Bronchodilator and other pharmacological activities of R-836 (2,5-diethyl-7-(4-thiomorpholino)-1,2,4-triazolo[1,5-c]pyrimidin e).

The bronchodilator activity of R-386 (2,5-diethyl-7-(4-thiomorpholino)-1,2,4-triazolo[1,5-c]pyrimidine) was demonstrated in isolated guinea-pig tracheal preparations and in vivo in dogs, guinea-pigs and rats. Guinea-pig tracheal preparations contracted by histamine, acetylcholine, BaCl2, leukotriene C4 or antigen were relaxed 50% by concentrations (IC-50 values) of R-836 of approximately 0.3 microgram/ml (10(-6) M) in all cases. In the conscious guinea-pig, oral or i.p. administration of R-836 prevented asphyxial collapse, death or dyspneic changes produced by histamine, antigen of LTC4. In anesthetized guinea-pigs, R-836 reduced bronchoconstriction produced by antigen or PAF (Konzett-Rössler preparation). In the dog, i.v. or intraduodenal administration of R-836 reduced bronchoconstriction produced by methacholine or histamine. In the rat, i.p. administration of R-836 reduced bronchoconstriction produced by 5-HT or antigenic challenge. In these in vivo models, when direct comparisons were made, R-836 was estimated to possess 2 to 3 times the potency of theophylline. R-836, at doses 80 times those necessary to produce bronchodilation, had no effect on blood pressure or heart rate of guinea-pigs. R-836 was not a CNS stimulant in mice, was not diuretic in rats, only marginally inhibited adenosine-induced responses in mice and guinea-pigs and was a weak inhibitor of phosphodiesterase in vitro.

Inhibition of Paf-acether-induced edema of the rat's paw.

Three classes of drugs were found, after their i.p. administration, to inhibit Paf-acether-induced edema of the rat's paw. These were beta-adrenergic agonists (isoproterenol, salbutamol), alpha-adrenergic antagonists (prazosin, ergotamine, yohimbine, phenoxybenzamine), and calcium entry blockers (nifedipine, verapamil, diltiazem). A number of other drugs including steroidal and nonsteroidal antiinflammatory agents, alpha-agonists, beta-antagonists, pyrilamine, atropine, methysergide, a lipoxygenase inhibitor, and a leukotriene antagonist did not inhibit the development of the edema. Propranolol, but not practolol, antagonized the inhibitory effect of isoproterenol which provided evidence for involvement of beta-2 receptors in the mechanism of action of the beta agonists. It is suggested that cellular calcium influx is involved in the edemagenic response observed after the injection of Paf-acether into the rat's paw.

Dissociation of catch-up growth control and neural control of growth hormone secretion in the stunted head-irradiated rat.

Male Long-Evans rats were irradiated to the head only at 2 days of age; littermates of the same sex were sham-irradiated. At 40 days of age the irradiated rats were divided into two groups, one of which was fasted 48 h and the other fed a normal diet. The irradiated rats, fasted and nonfasted, were cannulated in the superior vena cava at 48 to 50 days of age. Between 54 and 58 days of age the cannulated undisturbed rats had blood samples withdrawn at 15-min intervals over an 18-h period (9 h light and 9 h dark). Body weight and tail length data showed characteristic stunting following irradiation. The superimposed fast caused transient growth retardation; on refeeding, the fasted rats showed a pattern of catch-up growth limited to the irradiated non-fasted body size. Plasma growth hormone (GH) concentration in the fasted-refed rats as compared with the nonfasted irradiated rats showed no change in the average period of the bursts of GH secretion, the numbers of values in ranges of GH concentration, or the area under the curve of the plasma GH concentration versus time. No difference in these parameters was present in light or dark, considered separately. We conclude 1) that the link between the catch-up growth control and neural mechanisms controlling GH secretion is impaired as a consequence of the neonatal head-irradiation and 2) that catch-up growth acceleration is not dependent on increased GH secretion.

Growth hormone secretion in the stunted head-irradiated rat.

