The hemodynamic profile of urapidil (URP) was evaluated in patients with hypertension during weight-sustaining isometric exercise (WSIE) and compared with metoprolol (MTP) and prazosin (PRZ).
Method: Forty-two patients were divided into three groups randomly after a twoweek control period. The average dose of each drug used was 4.9±1.7 mg/day for PRZ, 118±49mg/day for URP, and 143±33mg/day for MTP. WSIE was performed for four minutes before and after eight weeks of treatment. Heart rate (HR) and blood pressure (BP) were measured before exercise and at one-minute intervals during and after exercise. The cardiac index (CI) was also determined before, during, and three and six minutes after exercise by the dye dilution method using an earpiece densitometer.
Results: Thirty-one patients completed the study, and blood pressure fell equally in all groups. In the MTP group, HR and CI decreased and systemic vascular resistance (SVR) increased significantly at rest. On the other hand, PRZ increased HR and CI slightly and decreased SVR, while there was no significant change in HR and CI in the URP group.Although the increment of SVR caused by WSIE was enhanced in the MTP and PRZ groups, it was attenuated by URP treatment. The elevation of diastolic blood pressure by WSIE was also accentuated in the MTP group, while URP sun: tressed the elevation.
Conclusion: The hemodynamic effects of URP lie between those of PRZ and MTP. These results suggest that, although pharmacologically α₁-antagonistic action is ten times stronger than that of β₁, from a clinical standpoint URP has both α₁-and β₁-antagonistic action in equal balance.

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Diuretic and uricosuric effects of traxanox sodium (TRX, 180 mg three times daily for 8 days) were investigated by double blind, cross over comparison with hydro chlorothiazide (HCT, 25 mg twice daily for 8 days).
Urine volume and urinary excretion of electrolytes increased after the administration of TRX. Asimilar trend was observed on HCT. The urinary excretion of uric acid increased and serum concentration of uric acid decreased on TRX. However, the urinary excreti on of uric acid decreased and serum concentration of uric acid in creased on HCT.
Serum Na, K and Cl decreased, while serum Ca and PRA increased on HCT, while only serum Cl decreased on TRX. Neither drug induced any significant changes in blood pressure, pulse rate, body temperature or body weight.
These results show that TRX has a uricosuric effect in humans.

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With the object of obtaining information about factors influencing the effect of isosorbide dinitrate (ISDN) tape (Frandol tape®), the effect of bathing, application site, water content of the corneal layer of epidermis, tissue blood flow and age on the plasma ISDN concentration was studied by applying Frandol tape® to healthy male volunteers, and the following results were obtained.
1. The plasma ISDN concentration was enhanced transiently upon bathing.
2. A higher plasma ISDN concentration was obtained when the tape was applied on the back or leg than on the breast.
3. There was no relationship between plasma ISDN concentration and water content of the corneal layer or on the tissue blood flow.
4. High plasma ISDN concentrations were exhibited in younig men, but were not Significant.

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A double-blind controlled study was conducted in 140 patients with ventricular premature contractions to find the optimal regimen for propafenone hydrochloride in Japanese patients. Three dose levels, 300 mg/day, 450 mg/day, and 600 mg/day, were compared.
Response was assessed by the reduction in number and severity of premature contractions. The rate of the response was 24 % at 300 mg/day, 56% at 450 mg/day, and 63% at 600 mg/day. The two higher dose levels were significantly better than the lowest dose of 300 mg/day.
Side effects were reported from 8 patients (17%) who received 300 mg/day, 2 (4%) at 450 mg/day, and 14 (30%) at 600 mg/day. The incidence was low at all doses, but it was significantly lower at 450 mg/day than at the two other dose levels. Conduction disturbance was related to 600 mg/day in some patients.
The clinical value of the drug was assessed, considering both the response of ventricular premature contractions and the incidence of adverse reactions. The drug was valuable or better in 24% of the patients who received 300 mg/day, 52% at 450 mg/day, and 56 % at 600 mg/day. The two higher dose levels were significantly better than the lowest dose of 300 mg/day. In conclusion, propafenone hydrochloride was shown to be effective in Japanese patients with ventricular premature contractions. Data on response and safety suggest an optimal dose of 450 mg/day.

