Cibenzoline is a newly developed antiarrhythmic drug which possesses a local anesthetic action. We studied the pharmacokinetics of cibenzoline and its effects on ventricular premature contractions (VPCs) in 27 patients by a single oral administration method.Blood samples were drawn before and at 0. 5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hr after the drug administration (4 mg/kg) to measure the plasma drug concentration using high performance liquid chromatography (HPLC). A standard 12-lead ECG was recorded at the time of blood sampling to evaluate the effects of cibenzoline on electrocardiographic parameters and a 24-hr dynamic ECG was also obtained on the day before and after the drug administration to assess the suppressive effects on VPCs. T_max. was 2.9±1.5 hr in 23 patients with normal renal function (group A) and 3. 1±1. 5 hr in 4 with renal dysfunc tion (group B). C_max was 596±228 ng/ml for group A and 739±134 ng/ml for group B. T_1/2β was 10. 1±5.1 hr for group A and 13. 5±1. 8 hr for group B, and AUC was 5, 880± 2, 334ng/ml·hr for group A and 11, 864±5, 165ng/ml·hr for group B. Urinary excretion rate was 43±16% for group A and 31±20% for group B. Effective suppression of VPCs was found in 17 out of 20 patients who had VPCs of more than 1, 000/24 hr. The average of the minimum effective plasma concentration that was defined as the one showing more than 75% reduction of the baseline frequency of VPCs (beats/hr) was 329±147 ng/ml. RR, PQ and QTc intervals, and QRS duration were prolonged, and blood pressure was slightly elevated after the drug administration. However, there were no serious adverse effects in any patient. These data suggest that 1) pharmacokinetics of cibenzoline strongly depends on the renal function of individual patients, 2) cibenzoline was a safe and highly effective antiarrhythmic drug on VPCs, 3) the drug concentration should be monitored during the maintenance therapy in patients with renal dysfunction.

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Nitrendipine is a dihydropyridine calcium entry blocker. The effect of nitrendipine on hemodynamics at rest and during exercise with a supine bicycle ergometer with multistage protocol was studied in 10 cases of effort angina pectoris with old myocardial infarction.
Nitrendipine was given orally at a daily dose of 10 mg for one week and various hemodynamic parameters were measured at rest and during exercise before and after the treatment with nitrendipine. At rest, the blood pressure was reduced, total peripheral resistance and pulmonary artery pressure tended to decrease, heart rate, cardiac index and stroke index were unchanged, and left ventricular ejection fraction tended to increase.
At peak exercise, the blood pressure tended to decrease, heart rate, cardiac index and stroke index tended to increase, the rise in pulmonary artery pressure was suppressed, the pulmonary vascular resistance decreased, and the decrease in the left ventricular ejec tion fraction was reduced.
It is concluded that nitrendipine exerts antianginal action without decreasing cardiac function.

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N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a newly developed anti-anginal drug, is a coronary vasodilator whose action is comparable to papaverine. We examined this drug to determine whether it could be useful in relieving cerebral vasospasm using helical cut dog basilar artery (in vitro) and vasospasm model dog (in vivo).
In each vessel stimulated to contract by PGF₂α, U-46619 or K⁺, the addition of nicorandil (10^-9-10^-4M) caused dose-dependent and persistent relaxation. In the basilar arteries, con tractions induced by PGF₂α and U-46619 were attenuated by prior treatment with nicorandil, but contractions induced by K⁺ were not. Twice-a-day intravenous injection of nicorandil could not prevent vasospasm in the model dogs. But, intrathecal injection of nicorandil caused marked dilatation of the spastic basilar artery of model dogs.
In in vitro experiments, nicorandil dilated a basilar artery which was constricted by various spasmogenic substances and the prior treatment with nicorandil had attenuated the contractile responses to endogenous prostaglandins, which are known to play an important role in cerebral vasospasm. In in vivo experiments, owing to the short half-life of nicorandil, intravenous injection could not prevent cerebral vasospasm: however, intrathecal injection showed a marked effectiveness. In conclusion, we think nicorandil may be useful for the treatment and prophylaxis of cerebral vasospasm with an adequate usage.

