Minus Sign1 Research Articles

Effect of Calcium Entry Blocking Agents (Nifedipine and Verapamil) on Myocardial Recovery during Reperfusion.

A comparative study on isolated guinea pig hearts was carried out to determine the effect of calcium entry blocking agents: nifedipine- and verapamil-added reperfusion solutions on myocardial recovery after global ischemia. After 20 min of normothermic ischemia, three groups of solutions were used for reperfusion (10 animals each): (1) Nifedipine-added (10--8 mmol L(minus sign1)) Krebs--Henseleit solution; (2) verapamil-added (10--8 mmol L(minus sign)) Krebs-Henseleit solution; (3) Krebs--Henseleit solution. Postischemic myocardial functions (ventricular contractile force and heart work) and enzyme activities were compared with their preischemic values. The addition of calcium entry blocking agents does not have any significant advantage over control solutions in myocardial recovery.

The Dose--Plasma Concentration Relationship of Tranexamic Acid during Surgery.

Plasma specimens from 59 patients undergoing cardiac operations utilizing extracorporeal circulation underwent determination of tranexamic acid concentration to explore the effect of dose administered to plasma concentration. Each patient received one of five doses of tranexamic acid in double-blinded, randomized fashion, ranging from 2.5 to 40 mg kg(minus sign1) for the loading dose and from 0.25 to 4.0 mg kg(minus sign1) h(minus sign1) for a subsequent infusion. Plasma collections occurred after completion of the loading dose, during extracorporeal circulation, before protamine infusion, after protamine infusion, and following arrival in the intensive care unit. The samples were analyzed using high-performance liquid chromatography. The logarithm of plasma concentration varied linearly with the logarithm of dose administered at each sampling time (r(2) values 0.82, 0.95, 0.89, 0.74 and 0.93 for the respective collection times). Plasma concentrations did not decrease during extracorporeal circulation despite absence of tranexamic acid in the pump prime. However, concentrations varied inexplicably following protamine administration and decreased in the intensive care unit.

Disposition of Misoprostol and Its Active Metabolite in Impaired Hepatic Function.

The pharmacokinetics of misoprostol and its active metabolite, misoprostol acid, was assessed in 17 healthy subjects and 17 subjects with various degrees of hepatic impairment. Before misoprostol administration, subjects underwent antipyrine and indocyanine green clearance studies to assess hepatic functional capacity. Subjects were administered 400 mcg of oral misoprostol in an open-label design. There was a lower antipyrine clearance in the group with hepatic disease as compared to normal volunteers (0.56 versus 0.80 ml min(minus sign1) kg(minus sign1), respectively, p = 0.022). There was no difference in indocyanine green clearance values between groups. The C(max), t(1/2)&bgr, and [Formula: see text] tended to be larger in the hepatic group; however, there was no statistical difference. Adverse events, mostly gastrointestinal in nature, occurred more often in the subjects with hepatic disease. These data suggest the pharmacokinetics of misoprostol may be altered in the presence of hepatic disease. However, because of significant interpatient variability, definitive dosing recommendations cannot be made. Further study in this area is needed.

Dose-Related Hepatic Blood Flow Effects Differentiate Nicorandil, Hydralazine, and Isosorbide Dinitrate in Healthy Subjects.

