Kunihiko Takeyama

Antihypertensive effects of AJ-2615, a new calcium antagonist with α1-adrenergic blocking activity in experimental hypertensive animals

The antihypertensive effect of AJ-2615 [(±)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluorophenyl)-1-piperazinebutanamide maleate], a novel calcium (Ca) antagonist having α1,-adrenergic blocking activity as well, was compared with that of the existing Ca antagonists (diltiazem, nifedipine, and nicardipine) in various hypertensive models of dogs and rats. When given orally to renal hypertensive dogs (RHDs) and spontaneously hypertensive rats (SHRs), AJ-2615 (RHDs, ED25 mm Hg = 6.0 mg/kg; SHRs, ED25 mm Hg = 24.9 mg/kg) was approximately as effective as diltiazem (RHDs, ED25 mm Hg = 6.3 mg/kg; SHRs, ED25 mm Hg = 54.7 mg/kg) in lowering the blood pressure. This antihypertensive effect was slower in onset and longer in duration (RHDs, ≧ 9 h; SHRs, ≧ 20 h) compared with any of the other reference drugs. AJ-2615 (10 mg/kg p.o.) given to RHDs once daily for 29 days significantly reduced the blood pressure measured 24 h after each dose and caused a stable antihypertensive effect without major diurnal variations. When given in single oral doses to RHDs and SHRs, AJ-2615 had no large effect on the heart rate while the reference drugs induced a large increase or decrease in heart rate in response to a blood pressure fall. These results suggested that AJ-2615 has potential as a long-acting (once daily dosage regimen) antihypertensive drug without causing a steep blood pressure fall and tachycardia.

The equivalent bronchodilator effects of salbutamol formulated in chlorofluorocarbon and hydrofluoroalkane-134a metered dose inhalers on the histamine-induced pulmonary response in dogs.

AbstractPurpose. The bronchodilator effect of salbutamol formulated in hydrofluoroalkane-134a (HFA-134a), a Chlorofluorocarbon (CFC)-free propellant for metered dose inhalation (MDI) devices, was compared with that of salbutamol formulated in CFC in anesthetized dogs. Methods. Bronchospasms were induced by the intravenous injection of histamine, and bronchial resistance was measured by the method of Konzett and Rossler. Results. While the placebo vehicles (HFA-134a and CFC propellants) had no significant effect on histamine-induced bronchospasms, the salbutamol/HFA-134a and salbutamol/CFC MDI formulations had equivalent dose-related inhibitory effects. Conclusions. These data indicated that salbutamol formulated in HFA-134a and that in CFC propellant are bioequivalent.