Comparison of hydrochlorothiazide and hydrochlorothiazide plus bevantolol in hypertension.

The added hypotensive effect of bevantolol, a new cardioselective beta-blocker, was studied in 244 patients with mild to moderate essential hypertension following prior treatment with hydrochlorothiazide or placebo. After four weeks of monotherapy with 50 mg/day or 100 mg/day of hydrochlorothiazide or placebo, the mean diastolic blood pressure of the patients in these groups decreased from baseline by 8.6, 8.8, and 4.3 mmHg, respectively. During the subsequent four weeks of dual therapy with 400 mg/day of bevantolol added to the regimen, additional and uniform mean decreases of 7.5, 7.3, and 7.5 mmHg occurred, providing total mean diastolic pressure decreases from baseline of 16.1, 16.1, and 11.8 mmHg in the three groups, respectively. These diastolic pressures were significantly lower during dual therapy than during monotherapy and lower in both diuretic groups than in the placebo group during monotherapy and dual therapy (P less than 0.001). Fewer adverse reactions occurred during dual therapy than during monotherapy. The addition of bevantolol to a thiazide diuretic regimen provided safe and significantly better control of mild to moderate hypertension than did the diuretic alone.

Antihypertensive activity of 6-arylpyrido[2,3-d]pyrimidin-7-amine derivatives. 2. 7-Acyl amide analogues.

The effect of acylation with a variety of acids on the antihypertensive activity of 6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidine-7-amine (1) is reported, and structure-activity relationships are discussed. Although several of the compounds show good oral antihypertensive activity in the conscious, spontaneously hypertensive rat (SHR), their activity profile appears to differ from 1 in that the onset of action is shortened at comparable blood pressure lowering doses, and the magnitude of effect is considerably greater at higher doses. A variety of urea, thiourea, guanidine, and amidine analogues also were prepared. Although many of these derivatives showed some antihypertensive effects when dosed orally to SHR, this activity was weaker and of shorter duration than that obtained with 1. Aqueous solubilities and hydrolytic stabilities for four of the more active compounds were measured and suggest that these do not function as prodrugs of 1.

Antihypertensive activity of 6-arylpyrido[2,3-d]pyrimidin-7-amine derivatives.

A series of 51 6-arylpyrido[2,3-d]pyrimidin-7-amine derivatives was prepared and evaluated for antihypertensive activity in the conscious spontaneously hypertensive rat. A number of these compounds, notably 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine (36), lowered blood pressure in these rats in a gradual and sustained manner to normotensive levels at oral doses of 10-50 mg/kg. Normalized blood pressure levels could then be maintained by single daily oral doses. The effect of structural variation in the 6-aryl group and in the 2 and 4 positions of the pyridopyrimidine ring on activity is reported and discussed.

Duration of antinociceptive action of morphine, methadone and alpha-l-acetylmethadol subcutaneously in rats.

The duration of antinociceptive action of alpha-l-acetylmethadol (LAM), determined in the rat tail pinch test, was 6 times that of morphine and 3 times that of methadone. Onset of activity was considerably later after LAM than after morphine or methadone.

A sensitive method for the comparative bioassay of nonsteroidal anti-inflammatory compounds in adjuvant-induced primary inflammation in the rat.

A method for the comparative bioassay of nonsteroidal anti-inflammatory agents is presented which exploits the early inflammation induced by injection of adjuvant into the plantar surface of a hind paw of the rat. The inflammation reaches a peak on the 4th postinjection day. Daily treatment with nonsteroidal anti-inflammatory agents reduces paw volumes and the associated impairment of body growth with optimal improvement on the 4th postinjection day. In this model, phenylbutazone has shown significant activity at doses as low at 1.33 mg/kg/day. Statistically valid comparative assays conducted at dose levels equivalent to or below those used in human therapy yield potency ratios with relatively narrow confidence limits. Potencies relative to phenylbutazone for inhibiting primary adjuvant-induced inflammation are: aminopyrine, 0.066 (0.36-0.11)95%; aspirin, 0.087 (0.039-0.19)95%; mefenamic acid, 0.98 (0.64-1.6)95%; flufenamic acid, 13 (7.4-26)95%; meclofenamic acid, 23(16-33)95%; and indomethacin, 53 (35-82) 95%. Ancillary and sometimes quantitative information is also provided by the improvement in well being of the animals as reflected in body weight changes with treatment.

Comparative activities, tolerances and safety of nonsteroidal anti-inflammatory agents in rats.

Relative anti-inflammatory potencies of aspirin, phenylbutazone, indomethacin, three fenamates and several other nonsteroidal anti-inflammatory agents were obtained in several laboratory models of acute and chronic inflammation. Relative toxicities and ulcerogenicities were determined in rats of the same source, strain and sex. The acute ulcerogenic assay measures the minimal irritation potential of these agents and leads to a sensitive index of the safety of such compounds when compared with their therapeutic potencies. By these criteria, meclofenamic acid is a highly potent, acceptably safe and exceptionally well tolerated anti-inflammatory-antipyretic agent in rats when compared with other such drugs.