SUMMARY1. Smooth muscle activities in rectum and internal anal sphincter have been recorded using intraluminal balloons.2. Reflex activation of the sphincter, caused by distension of the rectum, has been assessed before and after various combinations of blocking drugs.3. Responses to stimulation of hypogastric or sacral nerves, or to the administration of drugs with autonomic actions have been tested before and after various combinations of blocking drugs.4. Results indicate that the tone of the internal anal sphincter is influenced by a number of neural mechanisms. These include motor pathways involving both a-adrenergic and cholinergic mechanisms and inhibitory pathways involving both /J-adrenergic and non-adrenergic noncholinergic mechanisms.5. Cholinergic contractions of the sphincter were converted to relaxations after oz-adrenergic blockade. This indicates that the contractions are an indirect effect operating through an adrenergic reflex. Cholinergic relaxations may also be indirect and operate through reflex inhibition secondary to rectal contractions.6. Sphincteric motor activity is controlled largely through oc-adrenergic mechanisms by adrenergic nerves acting directly on the muscle.,8-Adrenergic inhibitory mechanisms are thought to operate indirectly via ganglia.7. The over-all control of the sphincter is by complex reflex mechanisms involving numerous pathways and the activity of the sphincter at any one time is determined by the net balance between motor and inhibitory influences.

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Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety, and tolerability of oxfendazole were evaluated in healthy volunteers in this phase 1 first-in-human (FIH) study. Seventy subjects were randomly assigned to receive a single oral dose of oxfendazole (0.5, 1, 3, 7.5, 15, 30, or 60 mg oxfendazole/kg body weight) or placebo and were followed for 14 days. Blood and urine samples were collected, and the concentrations of oxfendazole were measured using a validated ultraperformance liquid chromatography mass spectrometry method. The pharmacokinetic parameters of oxfendazole were estimated using noncompartmental analysis. Oxfendazole was rapidly absorbed with a mean plasma half-life ranging from 8.5 to 11 h. The renal excretion of oxfendazole was minimal. Oxfendazole exhibited significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses of 0.5 mg/kg to 60 mg/kg. This nonlinearity of oxfendazole is likely due to the dose-dependent decrease in bioavailability that is caused by its low solubility. Oxfendazole was found to be well tolerated in this study at different escalating doses without any serious adverse events (AEs) or deaths. There were no significant differences in the distributions of hematology, biochemistry, or urine parameters between oxfendazole and placebo recipients. (This study has been registered at ClinicalTrials.gov under identifier NCT02234570.)

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