The toxicology profile of the anti-inflammatory drug proquazone in animals.

Proquazone is a chemically distinctive non-steroidal anti-inflammatory drug (NSAID) and is orally effective as an anti-inflammatory, analgesic and anti-pyretic in animals. As with other NSAID's the main toxic effect was gastrointestinal irritation with sequellae. Comparative relative potency of proquazone with other NSAID's with regard to gastrointestinal effects was: rat-indomethacin greater than naproxen = proquazone greater than phenylbutazone; dog-indomethacin greater than naproxen greater than proquazone greater than phenylbutazone. In addition to gastrointestinal effects in minipigs, inflammatory renal changes occurred; renal changes also occurred in pigs treated with phenylbutazone. No evidence of carcinogenicity was seen in rodent oncogenicity studies. Evidence of teratogenicity was not seen in rat and rabbit teratological studies. In reproduction/perinatal studies in rats dose levels that induced intestinal lesions in the dams resulted in decreased survival of young to weaning. A major human metabolite of proquazone, the m-hydroxy derivative, was shown to be less toxic than the parent compound.

Inhibition of glucose absorption by 3-phenylpropylaminoguanidine-HCl (SaH 43-522) in laboratory animals.

The present studies were undertaken to define the effects of 3-phenylpropylaminoguanidine-HCl (SaH 43-522 or 43-522) on glucose active transport in the gastrointestinal tract. A comparison with phenformin (DBI) was made in certain studies. SaH 43-522 is 2 to 3 times more potent than DBI with regard to its inhibitory effect on glucose active transport in the gastrointestinal tract of rats. The activity lasts for 5 hr after oral administration. SaH 43-522 also inhibits intestinal glucose absorption in the hamster, guinea-pig, dog, and monkey in either in vitro or in vivo systems. SaH 43-522 differs from DBI in that when glucose active transport is studied in vitro by adding drug into the incubation fluid, DBI is active only when the drug is present in the incubation fluids on both the mucosal and serosal sides, whereas SaH 43-522 is active in inhibiting intestinal glucose active transport when the drug is present in mucosal fluid only.

The anti-inflammatory profile of proquazone.

Proquazone, 1-isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone is an orally effective anti-inflammatory analgesic and antipyretic compound in animal models. The compound is less ulcerogenic than indomethacin in the rat and appears to potentiate the anti-inflammatory and thymus involution effects of hydrocortisone in this species. That a nonacidic nonsteroidal compound would display a spectrum of anti-inflammatory activity similar to that previously found only with acidic compounds will be the subject of further investigations.

Pharmacological analysis of a new anorexic substance: 5-hydroxy-5(4'-chlorophenyl)-2, 3-dihydro-5H-imidazo-(2, 1-a) isoindole (Mazindol).

5-Hydroxy-5-(4'-chlorophenyl-2, 3-dihydro-5H-imidazo (2, 1-a)isoindole (mazindol), a novel tricyclic compound, has been shown to suppress food consumption in rats at doses causing weak central stimulation and little effects on blood pressure or heart rate. The substance produces dose-related decreases in the consumption of orange juice in cebus monkeys trained on an operant behavior schedule. The compound did not alter cardiac or pulmonary hemodynamics in the anesthetized dog but provided potentiation of norepinephrine pressor responses. Mazindol also demonstrated potent but incomplete antagonism of reserpine-induced hypothermia in mice, antagonism of tetrabenazine catalepsy in rats, and suppression of mouse-killing behavior of rats. Suppression of mouse-killing was reduced by lesions placed in the septal area of the brain. Brain monoamine oxidase or catechol-o-methyl-transferase activities were not altered, although preliminary experiments showed that mazindol reduced uptake of norepinephrine in brain tissue.