No abstract

AstraZeneca.

1 The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-of both drugs. Nineteen patients completed the study. 2 Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nm in extensive metabolisers, vs 590 and 750 nm in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3 Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer-and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethylclomipramine < 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4 Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5 Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.

No abstract

A single-blind imipramine dose titration study was conducted in 15 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by use of visual analog scales. Imipramine doses were individually adjusted until doses yielded plasma concentrations of imipramine plus desipramine that were well above 400 nmol/L or until all neuropathy symptoms had vanished. In all except one patient, there was marked relief of symptoms. In the responding patients (n = 14), much of the effect occurred at plasma levels of imipramine plus desipramine below 100 nmol/L, but a considerable interindividual variation was observed. Concentrations above 400 to 500 nmol/L were required to ensure maximal effect in all patients, and we did not find any indication of a decreased effect at high drug levels. The dose-dependent kinetics of imipramine was confirmed, and dose increments should therefore be carried out in small steps and preferably with monitoring of drug levels.