Pulsatile secretion profiles of pituitary growth hormone (GH) and size and number of cells of brain, heart ventricles, liver, kidney, and gastrocnemius muscle were determined in male Long-Evans rats which received 600 rad x-irradiation to the head only at 2 days of age. Controls consisted of sham-irradiated littermates. The irradiated rats showed significant stunting of body weight and tail length beginning prior to weaning and lasting throughout the period (64 days) of observation. In irradiated rats at 20-21 days of age, just prior to weaning, organ weight was significantly reduced in all organs studied. Brain showed a decrease in organ/body ratio (p less than 0.0005) and in total DNA content (p less than 0.0005), but these values were not significantly changed in the other organs. DNA/organ ratio was increased significantly in heart (p less than 0.025) and gastrocnemius muscle (p less than 0.025); brain, liver, and kidney had nonsignificant increases. Protein/DNA ratios were decreased significantly in brain (p less than 0.005), heart (p less than 0.01), and gastrocnemius muscle (p less than 0.05); liver and kidney had nonsignificant decreases. Blood samples were removed for GH determination from cannulated undisturbed irradiated and control rats at 15-min intervals for 18-h periods (9 h light and 9 h dark) at 47-64 days of age. Irradiated rats had normal periodicity of bursts of GH secretion. The area under the curve of GH concentration versus time of the irradiated rat was decreased in light (p less than 0.025) and in dark (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of anti-inflammatory compounds in the carrageenan induced paw edema model and the reversed passive Arthus model utilizing the same animal.

In order to better define antiinflammatory activity in new agents, a test was devised utilizing both carrageenan induced paw edema and the reversed passive Arthus reaction in the same animal. The model of carrageenan induced rat paw edema is a standard laboratory assay used to predict classical "aspirin-like" antiinflammatory molecules. The reversed passive cutaneous Arthus reaction involves precipitating antigen-antibody complexes, complement and infiltrating polymorphonuclear leukocytes (PMN's) and can be used to identify agents that affect one or more of these factors specifically. Antiinflammatory compounds were given orally one hour prior to the administration of carrageenan and goat anti-rat serum. Comparisons were made between several non-steroidal compounds and the steroid hydrocortisone. All of the compounds tested gave good carrageenan activity, but only hydrocortisone produced significant Arthus lesion inhibition in this assay.

Use of a simple in vivo technique to investigate components of the immediate hypersensitivity reaction in conscious guinea pigs.

A semiplethysmographic method was used to delineate the effects of aerosol antigen challenge on the respiratory pattern of conscious, sensitized guinea pigs. Chlorpheniramine pretreatment prevented death, delayed the onset of respiratory symptoms and decreased the severity of the hypersensitivity reaction. This reaction could be further diminished to varying degrees by the addition of FPL55712, atropine sulfate and/or imidazole to chlorpheniramine. Indomethacin and nordihydroguaiaretic acid (NDGA) with chlorpheniramine caused a potentiation in the severity of the hypersensitivity reaction. However, chlorpheniramine, NDGA and imidazole in combination blocked the hypersensitivity reaction. The technique appears to demonstrate the involvement of several suggested mediators in asthma and appears potentially useful as an indicator of effects on arachidonic acid metabolism and metabolites.

2,6-Di-tert-butyl-4-(2'-thenoyl)phenol(R-830): a novel nonsteroidal anti-inflammatory agent with antioxidant properties.

R-830, a di-tert-butylphenol, has been shown to be anti-inflammatory in a number of animal models. These include conventional systems such as carrageenan-induced edema and adjuvant arthritis of the rat and ultraviolet-induced erythema in the guinea pig in which the acidic nonsteroidal anti-inflammatory drugs (e.g., indomethacin) are effective. The anti-inflammatory activity of R-830 has also been demonstrated in other models (e.g., graft vs. host reaction and reversed passive cutaneous Arthus reaction in the rat, contact sensitivity in the mouse) in which the acidic nonsteroidal drugs are not effective. In vitro, R-830 inhibits guinea pig lung lipoxygenase and bovine seminal vesicle cyclo-oxygenase. The antioxidant properties of R-830 were demonstrated in two in vitro systems. We speculate that the antioxidant activity of this molecule might be related to its unusual profile of pharmacological activity.

A new method for treating carcinomatous biliary obstruction with intracatheter radium.

We describe a new method for relieving biliary obstruction due to malignant solid tumors. The method consists of placement of radium needles in a Ring biliary drainage catheter for three days. After removing the radium needles, the catheter is left in place to allow for repair of irradiated tissues, then it is removed. The object is to leave the patient with a patent biliary tree without a biliary drainage prosthesis. The clinical course of six patients treated by this method is described, and the autopsy findings in three cases are outlined. Three patients died with a serum total bilirubin ranging from 1--4.5 mg/100 ml, two to three months after removing the drainage catheter. Two patients died before the bile drainage catheter could be removed. One patient is alive with a bile drainage catheter in place. Possible modifications in technique and catheters are being considered.

