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The muscle relaxant activity of cyclobenzaprine relative to chlorpromazine and diazepam in several animal models manifesting hypertonic skeletal muscle activity is described. In mice subjected to electrical and chemical induced tonic-extensor seizures, only cyclobenzaprine achieved a protective index greater than unity in all preparations. Cyclobenzaprine also appeared to be highly potent and selective in abolishing local tetanus in rabbits. Relative to the other compounds, cyclobenzaprine was consistently active in γ- and α-decerebrate as well as in ischemic spinal cord rigid cat preparations, at doses which produced no signs of motorincoordination (ataxia) or behavioural depression. Consequently, only cyclobenzaprine exhibited high protective indices and those of greater than unity for all three cat preparations. Furthermore, in contrast with chlorpromazine and diazepam, repeated administration of cyclobenzaprine to ischemic spinal cord rigid cats failed to induce tachyphylaxis. Cyclobenzaprine was also well absorbed orally in mice and cats. These observations suggest that cyclobenzaprine may be useful in the treatment of human pathological conditions manifested by excessive tonic skeletal muscle activity. The potential usefulness of cyclobenzaprine as a pharmacological tool for further studies involving somatic motor systems is also suggested.

1. The metabolism in vitro of cyclobenzaprine by rat liver microsomal preparations was investigated.2. Four metabolic products, cyclobenzaprine N-oxide, 10,11-epoxycyclo-benzaprine N-oxide, desmethylcyclobenzaprine and cyclobenzaprine-10,11-epoxide were isolated and identified by comparing physical properties with those of authentic compounds.

The efficacy of cyclobenzaprine 60 mg/day in the treatment of spasticity was assessed in a double-blind crossover trial of two weeks' duration in 15 patients suffering from cerebral or spinal spasticity. Independent clinical and electromyographic methods were used. The effects of cyclobenzaprine did not differ significantly from those of placebo. The administration of a higher dosage, 150 mg/day, to one patient revealed a dose-related response, but the degree of improvement was clinically small. Apart from a skin rash there were no significant untoward effects of therapy.

A sensitive method for the determination of cyclobenzaprine in biological samples is described. The extraction procedures used are different for urine and blood serum. The pH is a very important factor affecting the purity of the extract and the reproducibility of the recovery data, particularly for urine. By means of extraction, purification is achieved, while separation by thin-layer chromatography increases the specificity of the determination considerably. With a Vitatron TLD-100 densitometer, the substances separated can be measured as fluorescent spots from the thin-layer plates directly and quantitatively, with good reproducibility. The sensitivity is 1 ng and a linear relationship was obtained between 1 and 25 ng. extensive recovery studies were made in view of the forthcoming clinical evaluation of cyclobenzaprine. A number of experiments showed that this method has so far produced better results than can be obtained with the most sensitive gas chromatographic detection methods.