Carvedilol (DQ-2466) is a new β-blocker with vasodilating properties. In order to investigate the hemodynamics and safety of carvedilol after single oral administration, in a placebo controlled manner, each group of 5 healthy male volunteers was treated with ascending doses of 20, 40, or 60 mg. The following results were obtained: (1) Both systolic and diastolic blood pressures at rest decreased significantly from 2 hr to 24 hr after administration of carvedilol at each dose level (P<0.05-0.001). Maximum decreases of systolic and diastolic blood pressures were achieved at 3-4 hr after administration. The changes of systolic blood pressure (SBP Δ%) were 4. 2, 14. 6, 16. 2, and 16. 6% in placebo, 20, 40, and 60 mg group, respectively, at 3 hr after dosing. The changes of diastolic blood pressure (DBP Δ%) were 0.5, 16. 1, 13. 3, and 18. 8% in placebo, 20, 40, and 60 mg group, respectively, at 4 hr after dosing. There was no significant difference in the changes of pulse rate (PR Δ%) at rest between carvedilol administration group and placebo admistration group.(2) Stroke index (SI) and cardiac index (CI), which were determined by echocardiography, were not affected in the 20 mg group.SI and CI slightly decreased in the 40 mg group in comparison with the placebo group.There was a tendency of decrease in these parameters in the 60 mg group.Total peripheral vascular resistance (TPVR) decreased significantly at 4 and 29 hr after 20 mg dosing.(3) The increase of systolic blood pressure on treadmill exercise was significantly reduced with dose-dependency in carvedilol administration groups for 9 hr after dosing.(4) There were no abnormal laboratory findings. No subjective symptoms were observed in the placebo and the 20 mg group.One of 5 subjects in the 40 mg group 4 of 5 subjects in the 60 mg group showed slight dizzy feeling, heavy-headedness, nausea, and dizziness.(5) In conclusion, carvedilol appears to maintain marked hypotensive effects up to 24 hr after single oral administration of 20 mg, which was the lowest dose in this study. At less than 40 mg, there were no clinically significant subjective symptoms. This suggests that maximum daily dose should be less than 40 mg in the future investigation for multiple dosing.
Carvedilol is a newly developed β-blocking agent with vasodilating activities. The pharmacokinetics of carvedilol has been studied in healthy subjects following the single and multiple oral administration of the drug. In the single oral study, it was clear that the disposition of carvedilol is adequately described by a two-compartment model with first order absorption. Carvedilol was rapidly absorbed within 1.6 hr following oral dosing. The half-lives ranging from 6 to 14 hr are estimated. The study indicated that carvedilol follows linear pharmacokinetics with a slight deviation from linearity in the range of 5 to 60 mg dose. The deviation is attributed to about 4-fold inter-individual variation observed for AUC. Carvedilol is not excreted into urine, suggesting that the drug is eliminated from plasma primarily by metabolism. It is considered that the wide interindividual variation is attributed to variaton in hepatic first-pass metabolism of carvedilol. The plasma level of carvedilol glucuronide was about 2-fold greater than that of carvedilol and desmethyl carvedilol was 5 times lower than that of carvedilol. During the multiple oral administration of carvedilol for 14 days at a daily dose of 20 mg, plasma profiles showed no accumulation of the drug. The predicted steady-state for carvedilol is attained on day 11, and Css (max) and Css (min) values for the drug are calculated to be 46.4 and 2.1 ng/ml, respectlvely.
ObjectiveRecently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m2) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.
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.
In the present study, myocardial contrast echocardiographic enhancement was compared with left ventricular wall motion in an experimental ischemic heart according to the degree of narrowing of the coronary artery. Artificial blood (Fluosol-DA) was used as a contrast agent. In eight adult mongrel dogs, ischemic hearts with 0, 50, 70 to 90 and 100% narrowing of the coronary artery were produced by controlling a balloon catheter in a closed-chest system. Fluosol-DA was injected into the left main coronary artery and myocardial contrast echocardiograms were recorded. The short-axis images of the left ventricle were subdivided into octants using a "floating" reference system to analyze wall motion by an image analyzer (Cardias GP2000), and to evaluate density values in the echocardiogram by densitometry (MSR Vx-50). With 0 and 50% narrowing of the coronary artery, the entire circumferential myocardium was filled with marked contrast echoes, and no change was observed in left ventricular wall motion. In 70 to 90% narrowing, the perfusion area of the narrowed coronary artery was filled with mild contrast echoes compared to the other areas showing marked contrast echoes. But no change was observed in left ventricular wall motion. During total occlusion, the perfusion area of the occluded coronary artery was not filled with contrast echoes and a distinct difference was observed between this and the other areas. Marked abnormality of wall motion was also observed. The area with abnormal wall motion tended to be wider than the area of contrast enhancement defect. The ischemic area can therefore be more accurately confirmed by simultaneously observing the changes in contrast echocardiographic enhancement and in wall motion abnormalities.
