Barrie M. Phillips

Influence of quipazine, a potential anti-parkinsonian agent on the uptake of 3H-dopamine and 3H-serotonin into rat striatal tissue in vitro

Abstract Quipazine (2-(1-piperazinyl)quinoline maleate), an agent with anti-tremorine and serotonin-like activity, was found to inhibit the uptake of 3 H-dopamine and 3 H-serotonin into rat striatal tissue in vitro . Quipazine was shown to be three times more effective as an inhibitor of serotonin uptake than dopamine uptake, the IC 50 s being 2.98 × 10 −5 M and 1.00 × 10 −4 M, respectively. These data suggest that quipazine exerts serotonergic and dopaminergic effects in the central nervous system.

Aspirin-induced gastrointestinal microbleeding in dogs

Abstract 59 Fe-labeled ferrous sulfate was administered iv to 12 male dogs, and gastrointestinal microbleeding was determined by comparison of the 59 Fe specific activities of 24-hr stool collections and of whole blood. During a 69-day period following injection of 59 Fe, the dogs received 0, 32.5, 65, or 97.5 mg/kg aspirin po in gelatin capsules twice daily during four 7-day treatment periods (each of which was preceded by a 7-day period of no treatment) in complete changeover fashion. Over this range (approximately equivalent to 1, 2 or 3 five-grain aspirin tablets twice daily), aspirin increased gastrointestinal microbleeding in a dose-dependent manner. This response to aspirin was reflected in increased fecal blood loss beginning on the first day of drug administration, in contrast to the response in humans, which is generally delayed 24 hr. The dog does not become refractory to this effect of aspirin during 7-day treatment periods or during alternating control and aspirin treatment periods. It was concluded that the dog may be a suitable species for the evaluation of the effect of aspirin formulations on gastrointestinal microbleeding.

A method of evaluation of the influence of aspirin formulations on gastrointestinal microbleeding in humans.

Abstract Human (radiochromate) studies of the effects of aspirin on gastrointestinal microbleeding are limited to 4 treatment periods, and since adequate evaluation of the effect of a new formulation requires the use of both positive and negative aspirin-containing reference formulations as well as a placebo, only 1 new formulation can be evaluated in a given complete cross-over study. The use of an incomplete design allowed evaluation of a greater number of experimental formulations in a smaller number of subjects, with a reduction in statistical efficiency of only one-third. Four experimental buffered aspirin formulations were investigated in a total of 21 normal adult male human subjects. It was shown that treatment with aspirin may influence the fecal blood loss observed during the next period of treatment with a different aspirin formulation. Thus, any cross-over study of aspirin-induced gastrointestinal microbleeding should be balanced for residual effects.

The physical, animal and human pharmacologic, and toxicologic properties of desonide, a new, topically active, antiinflammatory steroid

Abstract Desonide, 16α-hydroxyprednisolone-16,17-acetonide, is a nonhalogenated steroid possessing physical properties predictive of potent topical antiinflammatory activity. Based on assay findings in 4 animal models (liver glycogen deposition, cotton pellet granuloma, ear edema, and ocular inflammation), desonide showed an average potency about 60 times that of hydrocortisone, which suggested that desonide should exhibit, on topical use, considerable antiinflammatory activity. Subsequently, desonide proved to be about as active as fluocinolone acetonide in human dose titration studies, having a more rapid onset than the reference steroid during the early phase of treatment. The absorption of desonide from a cream formulation applied to the skin of rabbits averaged 54% greater than that of triamcinolone acetonide (as predicted by the physical properties of desonide), an observation that may partially explain the apparently greater clinical activity of desonide. In view of the apparently greater clinical activity of desonide, this finding indicates that somewhat less steroid will be absorbed from clinically effective doses of desonide than from equieffective doses of triamcinolone acetonide. Desonide was only 6 times as toxic as hydrocortisone and one-fifteenth as toxic as triamcinolone acetonide on acute sc administration to rats. A cream formulation of desonide was virtually nontoxic on po administration to rats and dogs, and it elicited a low order of toxicity when administered topically in large doses to rabbits.

A subchronic study of the toxicity of an orally administered benzoquinolizinyl derivative in the rat and dog

The subchronic toxicity of the trans isomer of N-(1,3,4,6,7-hexahydro-11bH-benzo[a] quinolizin-2-yl) propionanilide hydrochloride (TR2379), a new antihypertensive agent, was studied in rats and dogs. TR2379 was well tolerated for 13 weeks at daily p.o. doses up to 200 mg/kg in the rat and 70 mg/kg in the dog. However, severe toxic manifestations, including death, were elicited in the rat at 820 mg/kg and in the dog at 160 mg/kg. Toxicity in both species was characterized by a reduction in body weight gain and an increase in the weight of several organs, (liver, heart, kidneys, adrenals, and thyroids). Serum alkaline phosphatase, which was not assayed in the rat, was markedly increased in the dog. Microscopic examination of the various tissues revealed no evidence of organ pathology in either species.

The influence of aspirin on gastrointestinal microbleeding in dogs with gastric ulcers

Fecal blood volume was determined daily in 11 dogs with single gastric ulcers. Beginning 11 days after production of the ulcers the dogs received, in crossover fashion, 2 placebo or ordinary 325-mg aspirin tablets orally twice daily during two 7-day treatment periods separated and followed by 5-day periods of no treatment. Mean daily fecal blood volumes of 0.52 and 3.25 ml were observed during periods of treatment with placebo and aspirin, respectively. However, in 7 previous studies in this laboratory a total of 24 normal dogs have received 7-day courses of treatment with 650 mg ordinary aspirin twice daily on 105 occasions; during these 105 treatment periods fecal blood volume averaged 2.90 ml/day. Thus, it is concluded that the effect of ordinary aspirin in dogs with gastric ulcers is essentially the same as the effect in normal dogs, and that there is no tendency for dogs with gastric ulcers to bleed massively in response to aspirin.

The influence of ocular instillation of phosphate buffer on intraocular pressure in rabbits.

Abstract For 12 weeks, after a 14-day pretrial period during which three baseline intraocular pressure (IOP) determinations were made, rabbits received 0.05 ml of a pH 7.0 phosphate buffer twice daily in the conjunctival sac, or were subjected to the same physical manipulation without buffer instillation, or received no treatment or manipulation. IOP determinations were made weekly. Group mean IOP values in buffertreated rabbits during weeks 10, 11, and 12 were significantly greater than the mean pretrial IOP, while IOP did not change in untreated or shamtreated rabbits.