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The present study was performed to determine the pharmacokinetic parameters of recombinant human erythropoietin (r-HuEPO: KRN 5702) in patients on maintenance hemodialysis.
After a single (300 IU; n=11, 1, 500 IU; n=8, 3, 000 IU; n=12, 6, 000 IU; n=7) and multiple (3, 000 IU; n=12, 3 times per week) intravenous administration of KRN 5702, plasma concentrations of KRN 5702 were analyzed by RIA method.
KRN 5702 was cleared from the circulation in an exponential fashion . Its half life (T_1/2: hr) and total clearance (Cl_tot: ml/hr·kg) showed dose dependency (T_1/2: 300 IU, 6.0; 1, 500 IU, 5.9; 3, 000 IU, 7.5; 6, 000 IU, 9.7; Cltot: 300 IU, 10.8; 1, 500 IU, 7.4; 3, 000 IU, 5.7; 6, 000 IU, 4. 1), although the apparent volume of distribution (V_d) remained unchanged.
After repeated administration of KRN 5702 (3 times per week for 2 wk and 6 wk), T_1/2 showed a tendency to decrease and Cltot showed a tendency to increase, although V_d remained the same. The accumulation of r-HuEPO was not observed.
These results suggest the existence of bone marrow saturation of KRN 5702 when administered at high dose, and the increase of bone marrow activity, which was responsible for accelerated utilization of KRN 5702 when administered repeatedly.

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Xamoterol (100 mg bd), a β1-partial agonist, was given to 13 patients with dilated cardiomyopathy for 12 months. The long-term effects after 3 and 12 months of treat ment with xamoterol were assessed. Xamoterol reduced cardiothoracic ratio from 57 ± 8 at baseline to 54±7 after 3 months and 54± 7% after 12 months of treatment (both P <0.05), and increased exercise tolerance from 4.8± 2.3 at baseline to 6.8± 2.4 and 6.5±2.3min, respectively (both P<0.01). Echocardiographic fractional shortening increased from 13±6 to 21±9 (P<0.01) and 19±11% (P<0.05). Pulmonary wedge pressure (PAW) during exercise at the same work load decreased from 40±12 to 25± 9 mmHg (P<0.01) at 3 months and 32±16 mmHg (NS) at 12 months. Resting PAW at 3 months decreased and was unchanged at 12 months. Exercise heart rate decreased from 118±9 to 106±6 beats/min at 3 months (P<0.01) and was unchanged at 12 months. The density of the β-receptors in lymphocytes increased from 1, 024±413 at baseline to 1, 976±497 (P<0.01) at 3 months and 1, 584±650 sites/cell (NS) at 12 months while the respective values for the affinity of theβ-receptors were 0 .67±0.27, 1.60±0.42 (P<0.01) and 1.21±0.54 nM (P<0.05).
It may be concluded that xamoterol improves exercise tolerance, haemodynamics, and subjective symptoms by its partial agonist action during long-term treatment.

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The plasma concentration and urinary excretion of 15 (R)-15-methylprostaglandin E₂ (Arbaprostil, CU-83) and its 15 (S)-15-methyl epimer (CU-83 (S)) were studied in healthymale volunteers after a single oral administration of CU-83.
Maximum plasma concentrations of CU-83 following the administration at doses of 20, 40 and 60μg were 127.4, 152.8 and 164.2pg/ml, respectively, from 0.6 to 0.9hr. On theother hand, maximum plasma concentration of CU-83 (S) following the administration was7.4 pg/ml at 1.1hr in the case of 20μg dose, 17.7pg/ml at 1.0 hr in 40μg and 44.1pg/mlat 1.0hr in 60μg.
Urinary excretion half-lives of CU-83 and CU-83 (S) were 1.2-1. 6hr and 3. 2-5.2hr, respectively. Of the administered dose, 1. 45-1. 65% as CU-83 and 0.98-1.62% as CU-83 (S) were excreted in urine until 24 hr after administration.

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Ambulatory blood pressure (BP) was obtained before and 2 months after the initiationof atenolol therapy in subjects with mild essential hypertension to determine whether theadministration of atenolol, a beta adrenoreceptor blocking agent, modifies the circadianpattern of blood pressure. BP was measured by a non-invasive automatic device with a15-min interval during a 24-hr period, and was analyzed by fitting of power-normal transformationmodel (PNT model).
The circadian pattern of systolic BP in 4 patients out of 6 and diastolic BP in 2 out 6were modified and the amplitude of systolic BP was reduced with a prolonged atenololtherapy.
These findings indicate that the circadian pattern of BP is modified by chronic atenololtherapy, which is caused by the suppression of the elevation of BP during the daytime

