Hemodynamic actions of bepridil during treatment of stable angina pectoris.

Bepridil, a new calcium-entry blocker, was evaluated in 13 patients with chronic stable angina in a single-blind trial that was placebo controlled within patients. Its antianginal effects were recorded and left ventricular (LV) function was assessed at rest and during exercise by gated blood pool scintigraphy. Mean anginal frequency was significantly reduced from 7.3 to 3.4 episodes/week (p less than 0.01). Total work performed increased from 336 to 625 kpm (p less than 0.01). Supine resting LV end-diastolic volume index, end-systolic volume index, stroke volume index, cardiac index and ejection fraction (EF) were not altered by bepridil. During supine exercise, the EF decreased from 60 to 55 during placebo therapy. Despite an increase in total work, the mean EF increased from 60 to 62 (p less than 0.05 versus exercise on placebo) during exercise with bepridil therapy. Maximal exercise stroke volume index and cardiac index were significantly greater during bepridil therapy. Exercise resulted in new or increased LV wall motion abnormalities in 7 of 13 patients during placebo therapy. During bepridil therapy, only 4 new or increased wall motion abnormalities were noted despite the increase in total work performed. Therefore, bepridil is an effective antianginal agent, allowing an increase in exercise workload while preserving LV performance.

Evaluation of bepridil, a new antianginal agent: clinical and hemodynamic alterations during the treatment of stable angina pectoris.

The antianginal effects of bepridil, a new calcium entry blocker, were evaluated in 20 patients with chronic stable angina in a single-blind trial that was placebo-controlled within patients. Of the 20 patients, 13 also underwent rest and exercise gated blood pool scintigraphy to assess the effects of the agent on left ventricular (LV) performance. Mean anginal frequency was significantly reduced, from 7.3 to 3.1 episodes/week (p less than 0.01). Total work performed increased from 410 to 581 kpm (p less than 0.005), and exercise time increased from 5.3 to 6.6 minutes (p less than 0.005). Supine resting LV end-diastolic volume index, end-systolic volume index, stroke volume index, cardiac index and ejection fraction (EF) were not altered by bepridil. During supine exercise, EF decreased from 60 to 55% during placebo therapy. Despite an increase in total work, the mean EF increased from 60 to 62% (p less than 0.05 vs exercise placebo) during exercise with bepridil therapy. Maximal exercise stroke volume index and cardiac index were significantly greater during bepridil therapy. Exercise resulted in new or increased LV wall motion abnormalities in 7 of 13 patients during placebo therapy. During bepridil therapy, only 4 new or increased wall motion abnormalities were noted despite the increase in total work performed. Thus, bepridil is an effective antianginal agent. The drug allows an increase in exercise work load and preserves LV performance.

Metabolism of triamcinolone acetonide-21-phosphate in dogs, monkeys, and rats.

The absorption, distribution and metabolic fate of triamcinolone acetonide-14C-21-phosphate were studied in the dog, monkey, and rat. A comparison of levels of radioactivity in blood or plasma, reached after intramuscular or intravenous administration, indicated that the drug was completely absorbed from the site of intramuscular injection within 10-15 min in all three species. Within 1-5 min after intramuscular or intravenous administration, the 21-phosphate ester was completely hydrolyzed to triamcinolone acetonide, which was present in the blood. The radioactivity was eliminated rapidly (t1/2 = 1-2 hr) from plasma (dogs, monkeys, and rats) and tissues (rats) after intramuscular or intravenous administration. In the three species, the major route of excretion was via the bile; however, the ratio of biliary to urinary excretion among the species varied considerably (from 1.5 to 15). In rats, excretion of radioactivity as expired carbon dioxide accounted for only 2-3 percent of the dose. 6beta-Hydroxytriamcinolone acetonide was the major metabolite in urine of the three species. Hydrolytic cleavage of the acetonide group did not appear to be significant.

Physical characterization and activity in vivo of polymorphic forms of 7-chloro-5, 11-dihydrodibenz[b, e][1, 4]oxazepine-5-carboxamide, a potential tricyclic antidepressant.