Comparison of croton oil and cantharidin induced inflammations of the mouse ear and their modification by topically applied drugs.

The inflammatory response to topical application of cantharidin or croton oil to the mouse ear was studied. Croton oil dermatitis developed more rapidly and reached its apparent peak earlier than cantharidin dermatitis. Either dermatitis detected topical rather than systemic antiinflammatory activity of glucocorticosteroids and distinguished between steroid esters and their alcohols. A number of drugs were tested for their ability, after topical application, to inhibit these dermatitides. Nonsteroidal antiinflammatory drugs weakly inhibited croton oil dermatitis but were without effect on cantharidin dermatitis. Beta-adrenergic agonists and antagonists inhibited both dermatitides. It is suggested that the use of these simple models of dermatitis is appropriate for identifying new, topically effective antiinflammatory drugs.

Antiallergic activity of tetracyclic derivatives of quinoline-2-carboxylic acids. 1.

Substitution of 1,4-dihydro-4-oxoquinoline-2-carboxylic acid by acetyl, benzoyl, and phenylsulfonyl substituents was found to enhance activity in the rat passive cutaneous anaphylaxis assay. A further increase in activity, to equipotency with DSCG, was achieved by incorporation of the 8-benzoyl moiety into a tetracyclic structure to give 1,4-dihydro-4,11(1H,11H)-dioxoindeno[1,2-h]quinoline-2-carboxylic acid (20). In contrast, the reverse isomer 19 was found to have little activity.

Evaluation of some standard arthritogenic adjuvants ('modified perrigens') in male rats.

Four commercially available arthritogenic adjuvants ('modified Perrigens') were compared with a Mycobacterium butyricum-mineral oil adjuvant for their ability to induce arthritis in male Holtzman rats. The induced arthritides were also compared with respect to their response to treatment with phenylbutazone and cyclophosphamide. Trivial differences were noted among the various adjuvants in their capability to induce the disease, the severity of the disease, or the response of the disease to therapeutic (phenylbutazone) or prophylactic (cyclophosphamide) administration of drugs. It was concluded that any one of the adjuvants was probably suitable for inducing an arthritis in rats for the testing of drugs and that perhaps other variables in the assay are more important in explaining inter-laboratory variation.

4-nitro-2-phenoxymethanesulfonanilide (R-805): a chemically novel anti-inflammatory agent.

The anti-inflammatory activity of the sulfonanilide, 4-nitro-2-phenoxymethanesulfonanilide (R-805) has been demonstrated in conventional models (carrageenan-induced edema of the rat's paw, UV-induced erythema of guinea-pig skin, adjuvant-induced arthritis of the rat). R-805 differs from most currently available acidic anti-inflammatory drugs in that its functional acidic group is not carboxyl. The relative anti-inflammatory potency of R-805 is comparable to indomethacin. Calculation of acute therapeutic indices (LD50/ED50) for 8 acidic anti-inflammatory drugs show R-805 to possess a more favourable index than the other drugs examined.

Antiinflammatory activity of alpha-methyl-3-phenyl-7-benzofuranacetic acid (R-803).

The antiinflammatory activity of R-803 (alpha-methyl-3-phenyl-7-benzofuranacetic acid), a new nonsteroidal drug, has been demonstrated. The oral administration of R-803 inhibits carrageenan-induced edema of the rat's paw, ultraviolet-induced erythema of guinea-pig skin, adjuvant-induced and 6-sulfonamidoindazole-induced arthritides of the rat at doses in the range of 1.0 to 6.0 mg/kg. It also inhibits the cotton pellet-induced granuloma in the rat at higher doses.

Antiinflammatory fluoroalkanesulfonanilides. 3. Other fluoroalkanesulfonamido diaryl systems.

A series of isosteres of 3-benzoyltrifluoromethanesulfonanilide involving alternatives to the carbonyl linking group was synthesized and screened for antiinflammatory activity in the carrageenan rat paw edema test. The systems examined were of the type m-CF3SO2NH-C6H4-X-C6H5, where X was -CROH-, -CHR-, -CH(OH)CH2-, -COCH2-, -CH2CO-, greater than C equal to CR2, -CR equal to CH, -C identical to C-, -CH2CH2-, CONH-, -NR-, -O-, -S(O)n- (n equal to 0,1,2), and carbon-carbon single bond. Many ortho and para derivatives were also tested. Several of these new trifluoromethanesulfonanilides proved equipotent with phenylbutazone. The effects on the anticarrageenan activity of both the nature and ring position of X are discussed.