Dale Richard Hoff

A super active cyclic hexapeptide analog of somatostatin

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

Chapter 14b. Animal Antiparasitic Agents

Publisher Summary Efficacy of pyrantel for the prevention of parasitic gastroenteritis in sheep is well established in field trials with lamb flocks harboring variable, but moderate infections of Nematodirus, Ostertagia, Trichostrongylus, and Haemonchus. Under the conditions of these trials, pyrantel is found to result in somewhat greater average daily weight gains than the other anthelmintics used for comparison, such as bephenium, methyridine, and thiabendazole. Pyrantel tartrate represents a new class of anthelmintics. All three are broad-spectrum and are efficacious against many species of important nematodes parasitizing the entire gastrointestinal tract of cattle and sheep. Poor control of Trichuris is a weakness common to all three. Tetramisole is effective against lungworms. Differences in the effects of these three anthelmintics against lungworm infections may be because of the varied physiological dispositions of these drugs, reflecting differences in absorption and metabolism. An impressive breadth of spectrum for tetramisole is suggested in the preliminary announcement of this drug, in which activity against at least 56 species of nematodes in thirteen hosts is listed. Pyrantel tartrate has a somewhat higher safety factor than tetramisole though neither approaches the high therapeutic index reported for thiabendazole. Thiabendazole, which is rapidly metabolized, has been shown to have a significant effect against lungworms (vide infra), although special dosing schedules are required. Pyrantel tartrate, not being well absorbed from the intestine, is said to be inactive against lungworms.