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The validity of the Giusti-Hayton method for dosage regimen adjustment in renal impairment was examined using a histamine H2-antagonist, ranitidine. Five healthy volunteers with normal renal function and 20 patients with varying degrees of renal impairment were enrolled in the study. The former received ranitidine at standard unit dose of 150 mg and the latter received doses calculated from the creatinine clearance value using the Giusti-Hayton method. Pharmacokinetic parameters were compared between healthy volunteers and patients after a single oral dose of ranitidine. As a result of dosage adjustment for each patient by the Giusti-Hayton method, the AUC_0→∞ of renally impaired patients became almost comparable to those from healthy volunteers.
In conclusion, the Giusti-Hayton method was considered useful to keep the ranitidine AUC_0→∞constant and, eventually, to keep mean blood levels of ranitidine in a constant steady state, irrespective of the renal function of the subject.

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2- [4-(2-Thiazolyloxy) phenyl] propionic acid (156-S) is a new acidic nonsteroidalanti-inflammatory and analgesic agent. Metabolism studies of 156-S in animals andhumans have revealed the metabolic and elimination pathways, but no pharmacokineticstudies in humans have been completed.
In this study, the pharmacokinetics of 156-S in healthy volunteers was investigated.Six healthy male volunteers were given 156-S orally at doses of 100, 200, and 400 mgwith at least one week's interval and six other healthy male volunteers participated in amultiple-dose study of 300 mg t. i. d. for 21 days. Plasma and urine concentrations of156-S and its metabolites were determined by HPLC. The pharmacokinetic parameterswere estimated using the one-compartment model. Serum protein binding wasdetermined by equilibrium dialysis.
In the single-dose studies, urinary recoveries at each dose were almost 100%independent of the dose, but the AUC increased more than proportional to the doses andthe half-life became longer as the dose increased, suggesting nonlinearity in thepharmacokinetics of 156-S.
In the multiple-dose study, half-lives at the 22nd, 43rd and 64th doses were almosttwice that at the 1st dose and AUCs were almost three-fold, although urinary recoveriesat each dosing interval were almost constant at about 90%. Protein binding of 156-S was98% and the binding was not affected by multiple dosing. These results suggest thatsome parts of elimination pathways are inhibited during multiple administration. Amongrenal clearance (CL_r), glucuronidation clearance (CL_g) and oxidative metabolismclearance (CL_m) of 156-S calculated by dividing the urinary excreted amount byplasma concentration, only CLm was reduced significantly during multiple administration.This oxidative metabolism inhibition was shown to be a reversible phenomenonand to recover after a washout period of a few days. However we must investigate theinteraction with other drugs which are eliminated by oxidative metabolism.

