We investigated the safety, tolerability, pharmacokinetics and pharmacologicalprofile of MK-954, a new angiotensin II receptor antagonist, in healthy male volunteersafter single oral administration.
Twenty-four subjects were divided into 4 groups (6 subjcts/group) and were given MK-954 (25, 50, 100 or 200 mg) after an overnight fast, followed by 100 mg afterbreakfast. The results were as follows: (1) Modest decreases in blood pressure occurredafter the administration of MK-954. Heart rate was increased slightly, but, dose dependency was not observed.(2) Signs and symptoms such as headache (n=3), feeling hot (n=1), orthostatic hypotension (n=4) and dizziness (n=1) were observed after MK-954administration these experiences were mild and transient. Abnormal laboratory findings such as increased serum creatinine (n=1) and decreased serum uric acid (n=1) were observed with the highest dose.(3) Mean plasma concentrations of MK-954 and itsactive metabolite E-3174 after dosing in the fasted state reached their peaks at 0.7-1.3and 2.0-3.7 hr, respectively, then diminished with a t_1/2 of 1.5-2.5 and 3.8-4.4hr, respectively. The C_max of MK-954 and E-3174 which exhibited dose dependency were 84.5-1394 .9 and 188.9-2219.0 ng/ml respectively, and their AUCs, also dose dependent, were201.3-2231.2 and 1348.9-10861.4ng⋅hr/ml, respectively. Although a decreased C_max andprolonged T_max were observed in the fed state, the AUC of MK-954 and E-3174 were 80%and 86%, respectively, of those obtained with the same dose in the fasted state, indicatingno difference in total systemic absorption between the fasted and fed state.(4) Serum uricacid decreased and urinary excretion of uric acid increased in a dose dependent mannerand without effects on urinary creatinine excretion. These findings suggest that MK-954has uricosuric effects.
In conclusion, it was demonstrated that single doses of 100 mg of MK-954 and lowerwould be safe and desirable to administer, because orthostatic hypotension was observedat the highest dose (200 mg).

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We investigated the safety, tolerability, pharmacokinetics and pharmacologicaleffects of MK-954, a new angiotensin II receptor antagonist, in healthy male volunteersafter oral administration of 100 mg once daily for 7 days.
Nine subjects were randomly divided into 2 groups (active drug 6, placebo 3). On the1st and 7th days, the test drug was administered in the fasted state (before breakfast), and on 2-6th days, it was administered after breakfast. The results were as follows: (1) A decrease in blood pressure was observed in the active drug group after 6 hoursfollowing the first drug administration.(2) Some adverse experiences such as headacheand dizziness on standing up were observed after MK-954 administration; these experiences were mild and transient. In laboratory findings, a decrease of serum uric acid wasobserved after MK-954 administration. No other abnormal laboratory findings wereobserved.(3) Mean T_max of MK-954 and its active metabolite E-3174 were 0.8 and 2.3 hr, respectively. MK-954 disappeared quickly from the plasma with a t_1/2 of about 2 hr ; the t_1/2 of E-3174 was 5 hr. There was no significant difference in the C_max and AUC of MK-954 and E-3174 between the first and the 7th days, suggesting a lack of accumulation of MK-954.(4) Serum uric acid decreased and the urinary excretion of uric acid increasedduring MK-954 treatment. The mechanism underlying the uricosuric effect remainedundefined.
In conclusion, it was demonstrated that 100 mg of MK-954 is safe for a 7-day dosageperiod with no accumulation in healthy male volunteers. Based on these results, 100 mgwas recognized as appropriate for the maximum dose in the proceeding early phase IIstudies.

