薬理と治療

Objectives A placebo－controlled, single－blinded, dose escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics when high doses of Sigmart（nicorandil） were administered intravenously to healthy male volunteers. Methods Sigmart was administered intravenously at either doses of 6 mg（stepⅠ）, 12 mg （stepⅡ）, 18 mg（step Ⅲ）, and 24 mg（step Ⅳ）or placebo at all 4 steps to nine subjects. One dosage, either Sigmart of placebo, was administered at every step to the same subjects. Results Adverse events caused by Sigmart were reported in 2 of 6 subjects in stepⅠ, 4 of 5 subjects in stepⅡ, 4 of 5 subjects in step Ⅲ, and 3 of 5 subjects in step Ⅳ. The most common events were headache, dull headache and nausea, which were all mild. A transientdecrease of blood pressure, and subsequent tachycardia, were observed in all treatment groups. These reactions were considered to be based upon the vasodilating action of Sigmart. Plasma concentration of nicorandil increased dependently upon the dosage of Sigmart. There was no marked difference in T1/2 among the groups. Non－linearity of pharmacokinetic parameters suggests that the elimination process of nicorandil might be saturated. In addition, a large variance in plasma concentration changes was observed between subjects.Conclusions These data demonstrated that single dose intravenous administration of Sigmart up to 24 mg was safe and well tolerated in healthy volunteer.

Objectives A placebo－controlled, single－blinded, dose escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics when Sigmart (nicorandil) was administered through the combination of a bolus injection followed by continuous infusion in healthy male volunteers. Methods Sigmart was administered intravenously at a dose of 12 mg over 5 minutes followed by continuous infusion at rates of 6 mg／hour（stepⅠ）, 9 mg／hour（step Ⅱ）and 12 mg／hour（step Ⅲ）or placebo was administered for 235 minutes in a total of 9 subjects, with 6 subjects receiving Sigmart and 3 subjects receiving placebo.Results Adverse events caused by Sigmart were recorded in 5 of 6 in step Ⅰ, 6 of 6 in step Ⅱ, and 4 of 4 in step Ⅲ. The most common events were headache, and dull headache. All events were mild to moderate, and recovered when continuous infusion finished. Sustained blood pressure reduction and subsequent reflex tachycardia were observed during the infusion, which were considered to be associated with the vasodilating effect of Sigmart. Plasma concentrations of nicorandil increased rapidly just after bolus injection, then decreased rapidly over 30 minutes, and remained stable or increased depending on infusion rate.Conclusions These data demonstrated that combined intravenous administrations of Sigmart were safe up to bolus injection of 12 mg and continuous infusion of 12 mg／hour. How ever, the next study with acute heart failure, should start from a 12 mg bolus and a low dose of continuous infusion, 3 mg／hour.

Objectives An open－label, dose escalation study was conducted to evaluate the safety, efficacy and pharmacokinetics of a single dose intravenous administration of Sigmart（nicorandil） in patients with acute heart failure or acute exacerbation of chronic heart failure. Methods Sigmart was administered intravenously at doses of 4 mg, 8 mg, 12 mg or 18 mg in 31 patients. Efficacy and safety parameters were measured for 3 hours in the 4 to 12 mg groups and 1 hour in the 18 mg group. Results In the“global improvement rate”assessment, the percentage of“improved”or better was 62.5％ at 12 mg and 100％ at 18 mg. Pulmonary artery wedge pressure（PAWP） decreased by over 20％ and cardiac index increased by over 10％ 5 to 15 minutes after administration of 12 and 18 mg of Sigmart. There was a significant correlation between plasma nicorandil concentration and PAWP decrease after the administration of Sigmart. There was no dose－proportionality in“safety rating”. Adverse reactions were reported in 2 patients, while both of them were mild and recovered without any treatment. Diastolic blood pressure decreased significantly 5（－15.9％）and 15 minutes（－9.3％）after the administration of 18 mg of Sigmart. Conclusions These results suggest that Sigmart can be safely administered and improves hemodynamics in patients with acute heart failure or acute exacerbation of chronic heart failure. In addition, the clinical optimal bolus dose of Sigmart is thought to be 12 mg.

Objectives A multicenter, open－label, dose escalation study was conducted to evaluate the safety, efficacy and pharmacokinetics of a bolus injection with the following continuous infusion of Sigmart（nicorandil）in acute heart failure or acute exacerbation of chronic heart failure. Methods Sigmart was administered intravenously with a bolus injection of 200μg／kg followed by continuous infusion of A）50μg／kg／hr, B）100μg／kg／hr, C）150μg／kg／hr, D） 200μg／kg／hr, or E）250μg／kg／hr in 51 patients. Administration of Sigmart was continued for 6 hours, and permitted to prolong to 24 hours. Results Pulmonary artery wedge pressure（PAWP）decreased by 21.0％, 18.4％, 33.5％ and 31.0％ at the end of study period in groups of B, C, D and E, respectively, with all of the changes being statistically significant. Cardiac index increased in group D and E, though not statistically significant. There was a dose－dependent increase in global improvement rate, the percentage of“improved”or better, being over 70％ in group D and E. Adverse reactions, one headache in group B and one flush in group C, were observed, while both reactions were mild and the infusion of Sigmart was allowed to be completed. Twelve abnormal changes in clinical laboratory values were observed in 6 patients, while none of them were clinically significant. Conclusions These results suggest that Sigmart is safely administered and improves the hemodynamics in patients with acute heart failure or acute exacerbation of chronic heart failure. In addition, the clinical optimal dose of Sigmart is considered to be a bolus injection of 200μg／kg followed by a continuous infusion at a rate of 200μg／kg／hr.