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2 [4-(2-Thiazolyloxy) phenyl] propionic acid (156-S) is a new acidic nonsteroidalanti-inflammatory and analgesic agent. The pharmacokinetics of 156-S in elderlypatients were studied in comparison with those in healthy volunteers. The elderlypatients females, N=6, age: 84.7±2.1yr old, body weight: 29.7±2.0kg, serumconcentration of albumin: 3.3±0.1g/dl, creatinine clearance (CLcr: 61.3±8 .0ml/min ; all data are represented as mean±S. D.) were given 156-S (300mg) orally andblood and urine samples were taken after dosing. The same schedule applied to healthyvolunteers (males, N=6, 28.0±4.6yr old, 66.7±5. kg, 4.3±0.3g/dl, 91.1±14.0ml/min). The pharmacokinetic arameters of 156-S in both groups were calculated bythe one-compartment model. Although C_max and K_ab of 156-S in elderly patients were notdifferent from those in healthy volunteers, T_max, AUC, t_1/2 and Vd of 156-S in elderlypatients were shown to be significantly increased.
More than 90% of the dose of 156-S was excreted in urine until 24 hr afteradministration in both groups. The value of CLr (M-I) (renal clearance of M-I, 156-Smajor metabolite) or CL_r (total M) (renal clearance of total 156-S metabolites) obtained was bigger than that of CL_cr in healthy volunteers, indicating that oxidativemetabolites of 156-S were excreted by glomerular filtration and renal tubular secretion.In elderly patients reduced CL_r (M-I) and CL_r (total M) were shown to be 40% ofthose in healthy volunteer and CL_cr were about 60% . These data suggest that bothglomerular filtration and renal tubular secretion in elderly patients are reducedcompared to those in healthy volunteers.
Hepatic clearance of 156-S in elderly patients, CL_g (hepatic glucronidative clearanceof 156-S) and CL_m (hepatic oxidative clearance of 156-S), were 30-40% of those inhealthy volunteers, indicating that hepatic metabolism of 156-S in elderly patient isreduced compared to those in healthy volunteers. Serum albumin binding ratios weresignificantly different between the two groups and serum concentration of albumin inelderly patients was much lower than in healthy volunteers. From these results, when wegive 156-S to elderly patients, we have to consider the adjustment of the dosing intervalrather than the dose of 156-S.

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In order to elucidate the pharmacokinetic characteristics of digoxin in patients with Duchenne muscular dystrophy (DMD), digoxin was administered to nine patients with DMD and five healthy male volunteers.
The two-compartment model was fitted to the digoxin plasma concentration-timecurve, using the nonlinear least-squares regression program APAS following a singleoral administration of digoxin 7μg/kg.
The results were expressed as M± SE. The obtained pharmacokinetic parameterswere compared between DMD patients (n=9) and healthy volunteers (n=5).
The volume of distribution (Vdss) was significantly lower in DMD patients (5.87±0.43l·kg^-1) than in normal volunteers (8.28±0.84l·kg^-1) (P<0.05). The half-life in βphase (t_1/2 β) was significantly shorter in DMD patients (16.93±2.17 hr) than innormal volunteers (33.73±5.20 hr) (P<0.05). The area under the curve (AUC₀→_∞) was significantly smaller in DMD patients (16.41±1.68ng·ml^-1·hr) than in normalvolunteers (25.09±3.26ng·ml^-1·hr) (P<0.05). The elimination rate constant (K_el) was significantly larger in DMD patients (0.29±0.04hr^-1) than in normal volunteers (0.15±0.02hr^-1) (P<0.05).
It is concluded that the dose of digoxin must be modified on the basis of these resultsin DMD patients.

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The purpose of the present study was to assess the influence of liver diseases on the hepatic drug metabolism of antipyrine. The single-dose pharmacokinetics of antipyrine were studied in 4 normal subjects, 6 patients with hepatitis and 6 patients with liver cirrhosis. Antipyrine in plasma or saliva, and antipyrine and its main metabolites in urine after oral dosing, were measured by HPLC.
The serum half-life of antipyrine was significantly longer (P<0.05) in patients with liver cirrhosis than that in patients with hepatitis or in normal subjects. Total body clearance of antipyrine was significantly reduced (P<0.01) in patients with hepatitis and liver cirrhosis. The total body clearance was significantly correlated with serum albumin concentrations, the ICG-K values and GOT.
The excretion of the 4-hydroxy-antipyrine and the 3-hydroxymethyl-antipyrine in urine was significantly reduced in patients with liver cirrhosis.
Thus, the results of the present study suggest that the antipyrine metabolism isreduced in patients with liver cirrhosis.

