The pharmacokinetics of the alpha-blocking agent urapidil have been elucidated only in subjects with normal renal function. In the present study, BKU-15 (sustained-release capsules containing 15mg of urapidil) was administered for 7 consecutive days to 7 hypertensive patients with mild to moderate impairment of renal function. Treated were 3 males and 4 females between the ages of 24 to 74 years, and the dosing regimen was BKU-15 s. i. d. at 8: 00 a. m. on days 1 and 7, and b. i. d. at 8: 00 a. m. and 5: 00 p.m. on days 2 to 6.
The minimum plasma concentration of urapidil determined at 8: 00 a. m. stabilized by day 5, measuring 74.0±19.8ng/ml on day 7. The pharmacokinetic parameters calculated after administration on day 7 were as follows: Cmax 205.5±31.0ng/ml; Tmax 4.3±0.3hrs; kel 0.1±0.02/hr; t1/2 8.4±1.5hrs. The absorption rate constant, minimum plasma concentration, and Cmax of urapidil were comparable to the corresponding values in healthy subjects given a 2-fold dose (Ebihara et al.), whereas elimination was delayed by a factor of two.
A decrease in blood pressure was observed at 2 to 10 hours after administration of BKU-15. There was no significant change in heart rate. Two patients complained of hot flushes and throbbing in the temporal region, which might be related to the pharmacological effects of the drug. Severe nausea was noted in another patient.
It is thus considered that BKU-15 b. i. d, may be adequate as the initial dosage in treating hypertensive patients with impaired renal function.

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The comparative effectiveness of two dosage forms of metoprolol, the 120mg slow release tablet (SR) administered once daily and the 40mg conventional tablet (CO) given three times daily, on premature ventricular contraction (PVC) and heart rate (HR) was examined in patients with PVC of≥3, 000 beats/24 hr by employing a Holter ECG with a 24-hour monitor using a cross-over design, and changes with time in plasma concentrations after administration of SR and CO were measured.
The mean of the PVC values which were monitored three times in the observation period under placebo was 710±184 beats/hr (Mean±S. E.) and the diurnal variation of PVC was high, averaging 34.2±6.5%. In the treatment periods, five patients showed significant reduction of PVC values by more than 25% in comparison to the placebo treated period in one of the intervals, showing reduction values during the whole day, the daytime, and the night-time of 37.8±13.3%, 46.5±15.1%, and-91.7±103.3% under SR, respectively. The reduction rates under CO tended to be higher in comparison to SR, showing 52.6±12.3%, 59.7±11.0% and 24.5±15.0%, respectively. No significant difference was noted between SR and CO . The duration of inhibitory effect on PVC was about 12 hours under SR and about 17 hours under CO.
In the treatment periods, HR under both SR and CO was inhibited significantly in comparison with that in the observation period . No significant difference in inhibition of HR was seen between SR and CO. The inhibition on HR under CO was slightly higher than that under SR during the interval from night to early morning . These inhibitions were maintained over 24 hours.
The plasma concentrations after administration of SR and CO did not show any significant difference. The plasma concentration level which is considered to be sufficient to inhibit HR was maintained even at 24 hours after administration of SR, (11.3±7.8ng/ml).
In conclusion, SR maintained the inhibitory effect on HR for 24 hours similarly to that under CO, but was thought to be inferior to CO in its inhibitory effect on PVC . This may be due to the difference in the threshold plasma concentrations to inhibit HR and PVC and the lower plasma concentrations during night-time in the SR treatment period.

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The effect of age on the pharmacokinetics of pranoprofen, a propionic acid derivative with analgesic and anti-inflammatory properties, was investigated in 6 young subjects (ages: 24-28, mean 25.3yr) and 7 elderly subjects (ages: 67-87, mean 77.3yr).
The plasma concentration of the unchanged form was determined by HPLC serially for 10hr after a single oral dose of 75mg pranoprofen.
For pharmacokinetic analysis, the two-compartment open model was applied to the time course of the pranoprofen plasma levels.
The terminal elimination half life of pranoprofen was significantly longer in the elderly subjects than that in the young subjects (3.13: 1.86-5.26vs. 1.48: 1.14-1.92hr [mean: two sigma limits] P<0.01), and the plasma clearance was significant ly lower in the elderly subjects than that in the young subjects (1.45: 0.61-2.29vs. 2.73: 1.75-3.71 ml/min/kg [mean: two sigma limits] P<0.01).
These results suggest the existance of some differences in pranoprofen pharmacokinetics between young subjects and elderly ones.

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Thransfer of mepivacaine from the placenta was studied in terms of total and freelevels in 17 pregnant women who received epidural anesthesia during cesarean-section.
Concentrations of mepivacaine in maternal and umbilical venous blood weredetermined by gas chromatography.
The umbilical/maternal (U/M) concentration ratio of total mepivacaine and that offree mepivacaine were 0.53±0.14 (mean±SD) and 0.73±0.21, respectively.
The protein binding ratio of mepivacaine in umbilical blood was significantly (P<0.01) lower than that in maternal blood.
This result suggests the importance of determining the free level of mepivacaine forconsidering the pharmacological effects on the fetus.