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Disopyramide (DP) is used widely as an antiarrhythmic agent. The antiarrhythmiceffects of DP's enantiomers vary, and its metabolism and protein binding are alsostereoselective. Population pharmacokinetic parameters of the disopyramide racemate (DP), enantiomers [S (+)-DP, R (-)-DP], and their unbound concentrations [uDP, S (+)-uDP, and R (-)-uDP] were analyzed using the NONMEM program (Nonlinear Mixed Effects Model). Data were available from 108 points of 33arrhythmic patients onmaintenance therapy of disopyramide racemate .We evaluated the factors, to whichpharmacokinetic parameters are attributed. We also studied the relationships betweenserum concentration [DP, S (+)-DP, R (-)-DP, uDP, S (+)-uDP, and R (-)-uDP] andthe arrhythmic effect.
The data were fitted to the 1-compartment model using NONMEM Ver IV.For DP, S (+)-DP, and R (-)-DP, elimination constants (ke) were estimated as 0.0648, 0.0663, and 0.0691h-1, respectively, and apparant distribution volumes (Vd/F) were estimatedas63.2, 54.1, and 71.6 L, respectively. For unbound disopyramide [uDP, S (+)-uDP, andR (-)-uDP], ke were estimated to be 0.100, 0.104, and 0.0990h^-1, and Vd/F were estimated as 181, 206, and 161 L, respectively. Using the ke, and Vd/F values which wereestimated by NONMEM, typical dosing (100 mg tid, or 100 mg bid) time-concentrationcurves were well fitted to the observed data.
Unbound fractions of both DP enantiomers showed nonlinearity and the bindingratio of S (+)-DP was 0.84±0.07.This binding ratio was higher than that of R (-)-DP [0.70±0.11 (p<0.01)].Unbound fractions of both DP enantiomers correlated with α₁-acid glycoprotein (AGP) (p<0.01), but did not correlate with total protein or albumin.On the other hand, using NONMEM, a significant proportion of the variability of Vd/Fcould be attributed to AGP (p<0.001), but not to body weight, gender, serum creatinine, total protein, or albumin. NONMEM could clarify the pharmacokinetic features in theprotein binding of disopyramide. For DP, intra-individual variability of Vd/F wasreduced from 32.9% in the simple model to 27.2% in the final model in which Vd/Fincludes AGP.
Individual steady state concentrations were estimated by NONMEM using theBayesian method. The average total concentrations of racemate and both enantiomers in9responders were similar to 4non responders. The average unbound concentrations ofall 9responders were higher than those of the 4 non responders, even though there wasno significant difference. Unbound concentrations may reflect drug concentrations in thetissue, which suggests that unbound concentrations may indicate the antiarrhythmiceffect rather than the total concentration.

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To evaluate the efficacy and safety of NKH477, a water soluble forskolin derivative, a multicenter group study was conducted in 68 patients with severe heart failure.
Patients were intravenously administered NKH477 at a rate of 0.25μg/kg/min (low) initially and the dose was increased hourly to 0.5μg/kg/min (intermediate) andfinally to 0.75μg/kg/min (high).
NKH477 improved the hemodynamics in the patients with severe heart failure, sincethis agent directly activates adenylate cyclase. The cardiac index (CI) increased significantly and pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR) were significantly decreased.
In the principal physicians' assessment of the global improvement, the percentage ofpatients judged as “improved” or higher was 20.3% in the low-dose group, 50.8% in theintermediate-dose group and 71.9% in the high-dose group.
Adverse events occurred in 5.9% in the low-dose group, 17.9% in the intermediatedose group and 30.0% in the high-dose group, increasing with dose. The most commonsymptoms were palpitation, flush and headache. It is important to also note an incrementof arrhythmias.
In the evaluation of usefulness based on the grobal improvement and overall safety, the percentage of patients in which the treatment was assessed as “useful” or higher was23.4% in the low-dose group, 57.1% in the intermediate-dose group which showed asignificant increase and 73.7% in the high-dose group.
In conclusion, the clinical optimal dose of NKH477 is thought to be 0.5μg/kg/min.

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Single and 7-day multiple dose studies of MK-217, a new aminobisphosphonate, were conducted on 5 Japanese postmenopausal female volunteers. The safety of the drug, pharmacokinetics and its effects on biochemical markers of bone turnover were inves tigated.
In the single dose study, 10 mg of MK-217 was administered to 5 subjects 2 hours before breakfast and in the 7-day multiple dose study, the same dose of MK-217 was administered one-half hour before breakfast.
No abnormal changes were observed in subjective symptoms, blood pressure, pulse rate, respiratory rate, body temperature, ECG and body weight in both studies. In the 7-day multiple dose study, an increase in alkaline phosphatase (Al-p) was observed in one subject. The relationship of this phenomenon to the drug was unknown. Following the 7-day multiple dose study, serum osteocalcin (CIS method) and urinary pyridinoline (deoxy-and hydroxylysyl pyridinoline) were decreased significantly.
Less than 1% of the administered dose of MK-217 was excreted in urine in both studies, although the excretion rate was higher in the single dose study than in the multiple dose study.