Background：In the previous open－label Phase 2 studies, the clinical efficacy and safety of Sigmart（nicorandil）were evaluated in patients with acute heart failure or acute exacerbation of chronic heart failure. Objectives To assess the clinically optimal dose of Sigmart for the treatment of acute heart failure or acute exacerbation of chronic heart failure, a multi－center, randomized double blind study was conducted. Methods Seventy two patients were randomly assigned into 3 treatment groups. Intravenous bolus injection of Sigmart at a dose of 200μg／kg was followed by a 6 hours infusion of Sigmart at rates of 50μg／kg／hr in group L（22 patients）,100μg／kg／hr for group M（27 patients）, and 200μg／kg／hr in group H（23 patients）. Results Sigmart decreased pulmonary artery wedge pressure（PAWP）significantly in all groups, and increased cardiac index in group M. There were significant dose－dependent decreases in systolic pulmonary pressure and pressure rate product, while there was no significant change in other parameters. Percentage of patients with PAWP decrease over 30％ tended to be the highest in group H. The reduction of PAWP after bolus injection was maintained throughout the infusion period in groups M and H, while it subsided rapidly in group L. The“usefulness rate”was 40.9％, 33.3％ and 52.2％ in groups L, M and H, respectively, which was not dose－dependent. There were 26 adverse reactions in 18 of 72 patients（25％）. The incidences were 9.1％, 37.0％ and 26.1％ in the 3 groups from low to high dose, while did not show statistically significant dose－dependency. The most common adverse reactions were headache, increase in GOT（AST）and increase in GPT（ALT）. The“safety ratio”was 90.9％, 59.3％, and 69.6％ in each group. Conclusions These results suggest that optimal dose of Sigmart for the treatment of acute heart failure is a bolus injection of 200μg／kg followed by continuous infusion of 200μg／kg／hr.

Background The previous Phase 2 studies have suggested that a bolus injection of 200μg／kg followed by an infusion of 200μg／kg／hr of Sigmart（nicorandil）is clinically efficacious and safe in patients with acute heart failure or acute exacerbation of chronic heart failure. Objectives To ascertain the efficacy and the safety of Sigmart in acute heart failure or acute exacerbation of chronic heart failure, a multi－center, randomized double blind placebocontrolled study was conducted. Methods Forty four patients were randomly assigned into the Sigmart group, who received a bolus injection of 200μg／kg followed by an infusion of 200μg／kg／hr for 2 hours of Sigmart （20 patients）, or placebo（24 patients）. Other medications for acute heart failure except digitalis was discontinued at least 3 hours before administration of the test drug. Results Pulmonary artery wedge pressure decreased by 14.5％ in the Sigmart group, significantly different from the placebo group which showed a 0.1％ increase（p＝0.018）. In addition, cardiac index increased by 9.8％ in the Sigmart group, while decreased by 3.8％ in the placebo group（p＝0.034）. Furthermore, Sigmart significantly decreased total peripheral vascular resistance, pulmonary vascular resistance, and significantly increased stroke volume as compared with placebo. One moderate adverse reaction was reported in the Sigmart group, and two mild adverse reactions in the placebo group. Conclusions These results demonstrated that Sigmart infusion is useful and safe in the treatment of acute heart failure or acute exacerbation of chronic heart failure.

Background In the previous phase 2 studies, intravenous infusion of Sigmart（nicorandil）for 6 hours has been well demonstrated to improve hemodynamics in acute heart failure or acute exacerbation of chronic heart failure. Objectives The multi－center, open－label study was conducted to assess the efficacy, safetyand pharmacokinetics of Sigmart continuous infusion for 48 hours in combination with standard therapy in acute heart failure or acute exacerbation of chronic heart failure. Methods Sigmart infusion was started with a bolus injection of 200μg／kg, then followed by continuous infusion of 200μg／kg／hr in 23 patients. The subsequent infusion rate was adjusted based on the condition of the patients, ranging from 50 to 200μg／kg／hr and continued for 48 hours. All the patients received one or more of conventional drugs together with Sigmart.Results Sigmart decreased pulmonary artery wedge pressure and increased cardiac output significantly throughout the infusion period. The subset of Forrester classification improved from subsetⅡ or Ⅳ to subsetⅠ with treatment. The symptoms of dyspnea, palpitation, rales, engorgement of jugular vein, and edema in the extremities improved significantly after 48 hours of treatment. Twenty one adverse reactions（AR）were reported in 13 patients（59.1％）.The most common ARs were hypotension（6 patients, 27.3％）and headache（4 patients, 18.2％）. There was no relationship between the incidence of ARs and plasma nicorandil concentration. The infusion was completed for 48 hours in all patients, while the dose was decreased in 7 patients because of ARs.　Conclusions These results demonstrated that Sigmart infusion is useful and safe in the treatment of acute heart failure or acute exacerbation of chronic heart failure.