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A newly-designed sustained-release suspension, Pharma Zomes ®-acetaminophenliquid, was evaluated for its release characteristics in vitro and its bioavailability following oral administration to human volunteers.
The in vitro studies showed sustained release of acetaminophen in which the release rate was not influenced by pH, ionic strength, or the presence of a surfactant inthe release media. The release profiles and scanning electron micrographic observation indicated that Pharma Zomes®suspension contained polymer microchips encasing the drugs and the mechanism of sustained release was mainly by diffusionthrough water-insoluble monolithic system.
The extent and rate of bioavailability of acetaminophen following oral administration of Pharma Zomes ® suspension were studied in five normal volunteers. Pharmacokinetic parameters were determined by measuring the salivary concentrations of thedrug after single administration. Comparing Pharma Zomes ® with simple solution and powder, AUC_0-∞ values were not significantly different. On the other hand MRT_0-∞and kei were significantly longer or smaller, respectively . The in vivo study demonstrated that Pharma Zomes® showed sustained release properties with adequatebioavailabiity.

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In the past decade, many new non-steroidal anti-inflammatory drugs (NSAIDs) havebeen introduced into Japan and they are now widely used to treat inflammatory andrheumatic disorders. NSAIDs have recently received a great deal of attention because ofreports of various adverse reactions. However, the frequency of the adverse reactions to NSAIDs has varied among the clinical studies. Special caution should be taken wheninterpreting the data on adverse reactions in clinical studies carried out in different patientsby different physicians. It is the purpose of this study to evaluate accurately theclinical safety of NSAIDs. Twelve acidic NSAIDs were examined for which clinicaldata were published in comparison with indometacin in double blind trials in patientswith rheumatoid arthritis. The ratio of the test drug to the standard drug indometacin inthe frequency of adverse reactions in each trial was used as an index of the frequency ofadverse reactions to each NSAID. Discussion of the comparative frequency of adversereactions among the various NSAIDs was possible by using this index. The severity ofadverse reactions was estimated by observing the number of patients for whom themedication was withdrawn because of adverse reactions . The ratio of the test drug to thestandard drug in the frequency of withdrawal from each trial was used as an index of theseverity of the adverse reactions to each NSAID . The safety of drugs must be evaluatednot only by the frequency of the adverse reactions but also by their severity . It is suggested that the procedure described in this paper may be useful for evaluating the clinical safety of drugs.

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In order to investigate the effects of K-351 (Nipradilol), a single-blind controlledstudy was performed in 10 patients with chronic stable angina pectoris .
A multistage treadmill test was performed by the Bruce protocol on the control (drugfree) and at 2 hours after a single oral administration of either placebo or the activedrug (K-351, 6mg). Blood samples were taken for the measurement of plasmaconcentrations of K-351 just before the treadmill test.
Analysis of variance showed that K-351 significantly improved exercise duration by27% and the time to the onset of ischemia by 46%, as compared with placebo. K-351also significantly decreased peak heart rate, peak rate-pressure products, and systolicblood pressure at the, same level of exercise as the peak exercise level with placebo .
Plasma levels of K-351 ranged from 1.4 to 7.8ng/ml with the mean of 5.3±1.8ng/ml. There was no relation between plasma levels and exercise capacity .
In conclusion K-351 significantly increased exercise tolerance in patients withchronic stable angina pectoris.

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Recently, nicorandil, an anti anginal drug, has been shown to increase membranepotassium conductance in cardiac fibers. Therefore, electrophysiologic effects ofnicoandil 4mg iv were studied in 20 patients (pat.) with sick sinus syndrome (8 pat.), AV block (5 pat.), and paroxysmal supraventricular tachycardia (7 pat.). The plasmalevel of nicorandil was also estimated.
Nicorandil did not change sino-atrial conduction time, AH interval, HV interval, AVnodal effective refractory period (ERP), ventricular ERP, or ERP of the accessorypathway. The sinus cycle length and sinus recovery time were shortened from 914.8±51.7 to 819.8±44.0 msec (mean±SE, P<0.01) and from 1, 375.1±111 to 1, 284.3±101 msec (P<0.05), respectively. The minimum atrial pacing rate resulting in Wenckebach AV block was increased from 152.5±12.0 to 158.3±10.9/min (P<0.05)
The atrial ERP was shortened from 267.2±10.7 to 250.6±9.6 msec (P<0.01).Intraatrial reentrant tachycardia could not be initiated by electrical stimuli afternicorandil in one case. However, these changes might have been attributable toanatonomic nervous reflexes caused by vasodilating action, rather than any direct effectof nicorandil. In conclusion, nicorandil can be used safely even for cases of coronaryartery disease associated with sick sinus syndrome or AV block, because nicorandil hasno negative chronotropic effect on human hearts. Additionaly, nicorandil may beeffective for intraatrial reentrant tachycardia.

