Comparative anti-inflammatory, analgesic, and antipyretic activities of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one and 5-chlorosalicylic acid in rats.

Evidence is presented which indicates that 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b) (1,3)-benzoxazin-9-one (I) and 5-chlorosalicylic acid, its major metabolic end-product, are equally effective as anti-inflammatory and antipyretic agents, while the former is a somewhat more effective analgesic than its metabolite in the rat. However, at the equimolar doses used in this study, I is not ulcerogenic, while 5-chlorosalicylic acid does possess this untoward effect in the fasted rat. Moreover, the LD50 for 5-chlorosalicylic acid (261.0 mg/kg) is approximately 6.5 times less than that of I (1710.0 mg/kg) in the nonfasted rat. These results support the postulation that 5-chlorosalicylic acid is most likely responsible for the pharmacological activity displayed by I; i.e., the latter acts as a carrier or delivery system, allowing attenuation of the toxic properties of its active metabolite.

Absorption, distribution, and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one in rats, dogs, and humans.

The absorption and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one (I) was studied in rats, dogs, and humans. Orally administered I was readily absorbed by all species. In the rat, orally administered I was converted to its metabolite, 5-chlorosalicylic acid, by the intestinal wall. The half-lives of blood radioactivity, after the oral administration of I-9-14C, were about 18 and 12 hr in the rat and beagle hound, respectively. In human subjects, no intact I was detected in the bloodstream; however, the clearance of the metabolite, 5-chlorosalicylic acid, had a half-life of about 33 hr. Cleavage of the oxazine ring of I generated 5-chlorosalicylic acid, which was excreted both in the free form and conjugated with glycine and glucuronic acid. The isoxazole moiety was converted to beta-hydroxybutyric acid and its metabolites carbon dioxide and fumaric, citric, alpha-ketoglutaric, succinic, and malic acids. Binding of I to plasma proteins was extensive but was less than that of 5-chlorosalicylic acid.

Optic nerve head stereoscopic digital imaging using bichromatic techniques.

The variability of optic nerve parameters obtained with versions 3.4 and 3.5 of the Topcon IMAGEnet computer stereo analysis system was studied. The consistency of horizontal cup-to-disc ratio, vertical cup-to-disc ratio, cup volume, neuroretinal rim area, neuroretinal rim-to-disc area, and the percentage of poorly correlated conjugate points (bad points) on the stereo pair was compared. The updated computer program for stereo analysis provides a significantly more accurate means to assess both the cup volume and the neuroretinal rim area as evidenced by the smaller number of bad points.

Effects on the immune response of rats rendered leukopenic with 4-(p-chlorophenylthio)-butanol (W-2719) and its major metabolites.

4-(p-Chlorophenylthio)butanol (W-2719) and its major acid metabolites W-2718 (butyrate) and W-2683 (acetate), when administered as drug-diet admixtures to male and female Sprague-Dawley rats for five weeks (approximately 200.0 mg/kg/day), induced a marked leukopenia. Effect on the primary and secondary immune responses to bovine serum albumin (BSA) immunization was that of suppression as evidenced by strikingly reduced passive hemagglutination serum titers.

Absorption, distribution and metabolic fate of 2,3-dihydro-9H-isoxazolo-[3,2-b]quinazolin-9-one (W2429).

After oral administration to rats, mice, beagle dogs and human volunteers, 2,3-dihydro-9H-isoxazolo [3,2-b]-quinazolin-9-one (W 2429) is readily absorbed. The initial half-lives for the elimination from the circulation of these four species are about 240, 20, 40 and 120 min, respectively. Studies in the rat, using 9-14C-W-2429 and 3a-14C-W-2429, showed that more than half of the radioactivity is excreted in the urine. The major urinary metabolite in the rat and dog is a conjugated form of W-2429. Metabolic cleavage of the pyrimidone ring of W-2429 yields 3-(o-carboxyphenylimino)isoxazolidine, which in turn is converted to anthranilic and malonic acids. Anthranilic acid is acetylated and hydroxylated, and these products are excreted partly in the form of their glycine and glucuronic acid conjugates. The isoxazole ring of W-2429 is also dehydrogenated during metabolism to yield 9H-isoxanzolo-[3,2-b]quinazolin-9-one.

General pharmacological properties of 4-(p-chlorophenylthio)butanol (W-2719).

