Kouichi Sugimoto

Dose Dependent Effect of Diltiazem on the Pharmacokinetics of Nifedipine

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double‐blind, Latin square method. On the fourth day, a 20‐mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half‐life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P < .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol × hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P < .05, 30 mg vs 90 mg, 0.1 < P < .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose‐dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose‐dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.

Simplified method of heterotopic rat heart transplantation using the cuff technique: application to sublethal dose protocol of methotrexate on allograft survival.

Rodent heterotopic heart transplantation (HHT) models have been developed for the study of transplantation immunology. Most of these transplantations are performed by hand‐suture techniques, requiring several months of training. We describe a modified technique of rat HHT in the neck, using a cuff method that can be mastered by beginners within a few weeks. Our main modification of the rat HHT in the neck is that the right superior vena cava of the graft is chosen as an outflow duct, while the pulmonary artery has been taken as an effluent drainage in the ordinary HHT models. The aorta of the donor is anastomosed with the carotid artery of the recipient. Donation can be completed within 5 min and vascular connections in the recipient done within 3 min, resulting in a minimum of ischemia time. Using this minimum surgical intervention model, we tested the immunosuppressive effect of a sublethal dose of methotrexate (MTX), which has been widely used in cancer therapy. Our results showed that high doses of MTX severely suppressed the recipient bone marrow, but prolonged heart allografts for more than 365 days after HHT. In conclusion, the new model simplified the rat HHT procedure and made it possible for the beginner of rodent transplantation to master this skill within a few weeks. Using this minimized intervention technique, we found that the high doses of MTX can significantly prolong the survival of fully mismatched DA heart graft in PVG/c recipient.

Chronopharmacological study of nitrendipine in healthy subjects

Nitrendipine 20 mg or placebo was given orally to eight healthy subjects in a cross‐over design separated by 1 or 2 weeks. Drug was given at 9:00 AM (morning dosage) or at 9:00 PM (evening dosage). Systolic and diastolic blood pressure (SBP, DBP) were measured just before and 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs after treatment. Plasma nitrendipine concentrations were determined at 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs and plasma catecholamines were measured at 2 and 5 hrs following drug administration. SBP did not decrease significantly after nitrendipine compared to after placebo at 9:00 AM or at 9:00 PM. DBP decreased significantly at 2, 3, 4 and 5 hrs after nitrendipine at 9:00 AM, but only at 4 hours after the 9:00 PM dose. Mean plasma nitrendipine concentrations during the absorption phase were lower after the evening dosage compared to the morning interval. Maximum plasma concentration (Cmax) was significantly lower and time to maximum concentration (tmax) tended to be longer after the evening dosage. Area under the plasma concentration‐time curve from 0 to 24 hours (AUC0–24) and half‐life of the terminal elimination phase (t1/2β) of the morning and evening dosages did not differ. A significant correlation was observed between plasma nitrendipine concentrations and changes in DBP during the drug treatment. Plasma noradrenaline concentrations were significantly higher 5 hours after nitrendipine compared to after placebo at 9:00 AM, but not at 9:00 PM. These results suggest 1) that BP responsiveness to nitrendipine is relatively smaller after the evening dosage when compared to after the morning dosage, 2) that nitrendipine is absorbed more slowly from the gastrointestinal tract after the evening dosage than after the morning dosage, and 3) that the diurnal changes in the effects of nitrendipine are in part dependent on the time of administration and its subsequent effect on plasma concentrations of the drug.

Effects of diltiazem on the pharmacokinetics of nifedipine.