Dose response on hepatic blood flow of nicorandil (2.5, 5, and 10 mg), isosorbide dinitrate (5, 15, and 40 mg), and hydralazine (10, 25, and 50 mg) was assessed in 18 healthy subjects (6 per drug) using a three-period crossover design. Indocyanine green clearance was used to estimate hepatic blood flow before and at two timepoints after dosing. Greater hepatic blood flow changes occurred 90 (than 30) min after nicorandil and isosorbide dinitrate, and 60 (than 150) min after hydralazine. Nicorandil (mixed vasodilator) decreased hepatic blood flow by minus sign13 plus minus 4% (p < 0.05), minus sign15 plus minus 7%, and minus sign21 plus minus 6% (p < 0.05) (mean plus minus standard error of the mean) after 2.5, 5, and 10 mg, respectively; blood pressure was not reduced and heart rate was unchanged. Individual changes correlated poorly with plasma nicorandil concentrations. Isosorbide dinitrate (predominant venodilator) decreased hepatic blood flow by minus sign23 plus minus 9%, minus sign27 plus minus 5% (p < 0.05), and minus sign26 plus minus 7% (p < 0.05) after 5, 15, and 40 mg, respectively; blood pressure decreased (8--12 mm Hg) and heart rate increased (8 beats min(minus sign1)). Hydralazine (arterial dilator) increased hepatic blood flow by 29 plus minus 16%, 32 plus minus 11% (p < 0.05), and 33 plus minus 26% after 10, 25, and 50 mg, respectively; blood pressure was unchanged and heart rate increased (16 beats min(minus sign1)). Hepatic vascular resistance increased after nicorandil and isosorbide dinitrate but decreased after hydralazine. As assessed by hepatic blood flow response, nicorandil behaves more like a predominant venodilator than a direct arterial dilator. Dose and time variables were important to understanding the overall hemodynamic profile of each drug.

POPULATION PHARMACOKINETICS OF DIGOXIN IN DUCHENNE MUSCULAR DYSTROPHY (DMD) PATIENTS

Routine clinical pharmacokinetic data collected from Duchenne muscular dystrophy (DMD) patients receiving digoxin have been analyzed to evaluate the role of patients' characteristics for estimating dosing regimens. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of factors on digoxin clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the variables of body weight and combination with diuretics. The interindividual variability in digoxin clearance was modeled with proportional error with an estimated coefficient of variation of 25%, and the intraindividual variability in digoxin concentration was modeled with equal error with an estimated standard deviation of 0.0828 ng ml(minus sign1). In order to determine whether the population parameters obtained in this study were accurate, we administered digoxin according to individual dosage regimens in four DMD patients, using these values obtained by the Bayesian method. As a result, we found that mean prediction error, which indicates the deviation of prediction accuracy for digoxin concentration in plasma, was small, as were mean absolute prediction error and root mean squared error, showing the accuracy of this prediction method. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.

Electrophysiologic Changes in the Human Heart Produced by Enalaprilat (Angiotensin-Converting Enzyme Inhibitor).

Several trials have showed that angiotensin-converting enzyme inhibitors possess some extent of antiarrhythmic properties. To evaluate the effects of Enalaprilat on His bundle recording, patients undergoing diagnostic coronary angiogram due to angina pectoris and a positive thallium exercise test subsequently underwent His bundle electrogram. A double-blind crossover protocol was used with conduction velocity measurements at baseline and after saline (placebo) and Enalaprilat 2.5 mg intravenously. There were no significant changes in heart rate (64 plus minus 9 versus 65 plus minus 11 versus 65 plus minus to beats min(minus sign1)) at baseline, after saline and enalaprilat infusion, respectively, mean blood pressure (97 plus minus 11 versus 94 plus minus 10 versus 94 plus minus 7 mm Hg, respectively), atrioventricular conduction time (100 plus minus 20 versus 100 plus minus versus 100 plus minus 20 versus 100 plus minus ms), and His--Purkinje (HV) conduction time (40 plus minus 12 versus 40 plus minus 13 versus 40 plus minus 12 ms). Ventricular activity duration was 110 plus minus 11 ms at baseline, 110 plus minus 10 ms after saline infusion (p = NS), and 88 plus minus 13 ms after Enalaprilat administration (p < 0.001). Angiotensin-converting enzyme inhibition appears to produce significant reduction in ventricular activity duration (increase in intraventricular conduction velocity).

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers.

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure.

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg(minus sign1) as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h(minus sign1) kg(minus sign1) and volume of distribution was about 1.1 L kg(minus sign1). Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC(50)) of methylprednisolone disappear. The difference in IC(50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.

Food Enhances Bioavailability of the New Antiarrhythmic Agent Tiracizine by Affecting its Hepatic First-Pass Metabolism: Evidence by Serum and Urine Metabolite Kinetics.

