Hajime Nakashima

Pharmacokinetics and Pharmacodynamics of a New Transdermal Clonidine, M-5041T, in Healthy Subjects

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M‐5041T (M), and its safety were evaluated after single and repeated applications. In the single‐application study, one patch of M (4 mg → 6 mg → 8 mg) was applied for 3 days in eight healthy subjects. In the repeated‐application study, first (0–72 hours), second (72–144 hours), and third (144–216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single‐application study, plasma clonidine concentration increased in a dose‐dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half‐life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP‐lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated‐application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly. Two subjects complained of orthostatic vertigo caused by hypotension and were dropped out of the study. Mild erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension without unacceptable skin reactions. Orthostatic change in BP should be monitored carefully during treatment with M.

Pharmacokinetics of Beta‐Methyldigoxin in Subjects with Normal and Impaired Renal Function

Beta‐methyldigoxin (β‐MD) was administered orally (0.2 mg) to 24 patients with various degrees of renal function, to investigate its pharmacokinetic characteristics related to renal function. Serum and urine collected until 120 hours after dosing were assayed for β‐MD and digoxin by high‐performance liquid chromatography and fluorescence polarization immunoassay method. The steady‐state volume of distribution decreased proportionately as creatinine clearance (CLCR) decreased, although steady‐state volume of distribution of hemodialysis patients had large interindividual variability, and their mean value was not different from that of patients with normal renal function. Both renal clearance of β‐MD and digoxin were significantly correlated with CLCR (r = .820, P < .001 and r = .822, P < .01, respectively), and the slope of regression line for β‐MD was only 44% that for digoxin. Significantly reduced urinary excretion of total drug (β‐MD plus digoxin) was shown in patients with CLCR below 50 mL/minute/1.48 m2. This study suggests that the dosage modification is not necessary until CLCR decreases to below 50 mL/minute/ 1.48 m2, but careful attention should be given in the use of β‐MD in patients with CLCR below this value.

Chronopharmacokinetic Studies of Pranoprofen and Procainamide

There is increasing evidence demonstrating that plasma drug concentrations are affected by their time of administration. In the current study, the chronopharmacokinetic profiles of an antipyretic agent, pranoprofen, and an antiarrhythmic agent, procainamide, were examined. In the first study, 75 mg of pranoprofen was given orally in seven healthy subjects at 10:00 (morning trial) or 22:00 (evening trial). In the second study, 500 mg of procainamide was given orally in eight subjects with premature ventricular contractions at 10:00 or 22:00. Blood samples for plasma drug concentrations were taken for a 10‐hour (pranoprofen study) or a 24‐hour (procainamide study) post‐drug period.

Influence of food on the absorption of beta-methyldigoxin

Nine healthy subjects received 0.2 mg of beta‐methyldigoxin (β‐MD) orally in the fasting state, 30 minutes after and before a standard breakfast. The time‐to‐peak serum glycoside concentration was delayed and the peak concentration was lower in the postprandial state compared with the other regimens (P <.01). The absorption rate constant was significantly reduced when β‐MD was given after a meal (1.55 ± 1.75 hr−1) than before a meal (5.54 ± 2.16 hr−1) and in the fasting state (5.22 ± 3.06 hr−1)(P <.01). Although the area under the serum glycoside concentration‐time curve and the cumulative urinary excretion (CUE) of β‐MD, digoxin, and total drug (β‐MD plus digoxin) was not significantly different between three regimens, the CUE∞ tended to be smaller in the postprandial state compared with before a meal. The results indicate that the timing of drug administration in relation to a meal is an important factor leading to the fluctuations of serum glycoside concentration after oral β‐MD, which might be of some clinical importance.

Different chronotherapeutic effects of valsartan and olmesartan in non-dipper hypertensive patients during valsartan treatment at morning.

This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients.

Clinical Pharmacology of Dilevalol (III). A Pharmacokinetic Study of Dilevalol in Elderly Subjects with Essential Hypertension

Dilevalol (100 mg) was given once daily for 8 days in eight elderly subjects with essential hypertension. Blood samples for plasma dilevalol concentrations were taken during an 8‐hour post‐drug period following the first and eighth dosages, and the time to maximum concentration (tmax), maximum plasma concentration (Cmax), distribution half‐life (t1/2α), elimination half‐life (t1/2β) and area under the plasma concentration‐time curve (AUC) were determined.