talsaclidine-fumarate and Alzheimer-Disease

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscarinic Agonists; Peptide Fragments; Placebos; Quinuclidines; Receptor, Muscarinic M1

Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid beta-peptides (A beta). Thus, lowering A beta production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as beta-, gamma-, and alpha-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic alpha-secretase pathway in model systems. Talsaclidine was administered double-blind, placebo-controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total A beta were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of A beta significantly over time within the treatment group (n = 20) by a median of 16% as well as compared to placebo (n = 4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce A beta production and may thus be further evaluated as a potential amyloid-lowering therapy of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Double-Blind Method; Humans; Muscarinic Agonists; Placebos; Quinuclidines

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.

Topics: Administration, Oral; Adult; Alzheimer Disease; Blood Pressure; Brain; Dose-Response Relationship, Drug; Electroencephalography; Heart Rate; Humans; Male; Muscarinic Agonists; Quinuclidines; Receptor, Muscarinic M1; Receptors, Muscarinic; Salivation; Single-Blind Method

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.

Topics: Adrenergic beta-Antagonists; Adult; Alzheimer Disease; Animals; Bronchial Spasm; Dose-Response Relationship, Drug; Electroencephalography; Female; Guinea Pigs; Heart; Humans; Imines; In Vitro Techniques; Male; Middle Aged; Muscarinic Agonists; Muscle, Smooth; Neurons; Propanolamines; Quinuclidines; Rabbits; Rats; Receptors, Muscarinic

1. Talsaclidine is an M1-agonist under development for the treatment of Alzheimer's disease. The aim of the study was to investigate the absorption, distribution, metabolism and excretion (ADME) of single intravenous and oral doses of [14C]-talsaclidine in mouse, rat, rabbit and monkey. Previous data in humans showed that the drug was mainly excreted into the urine as the unchanged parent drug. The hypothesis was tested if animal data of drugs, which are mainly excreted renally, could be extrapolated to human. 2. The apparent volume of distribution at steady-state (V(ss)) was comparable in all animal species (2-5 l x kg(-1)) indicating an extensive distribution of the drug into tissues. The plasma protein binding was low and comparable in all species including man (< or = 7%). Elimination in terms of clearance was rapid-to-moderate depending on the species. The total plasma clearance (Cl) decreased in the order: mouse (128 ml x min(-1) x kg(-1))> rat (73.9) > monkey (10.6). Urinary excretion is the dominant route of excretion (> or = 86%). 3. A good correlation was achieved with human and animal data in allometric scaling of CI and V(ss). This confirms the hypothesis that renal filtration is scalable over the species and, given a comparable protein binding, animal data is predictive for man.

Topics: Alzheimer Disease; Animals; Blood Proteins; Carbon Radioisotopes; Female; Haplorhini; Humans; Kinetics; Male; Metabolic Clearance Rate; Mice; Muscarinic Agonists; Protein Binding; Quinuclidines; Rabbits; Rats; Species Specificity