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The purpose of the present study was to investigate the relationship between enalapril-induced cough and patient characteristics such as age, sex, smoking, dosage of enalapril, history of allergy and combined use of β-blockers in outpatients of 27 hospitals, 9 clinics and 16 pharmacies in Japan. The data of this cross-sectional study obtained through interview with patients taking enalapril, were analyzed by multiple regression analysis.
Of 3010 subjects, enalapril-induced coughing was found in 525 (17.4%). A significant correlation was found between cough and allergic factor, but the coefficient of determination was of low value (r²=0.0134, p<0.001). Furthermore, this odds ratio was 1.97 (95% CI, 1.60-2.43, p<0.001). These data suggest that allergic factors are related to enalapril-induced cough rather than background factors such as age, sex, smoking, dosage of enalapril and concomitant use of β-blockers.

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In order to clarify vancomycin pharmacokinetics in a Japanese elderly population, vancomycin (10 mg/kg) was repeatedly administered to 6 elderly female patients with methicillin-resistant Staphylococcus aureus (MRSA) infections (age 78 .3±5.9 years, weight 34.8±9.4 kg, CL_CR 41.9±19.8 ml/min, mean±SD) by 1-hour constant infusion for 6days. Vancomycin was given to elderly patients once on day l and 6, and twice on day 2 to day 5 at 12-hour.intervals. Six healthy male volunteers (age 22 .0±1.7 years, weight 62.7±7.5kg, CL_CR 115.0±9.6 ml/min, mean±SD) were administered vancomvcin once by 1-hour infusion. Serum and urinary vancomycin concentrations were measured by fluorescence polarization immunoassay and bioassay, respectively . Total clearance (CL) of vancomycin was 95.50±15.74 ml/min in the healthy control group subjects, while the value of CL was 35.21±13.29 ml/min in the elderly patients on 1st day. In elderly patients, vancomycin was substantially eliminated extrarenally in comparison with the healthy subjects. Pharmacokinetic parameters were compared between day 1 and day 6 in the elderly patients. Nonlinear pharmacokinetics was observed during multiple administration, t_1/2 was prolonged from 12.99±7.11 to 21.95±12.00 hour on day 6 (p<0 .05). CL significantly decreased from 35.21±13.29 to 23.64±8 .50 ml/min on day 6 (p<0.05).In contrast, renal clearance of vancomycin (CL_R) remained constant throughout the study (15.06±5.86 and 17.76±7.78 ml/min on day 1 and day 6, respectively). The ratio of non renal clearance (CL_NR) to CL was decreased from 0.568 (mean) to 0.268 after multiple dosing of vancomycin. The results suggested that vancomycin was eliminated mainly extrarenally in the elderly patients and that this extrarenal elimination was reduced during the repeated administration. These findings may have clinical implications for the long-term treatment of elderly patients with MRSA infections .

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A 46-year-old housekeeper with chronic myocarditis and congestive heart failure showed a dramatic response to a trial therapy employing the angiotensin-II receptor antagonist, TCV-116. On admission, her CPK was elevated and chest x-ray revealed huge cardiomegaly. The left ventricular (LV) chamber was markedly dilated, and the wall motion was reduced as assessed by echocardiography. On ^99m Technetium pyrophosphate (Tc-PYP) myocardial scintigraphy, intense positive staining projected to the lateral LV wall. When elevation of CPK recurred, the Tc-PYP uptake migrated to the other site, the postero-inferior wall. After trial-use of TCV-116, the patient's heart failure was improved and the Tc-PYP positive figure was eliminated completely. When the drug was withdrawn, Tc-PYP uptake reappeared. The new drug, TCV-116, seemed to be effective in the treatment of chronic myocarditis with congestive heart failure.

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