Phase I study of carvedilol (DQ-2466), a new .BETA.-blocker. (The 2nd report). The study in multiple oral administration.

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Following the investigation of single oral doses of carvedilol (DQ-2466) in healthy male volunteers, multiple dosing studies of 2 and 14 days were conducted to evaluate the hemodynamics and safety of the drug. In the 2-day multiple dosing study, daily doses of 20 mg and 40 mg were tested each for 4 regimen groups (i. e. 10 mg, 20 mg twice daily, 20 mg, 40 mg once daily). With respect to 14-day multiple dosing, a 20 mg once daily regimen was used. The following results were obtained: 1) Decrease of systolic and diastolic blood pressures at rest was enhanced on day 2 both for the once and the twice daily regimen in the 2-day multiple dosing. In the 14-day multiple dosing, decrease of systolic and diastolic blood pressures at rest was gradually enhanced up to day 7, and the decreased blood pressures were stabilized thereafter. Circadian variation of blood pressures was studied on the day of placebo (day 0), days 1, 7, and 14. The systolic and diastolic blood pressures on days 7 and 14 were roughly 10mm Hg and 7-8mmHg lower during the day, respectively, than those on the day of placebo (day 0). 2) Pulse rate at rest was shown to have a tendency of decrease on day 2 in the 40 mg once daily group, but there were no consistent changes in the other dose groups in the 2-day multiple dosing. In the 14-day multiple dosing, the decrease of pulse rates at rest was slight, 5 beats/min. 3) In the once daily dosing for 2 days, the increase of heart rate on treadmill exercise was significantly reduced for 29 hr after the dosing on day 2 with dose-dependency. 4) Echocardiographic examination at rest revealed no significant changes in the hemodynamic parameters obtained in the 2-day multiple dosing study. In the 14-day multiple dosing, cardiac index (CI) was significantly decreased on day 2 and day 3, but there were no remarkable changes in CI on the other days. Total peripheral vascular resistance (TPVR) did not change during the study. 5) There were no clinically significant abnormal laboratory findings in the 2-day and 14-day multiple dosing studies. Transient slight dizzy feeling was noted in 2 of 5 subjects both in the 20 mg twice daily and the 40 mg once daily regimen of the 2-day multiple dosing. In the 14-day multiple dosing, 3 of 5 subjects showed slight palpitation, slight dizziness, and slight nausea on day 7 and thereafter. 6) In conclusion, it is suggested that carvedilol can be administered in the patients of hypertension and angina pectoris at 20 mg or lower doses once daily.
一般社団法人日本臨床薬理学会の論文

Phase I study of carvedilol (DQ-2466), a new .BETA.-blocker. (The 2nd report). The study in multiple oral administration.

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