Synthesis of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids as possible superoxide scavengers and antiinflammatory agents.

A series of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids were synthesized and tested in vitro for superoxide scavenging activity, in vivo in the carrageenan-induced rat paw edema assay, and in the reverse passive Arthus reaction. The hydroxy-substituted compounds were effective as in vitro scavengers of superoxide but were not effective as in vivo antiinflammatory agents.

Anti-inflammatory and antiproteolytic properties of 1-(1-naphthylacetyl)-3-substituted carbamides.

Several 1-(1-naphthylacetyl)-3-substituted carbamides were synthesized, characterized, and evaluated for anti-inflammatory and antiproteolytic activity. The protection afforded by most of these carbamides against carrageenan-induced edema in rats at a dose of 100 mg/kg ranged from 4.4 to 50%. Some of these carbamides, which showed higher protection against carrageenan-induced edema, were further evaluated for their antigranulation effect against cotton pellet-induced granuloma formation in rats. All carbamides showed a poor degree of protection against granuloma formation. The antiproteolytic activity of these carbamides, as reflected by their ability to inhibit trypsin-induced hydrolysis of the bovine serum albumin, was of a low order and was unrelated to their anti-inflammatory activity.

Synthesis of substituted anilino-3-methoxy-4-substituted acetoxy) benzylidenes and their monoamine oxidase inhibitory and anticonvulsant properties.

Several substituted anilino-(3-methoxy-4-substituted acetoxy) benzylidenes were synthesized and characterized by their sharp melting points and elemental analyses. All substituted benzylidenes competitively inhibited the in vitro monoamine oxidase activity of rat brain homogenates and possessed anticonvulsant activity against pentylenetetrazol-induced convulsions in mice.

Anticonvulsant activity of N,N'-bis[3-(3-substituted urea)propyl]piperazines.

Several N,N'-bis[3-(3-substituted urea)propyl]piperazines were synthesized and characterized by their sharp melting points, elemental analyses, and IR spectra. All substituted piperazines were found to possess anticonvulsant activity, which was reflected by 20-70% protection observed against pentylenetetrazol-induced seizures in mice. Some of these compounds inhibited oxidation of pyruvic acid by rat brain homogenate. No correlation could be observed between the anticonvulsant activity possessed by these substituted piperazines and their ability to inhibit the oxidation of pyruvic acid.

Antihemolytic and antiproteolytic properties of substituted thiosemicarbazidophenothiazines and thiazolidonylphenothiazines.

Antihemolytic and antiproteolytic properties of several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines were investigated. In vitro protection of hypoosmotic hemolysis of human red blood cells by substituted thiosemicarbazidophenothiazines and substituted thiazolidonyl-phenothiazines was concentration dependent; the degree of protection ranged from 19 to 32 and 26 to 42%, respectively, at a final concentration of 0.1 mM. All phenothiazines exhibited antiproteolytic activity. The in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin by these phenothiazines was concentration dependent and competitive in nature; the degree of inhibition ranged from 30 to 50 and 32 to 79% for substituted thiosemicarbazidophenothiazines and substituted thiazolidonlyphenothiazines, respectively, at a concentration of 1mM. Cyclization of substituted thiosemicarbazidophenothiazines into the corresponding cyclized substitited thiazolidonlyphenothiazines increased the antihemolytic and antiproteolytic effectiveness of these phenothiazines.

13C-NMR spectra of strychnos alkaloids: brucine and strychnine.

The natural abundance 13C-NMR spectra of brucine and strychnine were obtained using the pulse Fourier transform technique. The chemical shifts of various carbon resonances were assigned on the basis of substituent effects on benzene shifts, intesities of signals, multiplicites generated in single-frequency off-resonance-decoupled spectra, and comparisons with the chemical shifts of structurally related compounds.

13C-NMR spectra of alpha-adrenergic blocking agents.

The natural abundance 13C-NMR spectra of five alpha-adrenergic blocking agents, tolazoline, dibenamine, azapetine, phenoxybenzamine, and phentolamine, are reported. The chemical shifts of various carbon resonances were assigned on the basis of chemical shift theory, multiplicities observed in single-frequency off-resonance-decoupled spectra, relaxation times, and comparisons with the chemical shifts of model compounds.

Synthesis of substituted thiobenzoxazoles/benzothiazoles: inhibition of cellular respiratory and monoamine oxidase activities and anticonvulsant property.