The serum and urine kinetics of tiracizine, a new class I antiarrhythmic agent, and three of its metabolites were assessed in eight healthy extensive metabolizers after a single oral administration of 100 mg tiracizine in fasted state and after a standard breakfast. Additionally, ECG changes caused by tiracizine were compared between the two states. With food, the mean A(0minus signinfty infinity) value of the parent compound was significantly increased (560.7 versus 419.0 ng h ml(minus sign1)). The amount excreted unchanged in urine (percentage of the dose) rose significantly (2.43% versus 1.78%). However, mean AUC(0--32 h) and C(max) as well as urinary excretion of the 3-amino-5-methylamino-acetyliminodibenzyl metabolite were decreased (1152.8 versus 1328.0 ng h ml(minus sign1), 43.6 versus 56.1 ng ml(minus sign1), and 8.59 versus 11.95%, respectively). Total urine recovery (sum of individual tiracizine and metabolite excretion) tended to decrease (31.1% versus 36.1%). Serum and urine metabolite kinetics indicate that food-induced enhancement of tiracizine bioavailability is caused by an alteration in hepatic first-pass metabolism. Reduced N-demethylation is considered to be the limiting step. Tiracizine-induced PQ and QRS prolongations in the ECG tended to be more pronounced with food. Due to the serum concentration dependence of these ECG alterations, food intake might alter the antiarrhythmic efficacy of tiracizine at higher doses. Therefore, patients should be advised to take tiracizine in a constant relationship to food to assure consistent bioavailability.

Equal Efficacy and Improved Tolerability with 50 mg Controlled-Release Metoprolol Compared with 100 mg Conventional Metoprolol in Hypertensive Patients.

The clinical efficacy and tolerability of 50 mg of a new controlled-release formulation of metoprolol (metoprolol CR) was compared with that of a double dose (100 mg) of conventional immediate-release metoprolol tablets in 64 hypertensives in a randomized, double-blind, crossover study. At the end of a 6-week placebo run-in period and after each of two 8-week active treatment periods, 3-min bicycle exercise tests were performed at 25, 1.3, and 5 h after dose intake. Twenty-five hours after dose the mean supine SBP/DBP on metoprolol CR 50 mg was 147/95 mm Hg and on conventional metoprolol 100 mg 148/94 mm Hg, respectively. The percentage of responders (DBP less-than-or-equal 90 mm Hg or reduction in DBP greater-than-or-equal 10 mm Hg) was 45% on both regimens. At 25 h after dose, exercise heart rate was lower on 50 mg metoprolol CR (136 versus 140 beats min(minus sign1); p < 0.001) than on 100 mg conventional metoprolol, whereas the opposite was found at 1.3 h (131 versus 107 beats min(minus sign1); p < 0.001) and at 5 h (131 versus 113 beats min(minus sign1); p < 0.001). In agreement with the more even plasma metoprolol concentration and exercise heart rate, the patients perceived less fatigue during exercise on 50 mg metoprolol CR at 1.3 h after dose, the approximate time of maximum plasma concentration for 100 mg conventional metoprolol. The total number of adverse events recorded on metoprolol CR 50 mg and conventional metoprolol 100 mg were 62 and 103, respectively (p < 0.01). Thus, this study has demonstrated that the new controlled-release formulation of metoprolol has made it possible to halve the dose of metoprolol and yet achieve the same blood pressure control as well as greater beta(1)-blockade at the end of 24-h dosing intervals. Corresponding to lower peak plasma metoprolol concentrations, perceived fatigue and overall tolerability was improved on metoprolol CR 50 mg compared to conventional metoprolol 100 mg.

Application of a Stable Isotope Technique for the Bioequivalency Study of Two Transdermal Nitroglycerin Systems.

A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of (15)N-labeled nitroglycerin ((15)N-NTG) solution. The total amount of NTG transdermally absorbed (AUC x CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 plus minus 3.3 versus 8.1 plus minus 2.6 mg; p = 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 plus minus 3.1 versus 10.8 plus minus 3.1 mg; p = 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 plus minus 0.21 mg h(minus sign1) at 1 h for the experimental system and 0.41 plus minus 0.15 mg h(minus sign1) at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and (15)N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of (15)N-NTG for all participating subjects. The momentary changes of clearance, estimated from (15)N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.