A new gas chromatographic method was developed for the quantification of levamisole in human plasma and urine, using a nitrogen-phosphorus flame ionization detector. The adsorption of the drug onto glass was prevented by treating the glassware with a siliconizing agent. The sensitivity of the assay was 10 ng ml-1 and as low as 2 ng ml-1 can be detected in plasma. The urinary metabolite p-hydroxylevamisole was analysed by high performance liquid chromatography with ultraviolet detection. The sensitivity of this assay was 0.50 micrograms ml-1. Plasma and urinary concentrations of levamisole were determined in 10 healthy volunteers including seven men and three women following the administration of a single 150 mg dose of levamisole. Levamisole was rapidly absorbed (tmax 1.5 h), giving a peak plasma concentration of 716.7 +/- 217.5 ng ml-1. The plasma elimination half-life of levamisole was 5.6 +/- 2.5 h. Only 3.2 +/- 2.9 per cent of the oral dose was recovered as unchanged drug in the urine, suggesting the importance of clearance of levamisole by routes other than the kidney, and most probably by hepatic metabolism. The urinary concentrations of p-hydroxylevamisole were determined before and after hydrolysis of the urine samples with beta-glucuronidase, and the level of conjugation of the metabolite with glucuronic acid was then estimated. Cumulative recovery of the metabolite accounted for 1.6 +/- 1.1 per cent and 12.4 +/- 5.5 per cent of the oral dose of levamisole before and after hydrolysis, respectively, indicating that p-hydroxylation is a relatively important route of metabolism of levamisole, and that the p-hydroxylated metabolite is excreted mainly in conjugation with glucuronic acid. Except for the absorption rate of levamisole which is approximately twice as rapid in women as in men, there is no marked difference in the pharmacokinetics of levamisole between healthy men and women.

The kinetics of the elimination of lidocaine upon discontinuation of lidocaine infusions lasting more than 24 h were studied in 12 patients with uncomplicated myocardial infarctions. In this group of patients the mean half-life of the elimination phase was found to be 3.22 h. This is significantly different from the half-life of 100 min that has been reported after bolus injections or infusions lasting less than 12 h. This longer half-life should be taken into consideration in estimating the duration of toxicity and the rate of administration of the drug during and after intravenous infusions lasting 24 h or more.

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The pre-and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague-Dawley rats. The potency of the presynap tic effect was estimated from their ability to depress the rate of firing of serotonin (5-HT)-containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5-HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5-HT, norepinephrine (NE) and y-aminobutyric acid (GABA).Consistent with their known 5-HT reuptake blocking property, acute intravenous administration of zimelidine and norzimelidine depressed the firing rate of 5-HT-containing dorsal raphe neurons. EDso of zimelidine and norzimelidine were respectively 1.1 mglkg and 0.8 mg/kg. Chronic administration of zimelidine (5 and 10 mg/kg, q.d. for 14 days) did not modify the responsiveness of hippocampal pyramidal cells to iontophoretic applications of 5-HT, NE and GABA, whereas chlorimipramine (5 mg/kg, q.d. for 14 days) increased selectively their sensitivity to 5-HT.Since the antidepressant efficacy of zimelidine is well documented, it is concluded that sensitization of forebrain postsynaptic 5-HT receptors is not a prerequisite for a drug to exert an antidepressant effect. It is suggested that an enhancement of the 5-HT-mediated synaptic transmission might be the final effect of the various types of antidepressant treatment whether their primary effect is pre-or postsynaptic.