Several 2-(substituted alkoxy/hydrazinocarbonyl acetanilidothio)benzoxazoles/benzothiazoles were synthesized and characterized by their sharp melting points, elemental analyses, and IR spectra. All thiobenzoxazoles/benzothiazoles possessed low anticonvulsant activity, which was reflected by the 10-40% protection afforded by these compounds against pentylenetetrazol-induced convulsions. All thiobenzoxazoles/benzothiazoles inhibited selectively the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, DL-isocitrate, and alpha-ketoglutarate by rat brain homogenates. NAD-independent oxidation of succinate remained unaltered. All 2-(substituted hydrazinocarbonyl acetanilidothio)benzoxazoles/benzothiazoles inhibited monoamine oxidase activity of rat brain homogenates. Greater monoamine oxidase inhibition was observed with thiobenzothiazoles than with the corresponding thiobenzoxazoles/benzothiazoles was found to be unrelated with their ability to inhibit cellular respiratory and monoamine oxidase activities of rat brain homogenates.

Fourier transform carbon-13 NMR spectra of ampyrone and aminopyrine.

The natural abundance 13C-NMR spectra of ampyrone and aminopyrine were obtained using the pulse Fourier transform technique. The chemical shifts were assigned with the help of the chemical shift theory, multiplicity generated in single-frequency off-resonance decoupled spectra, relaxation time, and comparison with structurally related compounds.

Endocrine control of inflammation: rheumatoid arthritis double-blind, crossover clinical trial.

A dysfunction in the endocrine control system for inflammation in rheumatoid arthritis serves as the theoretical basis for chronic inflammation in the study design described. Eighteen patients with rheumatoid arthritis, who acted as their own controls, were brought to a minimum symptom state through conventional means, trained, and allowed to control subsequent flares by a patient-initiated, flare-response prednisone regimen. The six-month trial was double-blind with a crossover at midpoint. While continuing stable non-steroidal anti-inflammatory and disease modifying antirheumatic drug therapies, the patients averaged additional 57% and 75% reductions from baseline in tender joint count and total pain score, respectively, on the prednisone therapy. The prednisone therapy was differentiated by improvement from that of a placebo by six of the nine parameters evaluated. The adverse events were no more frequent with prednisone than with placebo use. The efficacy of prednisone was increased threefold while reducing consumption by 40% when compared to the predecessor 5-mg prednisone/day clinical trial.

Antiestrogenic activity of 4-methyl-7-hydroxy-6,8-substituted coumarins.

Eight 4-methyl-7-hydroxy-6,8-substituted coumarins were synthesized and evaluated for antiestrogenic activity. All coumarins, possessing approximate LD50 values of 500 - greater than 800 mg/kg, antagonized the uterotropic effects of diethylstilbestrol (DES) in female rats.

Analgesic activity of substituted benzylidinohydrazines.

Sixteen substitued benzylidinohydrazines were evaluated for morphine-like analgesic activity by mouse tail-pinch test while aconitine-induced writhing test in mice was used to determine their ability to possess aspirin-like analgesia. All benzylidinohydrazines exhibited analgesic activity where protection against tail-pinch and aconitine-induced writhing response ranged from 16.7-83.3% and 16.7-66.7%, respectively.

Protection of carrageenin edema and trypsin hydrolysis of bovine serum albumin by naphthylthiosemicarbazides and their cyclized oxadiazoles.

Seven 1-(naphth-1-ylacetyl)-4-substituted thiosemicarbazides were synthesized and cyclized to the corresponding 2-(naphth-1-ylmethyl)-5-arylamino-1,3,4-oxadiazoles. All compounds, with the exception of two slbstituted oxadiazoles, possessed low anti-inflammatory activity. The protection afforded by these compounds against carrageen-in-induced edema ranged from 3 to 43% where cyclization, in general, decreased anti-inflammatory activity. All compounds (1 mM), possessed antiproteolytic activity where in vitro protection of trypsin-induced hydrolysis of bovine serum albumin, in most cases was greater with oxadiazoles.

Negative endocrine control system for inflammation in rats.

Inflammatory processes may be suppressed by endogenous mechanisms such as release of adrenocorticosteroid hormones through stimulation of the hypothalamus-pituitary-adrenal axis. In the present study, the relationship between the temporal development of carrageenan-induced edema in the hindlimb of the rat and release in plasma of the principal endogenous adrenocorticosteroid of the rat corticosterone was investigated. Suplantar injection of carrageenan produced a biphasic increase in basal plasma corticosterone levels that was not attributed to diurnal variation. The plasma level of corticosterone increased rapidly after injection of carrageenan and peaked 12-fold at 20 min. This first phase increase was attributed to the stress of the injection since it was mimicked by subplantar injection of saline. The second phase of corticosterone release was gradual and peaked 12-fold 7 hr after injection of carrageenan. The second phase was not elicited by subplantar injection of saline. When the hypothalamus-pituitary-adrenal axis is impaired via hypophysectomy, carrageenan-induced edema is more intense and lasts longer than in control rats. The results demonstrate that adrenocorticosteroid hormones are released as a result of the stress of injection and by the inflammatory response. Release of adrenocorticosteroids acts as a feedback mechanism to suppress the inflammatory response.