease [3].

High impact information on CI 979

• Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization [4].
• The effects on the binding to cholinergic and dopaminergic receptors in the brain during continuous intravenous infusion of the muscarinic cholinergic receptor agonist milameline (CI-979) were studied in the rhesus monkey by means of positron emission tomography [5].
• Corneal opacification and development of urinary tract pathology were inhibited by scopolamine, suggesting that these effects were related to the muscarinic mechanism of action of CI-979 [1].
• CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxyaldehyde-O-meth yl oxime, CAS 139886-04-7) is a non-subtype selective, partial muscarinic agonist that enhances cognitive performance and increases central cholinergic activity in rodents at doses below those required to increase peripheral cholinergic tone [6].

Analytical, diagnostic and therapeutic context of CI 979

• Regional brain distribution and binding of the muscarinic receptor agonist CI-979 studied by positron emission tomography in the monkey [7].
• Measurement of CI-979 (a candidate drug for the treatment of age-related disorders of cognition) in human plasma by capillary gas chromatography with nitrogen-selective detection [8].
• Thus, the safety profile supported further clinical evaluation and CI-979/RU35926 is currently in Phase II clinical trials [2].
• No other clinically significant CI-979-related changes occurred in physical examinations, clinical laboratory measurements, electrocardiograms, or ophthalmologic examinations [3].
• In summary, CI-979 doses of 1-mg q6h were well tolerated by all patients; 2-mg q6h was tolerated by most patients, and 2.5-mg and 3-mg doses were poorly tolerated, Dose titration to a maximum of 2-mg q6h will therefore be used in initial efficacy trials of CI-979 in patients with AD [3].

References