5 - Mononitrate Isosorbide Hemodynamic Effects, Tolerability And Pharmacokinetics Explored

Part 1The effect of extended-release isosorbide-5omononitrate on brachial blood pressure and central aortic pressure on healthy volunteersObjectiveTo investigate the effects of isosorbide-5-mononitrate on brachial blood pressure, central arterial pressure and arterial elasticity of healthy volunteersMethodsThis is a self-controlled study.(1) Control group:Parameters of pulse wave analysis, heart rate and blood pressure were measured in the pre-dose day at 6:30,7:30,8:00, 9:00,10:00,11:00,12:00,13:00,15:00,19:00,23:00 as baseline.(2)Single dose group:In the second day,60mg 5-ISMN was administered orally with 250ml warm water at 7:00 on an empty stomach.Parameters of pulse wave analysis,heart rate and the blood concentration of 5-ISMN were measured at the same time at the first day.(3)Multiple dose group:the third day as the period of elution,from the forth day,60mg IS-5-MN was administered consecutively for six days at 7:00,parameters of pulse wave analysis,heart rate,the blood concentration of 5-ISMN were measured in the ninth day at the same time. The parameters of PWA includes AI(Augmentation Index),CSP(central Systolic Pressure),CDP(central diastolic pressure),CPP(central pulse pressure).During the clinical trial period,all healthy subjects were not allowed to take other medicine,smoke and drink wine and forbidden to do heavy exercise.ResultsBoth single and multiple IS-5-MN administration markedly reduced AI and central artery pulse pressure.After six days of consecutive administer,these effects were significantly attenuated but did not disappear completely.Brachial blood pressure and heart rate had no significant change.ConclusionIS-5-MN improves the artery compliance and reduce central artery pulse pressure in healthy male volunteers,but is associated with development of vascular tolerance. Part 2The effect of consecutive administered extended-release isosorbide-5-mononitrate on sVCAM-1 level in healthy volunteersObjectTo investigate effectiveness of 7days consecutive administered isosorbide-5-mononitrate on sVCAM-1 level of serum in healthy volunteers.MethodsIsosorbide-5-Mononitrate(IS-5-MN) 60mg was administered to 18 healthy male volunteers once daily for consecutive 7 days.The serum sVCAM -1 levels of healthy volunteers were measured by Enzyme- linked Immunosorbent Assay(ELISA)at the pre-dose day,the second dose day and the sixth dose day and the ninth day.ResultsThe serum sVCAM -1 levels of healthy volunteers did not show significant statistical difference at various time(P＞0.05).ConclusionIn our research,the continuous 7days effectiveness of isosorbide-5-mononitrate could not influence on sVCAM-1 level in serum in healthy volunteers. Part3Relationship between polymorphisms of aldehyde dehydrogenase 2 gene and pharmacokinetic characteristics of isosorbide-5-mononitrate in Chinese healthy subjectsObjectTo investigate the relationship between the mutation in aldehyde dehydrogenase 2 gene(ALDH2) at positions Glu504Lys and pharmacokinetic(PK) characteristics of isosorbide-5-mononitrate(5-ISMN) in Chinese healthy volunteers.MethodsAmong 45 persons,twenty-two healthy male volunteers were selected and orally administered 60 mg 5-ISMN.HPLC-MS method was applied to analyze 5-ISMN plasma concentration.ALDH2 genotype was determined by PCR- RFLP. Pharmacokinetic analysis was performed and the effects of the genotypes on 5-ISMN pharmacokinetics was assessed.ResultsIn these 22 volunteers,13 homozygous GG and 9 heterozygous GA genotypes for ALDH2 at positions of Glu504Lys were detected by PCR- RFLP.5-ISMN plasma concentration,AUC_0-t,C_max and T_max did not show significant statistical difference between the two groups genotypes(P＞0.05).ConclusionThe polymorphisms of ALDH2 gene at positions of Glu504Lys could not influence the pharmacokinetics of 5-ISMN in our research.