Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease.

OBJECTIVES: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7-20 ng ml(-1) in the treatment of Alzheimer's disease. METHODS: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. RESULTS: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7 ng x ml(-1) who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P < 0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5 ng x ml(-1) and 9 ng x ml(-1) showed improvement in comparison to those with concentrations below these levels. CONCLUSIONS: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.

Characteristics of plasma protein binding of tacrine hydrochloride: a new drug for Alzheimer's disease.

The aim of this study was to characterise the plasma protein binding of tacrine hydrochloride (THA) in vitro. Binding was assessed in the plasma of 11 healthy individuals aged 20 to 27 years using ultrafiltration followed by HPLC assay. At THA concentrations from 10 to 100 ng/ml protein binding ranged from 78.6 to 71.0%. Binding to commercially available human albumin ranged from 41.7 to 38.3% and to human alpha 1-acid glycoprotein from 23.1 to 12.4% over the THA concentrations from 25 to 100 ng/ml. THA binding and total plasma protein, plasma albumin and alpha 1-acid glycoprotein were measured in healthy young subjects (n = 13), healthy elderly individuals (n = 12) and patients hospitalised with acute illnesses (n = 8). There were significant differences between the groups in total plasma protein, plasma albumin and in alpha 1-acid glycoprotein but no differences in the protein binding of THA which remained constant at about 75%. There was no correlation between THA binding and any plasma protein concentration. The THA binding was not high enough to be of major significance clinically or to reduce the validity of total plasma THA measurement in therapeutic monitoring.

Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease.

OBJECTIVE: To assess the value of serum measurements of tacrine hydrochloride and its metabolite in predicting risk of adverse reaction in Alzheimer's disease. METHODS: The study was an outpatient-based controlled clinical trial. Study subjects were 35 female and 31 male patients who were receiving 50 to 150 mg tacrine hydrochloride per day. RESULTS: Serum concentration of tacrine hydrochloride and ratio of tacrine hydrochloride to metabolite were significantly higher in the 45 patients with symptomatic adverse effects (p < 0.001). The tacrine hydrochloride to metabolite ratio was significantly higher (p < 0.05) in the 30 patients in whom abnormal liver function developed, but concentration of tacrine hydrochloride was not significantly higher. Women showed a higher incidence of adverse effects (p < 0.05), and tacrine hydrochloride concentrations were higher (p < 0.05). Tacrine hydrochloride concentration and tacrine hydrochloride to metabolite ratio were higher in both men and women in whom adverse effects developed. CONCLUSION: Tacrine hydrochloride concentration is valuable in predicting the development of adverse effects, and its measurement may improve the use of the drug.

Comparison of the chromatographic characteristics of metabolites of tacrine hydrochloride in human serum and urine with those of in vitro metabolic products from hepatic microsomes.

There may be as many as five metabolites of THA in man, four corresponding to products in the rat. The study provides some evidence that one of major metabolites is 1-hydroxy-THA but lends no support to the putative oxidative deamination pathway.

The effect of propranolol on paracetamol metabolism in man.

Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.

Pharmacokinetics of tacrine hydrochloride in Alzheimer's disease.

The clinical pharmacokinetics of tacrine hydrochloride have been characterized in patients who have Alzheimer's disease. Serum concentrations of the drug and of its probable metabolite were monitored in eight patients after a 25 mg oral dose, in six patients after a 50 mg oral dose, in four patients after repeated administration of 50 mg, and in two patients after a small intravenous dose. Urinary excretion of drug and metabolite for 24 hours was measured in one of the patients who received a small intravenous dose. The serum half-life was 1.59 +/- 0.15 hours (mean +/- SEM) after the 25 mg dose, 2.14 +/- 0.24 hours after the 50 mg dose, and 2.91 +/- 0.39 hours after continuous treatment. After intravenous administration, clearance was above 600 ml/min in both patients, and oral bioavailability was calculated at below 5%. Urine recovery was less than 3% of the dose. The low bioavailability of tacrine hydrochloride is partly explained by presystemic metabolism.