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Pharmacokinetic analysis of cefmenoxime (CMX) was carried out in preterm and terminfants after single intravenous administration.
The mean elimination half-life (t_1/2) value of CMX in four infants ranging in the agesfrom 6months to 2yr was calculated to be 0.83±0.06 (mean±SE) hr, which was similarto a reported value in adults. The mean t_1/2value in neonates, including preterm infants (postnatal age1.7±1.2day, birth welght 2, 426±242g), was 6.2±1.0 (mean±SE) hr, whichwas markedly longer than that in older infants. Total body clearance (Cl_tot) of CMX inneonates was reduced to 22.8±3.6 (mean±SE) ml/min/1.73m², which was less than onetenth of the Clot value of CMX in older infants. Apparent volumes of distribution werenot significantly different (P>0.05) among age groups.
We found that decrease in post-conceptional age tended to prolong t_1/2 and reduce Cl_tot.Clearance ratio (CR) of renal clearance of CMX to its glomerular filtration rate (GFR) wasalso calculated by measuring the drug in urine to evaluate the effect of tubular secretionof CMX by co-administration of probenecid. CR of CMX with co-administration of probenecid was reduced compared to that without probenecid in a healthy volunteer. It wasrecognized that a short postconceptional age tended to reduce CR of CMX. The decreasein glomerular filtration and tubular secretion function in neonates including prematureinfants is likely to cause a remarkable prolongation of a t_1/2 value of CMX. Thus, weconclude that adjustment of the dosing schedule of CMX in neonates in age of less than7 days will be required.

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Pharmacokinetics and pharmacodynamics of long-acting (LA) capsule of carteololhydrochloride were investigated in healthy adult male volunteers in the two comparisonstudies;
Study I: Comparison with single administration of 15 mg/person of LA and conventionaltablets (CT) under fasting condition
Study II: Comparison with single administration of 15 mg/person of LA and separateadministration of CT, 5mg/person, three times a day after meals
In study I, AUC was not significantly different between LA and CT, while C_max of LA was significantly lower than that of CT. The long-acting profile of LA was establishedfrom the prolongation of pharmacokinetic parameters; Tmax t_1/2, MRT and VRT of LAwere significantly longer than those of CT.
In study II, C_max of LA was not significantly different from that of CT. The pharmacodynamic indexes, heart rate, systolic blood pressure and double product during exercise, were not significantly different between the two groups.
The urinary excretion curves in study I and II supported the plasma concentration.
Pharmacokinetics of LA were not influenced by food consumption, since the pharmacokinetic parameters of LA did not differ significantly in study I and II.
In conclusion, a once-daily administration by LA is proposed as being clinically useful.

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Pharmacokinetics of long-acting (LA) capsule of carteolol hydrochloride were investigatedin healthy adult male volunteers. The LA group received 15 mg/person once daily whilethe comparison group received conventional tablets (CT), 5 mg/person, three times a day, for 9 days of repeated administration.
The plasma concentrations of both the LA and CT groups reached a steady-state on Day3.
Although the pharmacokinetic parameters, AUC, C_max, C_min, and C_max/C_min in the steadystaterevealed no significant differences between the two groups, t_1/2 was significantlydifferent between LA (9.3hr), and CT (6.9hr).
The plasma concentration profile on the LA repeated adminitsration corresponded wellto the prediction curves estimated from the LA single administration study. T_1/2 in thesteady-state of LA dosing was quite similar to that of a single adminitsration of LA. Thesefacts reveal that the prolongation of plasma concentration maintained by LA administrationdid not cause any accumulation of carteolol nor any change in the pharmacokinetics.
In conclusion, a once-daily administration by LA capsule is proposed as being clinicallyuseful.

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Beta-methyldigoxin (β-MD) is a cardiac glycoside widely used to treat heart failure and arrhythmia but its pharmacokinetics is not well known. Pharmacokinetic characteristics of β-MD were studied in five healthy volunteers. After a single oral dose of β-MD (0.2mg), the serum glycoside concentrations and urinary glycoside excretions were measured over seven days. The concentrations of β-MD and its metabolites in serum and urine were deter mined by high performance liquid chromatography-fluorescence polarization immunoassay method.
β-MD appeared in serum 15min after administration and reached the peak serum concentration (1.88±0.71ng/ml) at 0.70±0.33hr. Elimination half-life, volume of distribution, and renal clearance were found to be 46.5±14.1hr, 9.5±2.4l/kg, and 46.0±14.3ml/min, respectively. These kinetic parameters were different from data reported previously . Digoxin was the only metabolite observed in serum and its peak concentration was 0.31± 0.07ng/ml at 1.10±0.34hr. The percentages of the β-MD dose renally excreted by 156 hr as β-MD, digoxin, digoxigenin bisdigitoxoside, digoxigenin monodigitoxoside, and digoxigenin were 29.55, 23.42, 1.28, 0.36, and 0.50%, respectively. From serum concentration-time curves, the presence of enterohepatic circulation of β-MD was suggested.

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