To evaluate the effect of diltiazem pretreatment (60 mg three times a day for 3 days) on pharmacokinetics and pharmacodynamic effect of nifedipine, six healthy subjects received 20 mg nifedipine orally on two occasions using a double-blind cross-over, placebo-controlled method. Diltiazem induced a marked increment of the area under the plasma concentration-time curve (AUC) for nifedipine by a mean of 140% and reduced the total body clearance (Cl) from 0.0043 ± 0.0019 to 0.0017 ± 0.0006 ml/min/kg (p < 0.05, mean ± SD). The biological half-life (t) of nifedipine was prolonged from 2.46 ± 0.65 to 3.21 ± 0.92 h (p < 0.05) without any changes in indocyanine green (ICG) clearance. Diltiazem did not produce significant changes of AUC, Cl, and t for the acid metabolite of nifedipine. Blood pressure (B after nifedipine administration with diltiazem pretrer ment was more decreased than that without diltiazer Both a decreased hepatic clearance and an increased bi availability of nifedipine by diltiazem probably expla the significant changes in pharmacokinetics and hem dynamics of nifedipine. A clinically important drug ± teraction may occur with nifedipine when diltiazem administered concurrently.

Effects on autonomic function of a new angiotensin converting enzyme inhibitor, ramipril.

To investigate the effects of ramipril, a new angiotensin converting enzyme inhibitor, on autonomic function, autonomic function tests were performed in eight healthy male subjects, aged 22–26 years, after single oral administration of 5 mg of ramipril or placebo, in a randomized, double-blind, crossover design. Measurements of heart rate variability and diving reflex test were performed as indices of parasympathetic tone. Forearm isometric exercise (handgrip test) and cold pressor test were carried out to evaluate sympathetic nervous reactivity. Supine systolic blood pressure was decreased significantly after ramipril (F = 11.16, p < 0.01), but diastolic blood pressure was not. Heart rate at rest did not significantly differ between ramipril and placebo. Heart rate variability was significantly increased 120 min after ramipril [5.5 ± 0.7% (SEM) on ramipril and 3.7 ± 0.2% on placebo; F = 7.13, p < 0.05]. However, reflex bradycardia during the diving test was not enhanced after ramipril. Plasma norepinephrine concentrations before and after handgrip test were not influenced by ramipril. Increments of mean blood pressure and heart rate during handgrip or cold pressor test did not significantly differ between ramipril and placebo, either. These results suggest that ramipril may enhance cardiac vagal tone without affecting sympathetic nervous activity. Enhanced parasympathetic activity could be related to an absence of reflex tachycardia following the administration of ramipril.

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 indomethacin on a reduction in forearm blood flow induced by propranolol in healthy subjects.

The influence of indomethacin on a reduction in forearm blood flow (FBF) induced by propranolol was investigated in eight healthy subjects. Indomethacin was orally administered (75 mg daily for 3 days) in a randomized cross‐over design. Blood pressure (BP) was slightly decreased after a single oral administration of propranolol (40 mg) alone. However BP was slightly increased after the drug with indomethacin pretreatment. FBF was significantly decreased after propranolol with or without indomethacin. No significant difference was observed in FBF before or after propranolol between both groups. Plasma renin activity (PRA) was reduced by indomethacin pretreatment. These results suggest that the reduction in FBF induced by propranolol is not augmented with indomethacin.

Effect of Ranitidine on the Aldosterone Response to Angiotensin II in Healthy Subjects

T he H2-receptor antagonists ranitidine and cimetidine have been proven effective in decreasing acid production in the treatment of peptic ulcer and are therefore widely prescribed for this condition. For this reason it is important that real and potential side effects of these agents be studied. It was previously reported that cimetidine inhibits the aldosterone response to endogenous angiotensin II (All) after furosemide administration.1 Because ranitidine is a more potent antagonist and produces a longer antisecretory effect than does cimetidine,23 we might anticipate a similar effect if this is based on its H2-blocking properties. Because it is widely believed that the renin-angiotensin-aldosterone system is the primary hormonal modulator of posture and volume-dependent changes in man, it seems important to examine this possibility. Therefore, the current study was undertaken to evaluate the effect of ranitidine on the aldosterone response to endogenous All following administration of furosemide and on upright posture in healthy subjects.

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.