The biological availability in dogs and humans of 7-chloro-5, 11-dihydrodibenz[b,e][1,4]oxazepine-5-carboxamide, a potential antidepressant drug, was increased when the compound was administered in capsule formulations as micronized drug coated with 1% sodium lauryl sulfate or as a lyophilate with poloxamer 407. This increase with these two formulations had been predicted by dissolution tests in vitro. The lyophilized combination with poloxamer 407 was more soluble in 0.1 N HCl than was the untreated compound. Characterization of the lyophilate by differential thermal analysis, X-ray diffraction, and IR spectroscopy indicated that the increase in solubility was attributable to the formation of a polymorphic from. a polymorph of the compound designated form 8, was prepared. The solubility and dissolution characteristics of the two polymorphic forms, A and B, as well as of the lyophilized combination with poloxamer 407, were determined.

Clinical pharmacology of SQ 10,996, a potential antidepressive agent.

Single oral doses of SQ 10,996 ranging from 500 to 1000 mg (0.34 to 15.3 mg/kg), given once daily for 3 consecutive days to groups of healthy volunteers, were well tolerated. One of three subjects given 1250 mg (17.1 mg/kg) and two of three subjects given 1500 mg (15.6 and 21.4 mg/kg) became drowsy on the second and third days; this symptom disappeared within 24 hrs after cessation of dosage. A short-term, multiple-dose tolerance study was carried out with a formulation of SQ 10,996, the bioavailability of which was comparable to that of the formulation used earlier in the ascending-dose tolerance study. When 200-mg doses were administered every 12, 8, or 6 hrs over a 6-day period, mean steady-state serum concentrations of approximately 4, 7, and 8 mug/ml were attained within 48 hrs; unexpectedly, no subject showed any sign of drowsiness. The half-life for SQ 10,996 in serum, estimated from concentrations in serum after the last dose, was approximately 13 hrs, significantly shorter than the half-life found previously after the administration of single 10-mg doses. These clinical pharmacology studies in healthy volunteers have shown SQ 10,996 to be biologically available and well tolerated. Future studies will test its antidepressive potential in patients.

Inhibition of antigen-induced bronchoconstriction with reproterol, a new beta agonist-xanthine derivative.

The purpose of this study was to compare the efficacy of a new bronchodilator, reproterol with standard bronchodilators terbutaline and theophylline in patients with allergic asthma. Efficacy was determined by measuring the initial bronchodilating effect and the inhibition of antigen-induced bronchoconstriction. In a double-blind, randomized, controlled study with single doses of medication, patients were given reproterol (20 mg and 30 mg), anhydrous theophylline (200 mg), terbutaline (5 mg) and placebo prior to challenge with antigen. Prior to administration of antigen both reproterol and terbutaline had measurable bronchodilating effect when compared to placebo. The bronchodilating effect of theophylline was less than placebo. In comparison to placebo both doses of reproterol and terbutaline significantly attenuated the response to antigen challenge whereas the effect of theophylline was negligible.

Cephradine: absorption, excretion, and tissue distribution in animals of a new cephalosporin antibiotic.

Metabolic studies were conducted with cephradine administred by the oral, subcutaneous, intravenous, or rectal routes to mice, rats, and dogs. Peak blood levels were usually attained in 30 to 150 min after dosing, depending on the animal species studied. Based on urinary excretion, cephradine appeared to be well absorbed after oral or subcutaneous administration; after rectal doses, cephradine was absorbed poorly. In rats and dogs given oral or intravenous doses of cephradine, about 70 to 100% of the administered dose was recovered during a 24-h collection period. Cephradine was excreted unchanged. After the oral or intravenous administration of [(3)H]cephradine to rats and dogs, respectively, its plasma half-life was about 1 h. After oral administration to rats, cephradine was distributed widely throughout the body tissues, with the greatest concentrations in the kidneys and liver; at 45 min to 6 h postdose, cephradine concentrations in the kidneys and liver were about 8 and 3 times higher, respectively, than those in plasma.