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The efficacy and usefulness of the nitroglycerin tape preparation NT-1 (5 mg of nitroglycerin) under treadmill exercise testing were studied by a multicenter doubleblind trial in 24 patients with stable effort angina pectoris, and compared to the results with ISDN (isosolbide dinitrate) tape (40 mg of ISDN). The patients were randomly divided into two groups (NT-1 group: 12 patients, ISDN group: 12 patients). The treadmill exercise was performed according to the Bruce protocol both before and 4 hours after administration of the tapes, and the work tolerance was determined . The results are summarized as follows: (1) The first day's data only could be utilized to compare the two groups, because a carryover effects on work tolerance was noted in the NT-1 preceeded group (P<0.05).(2) Work tolerance was significantly increased in the NT-1 group as compared with that in the ISDN group (P<0.001), and also the duration of tolerable work was significantly improved. Improvement of the duration was 91.7% in the NT-1 group and 41.7% in the ISDN group, respectively. The NT-1 rate was significantly superior (P<0.05).(3) Evaluation of the usefulness of the drugs was studied, giving a ratio of 2: 1 for the duration rate of tolerable work and the change of ST deviation in ECG. NT-1 was significantly superior to ISDN (P<0.05).
(4) A significant decrease in systolic pressure (P<0.05) and a significant increase in heart rate (P<0.001) at the end of the exercise was observed in the NT-1 group before and after administration, whereas these parameters remained unchanged in the ISDN group.(5) No side effects such as headache, hypotension, or dermal symptoms were noticed in the two groups throughout the trial .
These results indicate that NT-1 more effective than ISDN concerning work tolerance in patients with effort angina pectoris, although both NT-1 and ISDN tapes are considered to be useful.

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Multi-gated blood pool scintigraphy, a method of clinically proven usefulness for the noninvasive evaluation of cardiac hemodynamics, was used to evaluate the efficacy of trapidil. The longitudinal image of the left ventricle was taken using a gammaray camera equipped with a 30°C slant hole collimator (Siemens model ZLC 75), and the collimator was set in the cranio-caudal direction with amodified LAO. The R waves on the ECG and the second sound on the phonocardiogram were used as synchronizing signals to clarify the target image. The ADAC system II nucleomedical data processor was used for processing and statistical analysis of the data. Ten subjects (9 men and 1 woman at the mean age of 64 years) were injected iv with 100 mg of trapidil over 2 minutes, and the scintigram was taken from immediately after the iv injection. The following results suggested the positive inotropic action with trapidil: 1. lowering of body blood pressure and increase in heart rate (P<0.001); 2. increase in the left ventricular ejection fraction (P<0.01), and increase in cardiac index (P<0.01); 3. increase in maximum left ventricular ejection velocity (P<0.05) and increase in the maximum left ventricular filling velocity (N. S.); 4. increase in the left ventricular work index (P<0.05); and 5. decrease in total systemic vascular resistance (P<0.01).

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The excretion pharmacokinetics of following total knee replacement with amikacinimpregnated bone cement was studied in 23 cases and 25 joints. The patients received 2 g of amikacin. Measurments of the amikacin concentration in drainage (2 hr, 4 hr, 24 hr, and 48 hr after operation) were carried out in all cases. Amikacin excretion-time curve was rapid during the initial phase lasting until 48 hours after operation. The concentration of amikacin in the knee joint was 5.73±0.81μg/ml at the 7 th day after operation and 1.28±0.16μg/ml at the 14 th day. The concentration of amikaicn on the 7 th day covered the MICs of Staphylococcus aureus, E. coli, and Pseudomonas aeruginosa.Amikacin-impregnated cement is thus considered useful for prophylactic treatment when total joint arthroplasties are operated upon.

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Nilvadipine, a new calcium channel blocking agent, was compared with nicardipine regarding antihypertensive effect and pharmacokinetic profile in essential hypertensiye patients after single administration. Nilvadipine at doses of 6 mg and 4 mg was compared with nicardipine 20 mg using a randomized crossover procedure. Nilvadipine at 6 mg doses was more potent and longer-lasting in antihypertensive effect than nicardipine. On the other hand, nilvadipine at 4 mg doses was comparable to nicardipin although its duration was a little longer. There was a good linear correlation between plasma concentration and antihypertensive effect of nilvadipine. The minimum effective plasma concentration (MEPC) of nilvadipine inducing 7% decrease in mean blood pressure was estimated to be 0.5-0.7 ng/ml. The adverse effects observed by nilvadipine were transient and not clinically significant. However, adverse effects by nilvadipine at doses of 6 mg occurred a bit more frequently than by nicardipine.
The antihypertensive effect and pharmacokinetic profile of nilvadipine were also studied after multiple administration in the hypertensive patients. Nilvadipine was given in the dosage regimen of 4 mg b.i.d. for 6-10 days. The plasma concentration at 12 hours after dosing on the final day of treatment was consistent with MEPC followed by prolonged antihypertensive effect.
These data show that nilvadipine is a potent antihypertensive drug, and suggest anoptimal dosage regimen of nilvadipine in essential hypertension at 4 mg or less, b.i.d..

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