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Following studies on the fluoropyrimidine metabolism in patients with advancedgastric cancer, which showed increased activities of both uridine and thymidinephosphorylase in gastric cancer tissues, we examined in this study uridine andthymidine kinase, and orotate phosphoribosyltransferase, all of which were concernedin the further activation of fluoropyrimidines. Moreover, dihydrouracil dehydrogenaseactivity, a rate-lemiting factor of fluorouracil degradation, was also determined invarious tissues. As a result, it was demonstrated that kinases are more active in cancertissues than in those of other normal organs. On the other hand, dihydrouracildehydrogenase activity was not changed in cancer or noncancer tissues, except for agreater increase (7-fold) in the liver. It was also noted that the dihydrouracildehydrogenase activity was inhibited by uracil, resulting an elevated concentration offluorouracil in the tissues as described previously.
Thus, it is suggested that fluoropyrimidines essentially have tumor-selective toxicityin patients with gastric cancer, and uracil coadministration would enhance the activityof fluoropyrimidines.

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The effects of enantiomeric bitartrates of disopyramide on blood glucose levels and heart rate were evaluated in Donryu rats. A transient blood glucose lowering response was noted 2 to 3 hr after oral administration of 300 mg/kg d-disopyramide. After oral administration of 1-disopyramide, however, a significant hypoglycemic response was noted which lasted for more than 5 hr. This hypoglycemic action of the individual enantiomers was significantly more potent in the levorotatory form than in the dextrorotatory form, with a relative potency of Pr (d/1) =11.8. The inhibitory effect of the individual enantiomers on the heart rate calculated in vivo from ECG tracings and in vitro from the contraction rate of a right atrial preparation showed no significant difference between the two stereoisomers. These results suggest the possibility of a decrease in the incidence of clinical hypoglycemia while maintaining an acceptable cardiac action by utilizing the dextrorotatory stereoisomer of disopyramide alone.

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In spontaneously hypertensive rats (SHR), blood pressure, heart weight and cardiac norepinephrine concentration were significantly increased at 16 weeks of age in comparison with age-and weight-matched Wistar-Kyoto rats. The prolonged oral administration of Daisaiko-to, Choto-san and Sairei-to in SHR did not efficiently block the development of hypertension, but decreased total cholesterol, triglyceride, β-lipoprotein, heart weight and cardiac norepinephrine concentration.
The results show that these drugs can block the development of hypertensive heart disease.

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We evaluated the efficacy of isosorbide dinitrate (ISDN) spray (E-1000) in exercise-induced anginal attacks in 20 patients with stable effort angina pectoris. E-1000 is a newly developed angina-relieving agent which contains 0.125 mg of ISDN in 1 spray and has a quick onset of action when applied to buccal mucosa by spraying. The patients were divided into two groups with different protocols. In protocol 1, the patientsunderwent treadmill exercise tests (Bruce protocol) and 1 or 2 sprays of E-1000 or a placebo were administered at moderate anginal pain, when the exercise was stopped after 1 min of cooling down, and pain-relieving time as well as 50% ST recovery time was measured in a single-blind cross-over manner. In protocol 2, the patients were administered 2 sprays of E-1000 or a placebo at the onset of chest pain and exercise was continued until it reached a moderate degree, and time from the onset of pain to the exercise end-point (onset-end point time), pain-relieving time, and ST recovery time were compared in a single-blind manner.
In protocol 1, no significant differences in pain-relieving time nor in ST recovery time were observed. On the .other hand, in protocol 2, onset-end point time was longer (111.3±41.4 sec vs. 73.1±21.9 sec, P <0.05) and ST recovery time (106±43 sec vs 135±49 sec, P <0.05) was less in the E-1000 run compared to the placebo run. There were no significant differences in the extent of ST depression and heart rate during exercise and the recovery period, while systolic blood pressure at 5th min of the recovery period was significantly lower in the E-1000 run.
It is concluded that the angina-relieving effects of ISDN spray are significant when it is administered at the onset of anginal pain, by suppressing the increase of chest pain as well making ST recovery quicker. ISDN spray is a useful angina-relieving agent due to its quick onset of action and ease of use.

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