4-(p-Chlorophenylthio)butanol (W-2719), a compound that inhibits histamine release from sensitized leukocytes also decreased tracheal smooth muscle tonus, inhibited synthesis and release of immunologically induced SRS-A (slow-reacting substance of anaphylaxis) in the rat and antagonized the in vitro activity of SRS-A. Furthermore, it significantly inhibited the platelet release reaction induced by collagen in vitro but not ex vivo. On the other hand, W-2719 did not possess marked CNS activity nor did it adversely affect the blood pressure, heart rate or respiratory rate. There was no evidence for sympathetic or parasympathetic activity. It had weak antipyretic activity, but exhibited no anti-inflammatory or analgesic activity.

Acute and subacute (30-day) toxicological investigations of 4-(p-chlorophenylthio) butanol (W-2719) in mice, rats and dogs.

The acute and subacute toxicity of 4-(p-chlorophenylthio) butanol (W-2719), on anti-allergy agent, was investigated in mice, rats and dogs. Acute LD50 values in the mouse (1145.0 mg/kg p.o.) and rat (greater than 1400.0 mg/kg p.o.) and maximum tolerated dose in the dog (420.0 mg/kg p.o.) were very high, indicative of a high degree of safety following a single oral dose. The subacute toxicity studies were conducted by repeated daily oral administration of the compound for 30 days. In the rat, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, when administered as a drug-diet admixture. A higher dose, i.e., 200.0 mg/kg/day, produced marked reductions in body weight gain, food consumption, RBC and WBC (females especially), and other hematological parameters. In the purebred beagle dog, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, the highest dose level tested in this species.

2,3-Dihydro-9H-isoxazolo[3,2-b]quinazolin-9-ones and 3,4-dihydro-(1,2)-oxazino [3,2-b]quinazolin-10(2H)-ones.

Two series of compounds, 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-ones and 3,4-dihydro-(1,2)-oxazino-[3,2-b]quinazolin-10(2H)-ones, were synthesized and evaluated for anti-inflammatory, antipyretic and analgesic activity. The isoxazolo compounds were generally more active than their oxazino homologs. Three compounds, i.e., 2,3-dihydro-9H-isoxazolo [3,2-b]quinazolin-9-one (W-2429) and its 2- and 3-methyl congeners, were the most active of all compounds tested in this study. On the basis of the biological results herein reported, W-2429 is considerably more effective than acetylsalicylic acid in inhibiting carrageenan-induced edema and in reducing brewer's yeast-induced fever in rats. Also, it was found to be more potent than propoxyphene hydrochloride in the Randall-Selitto test for analgesic activity.

Toxicological investigation of 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-one (W-2429). Acute and subacute toxicity in mice, rats and dogs.

The acute and subactue toxicity of 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-one (W-2429), a non-narcotic analgesic agent, was investigated in mice, rats and dogs. The subacute toxicity study was conducted by repeated oral administration of the compound for 30 days. Treatment with W-2429 was well tolerated by rats as well as dogs. In the dog, the only signs of toxicity observed were decreased appetite and salivation at 100 mg/kg/day. No other significant evidence of physical, chemical, gross or histopathologic change was observed.

4-(p-Chlorophenylthio)butanol (W-2719), a new non-antihistaminic drug for immediate hypersensitivity allergies.

p-Chlorophenylthiobutanol (W-2719) has been found to effectively inhibit immunologic and non-immunologic histamine release and mast cell degranulation. It has been found to effectively suppress passive cutaneous anaphylaxis (PCA) reaction not be antihistaminic action, but by inhibiting the release of allergic mediators.

Endotoxin-free biologically active component of Escherichia coli.

The proteinaceous component of gram-negative bacteria, which has been termed "protodyne," enhances nonspecific host resistance while eliciting a slight pyrogenic response equivalent to 0.2% that of a typical endotoxin. Since this material still contains small amounts of carbohydrate and lipid, it was imperative to establish that its biological activities are not the result of endotoxin contamination. Evidence that the protective activity of protodyne does not result from endotoxin contamination has now been obtained by an evaluation of the Pronase digestion products of this substance. These digestion products were found to be nonpyrogenic and to contain no measurable amount of 2-keto-3-deoxyoctonate, an essential component of bacterial lipopolysaccharides.