Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer's disease.
The safety, tolerability and pharmacological activity of WAL 2014, a new centrally-acting M1 agonist were examined in two clinical studies (0.5-80 mg and 100-160 mg). Single increasing p.o. doses were administered to groups of 8 volunteers (6 verum, 2 placebo) each. Both studies were placebo controlled with single-blind observation within the respective dose groups. Vital functions (BP, HR, resp. rate) did not reveal any clinically significant substance-induced changes up to a dose level of 60 mg. A slight, but obvious increase in HR was measured with a dose of 80 mg and higher; a slight increase in systolic BP was registered at the dose levels of 120 and 160 mg. No substance-related alterations were observed in the laboratory tests (exception: a significant, reversible increase of the salivary fraction of alpha-amylase in 3 volunteers at the dose levels 100 mg-140 mg). The majority of volunteers reported an increased salivary secretion with doses of 40 mg and higher; this was confirmed by the greater volume of measured saliva. Furthermore, with doses of 100 mg upwards there were isolated reports of side effects such as a desire to urinate, a burning sensation on urination, increased lacrimation and nasal secretion, disturbances of accommodation, heartburn, rumbling of the stomach as well as cramps, nausea, diarrhoea, excessive sweating and palpitation. WAL 2014 did not cause any abnormal changes in the EEG. Dose dependent central effects were observed with 40, 60, 80, 100 and 140 mg treatments. Pharmacokinetic data indicate a rapid and good absorption and an absolute bioavailabitlity > or = 70%. The pharmacodynamic and side effects observed in both studies are regarded as being drug-dependent and might be due to the cholinergic activity of the compound and a weak sympathetic activation via M1 receptors. In summary, the substance did not produce any effects in the dose range tested to suggest further use in man might be inadvisable.
Adamus
W S
WS
Human Pharmacology Centre, Boehringer Ingelheim, Germany.
Leonard
J P
JP
Tröger
W
W
D000284:Administration, Oral; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D018721:Muscarinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D011812:Quinuclidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D016037:Single-Blind Method
D018721:Muscarinic Agonists; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C079885:talsaclidine fumarate