Cefteram has a broad antibacterial spectrum against gram-positive and gram-negative bacteria, and its antibacterial activity has been reported to be superior to other oral cephalosporins. Cefteram pivoxil, a new prodrug of cefteram for oral administration, is expected to be hydrolyzed to cefteram by esterase in the gastrointestinal tract. It has been reported that the bioavailability of cefteram pivoxil was influenced by food intake, and amounts of the drug excreted in urine within 8 hr after dosing were 33% in a nonfasted group and 18% in a fasted group.The gastrointestinal absorption of many drugs has been shown to be altered by concomitantly administered antacids. In the present study, the bioavailability of cefteram pivoxil was examined by regimens allowing postprandial administration of the drug with and without the concomitant administration of dried aluminum hydroxide gel, an antacid, or aclatonium napadisilate, a stimulant of gastrointestinal smooth muscle activity and an accelerator of gastric emptying, in 5 healthy subjects. In this study, the mean cefteram serum concentrations after single oral administration of 200 mg of cefteram pivoxil were shown to be the same among the three examined groups. We found that t_max was 2.9±0.4 hr (mean±SEM) without any coadministered drug, 2.7±0.3 hr with coadministration of dried aluminum hydroxide gel, and 2.7±0.4 hr with coadministration of aclatonium napadisilate. C_max was 2.8±0.1, 2.9±02, and 2.8±0.3μg/ml, and AUC_0-∞ was 10.1±0.8, 9.8±0.7, and 9.6±1.0 (μg/ml) ·hr, for control, with the antacid, and with aclatonium napadisilate, respectively. These values were not significantly different. Thus bioavailability of cefteram pivoxil was not altered by concomitantly administered dried aluminum hydroxide gel or aclatonium napadisilate after a meal. The bioavailability of cefteram pivoxil was not influenced by coadministered drugs, probably because this study was performed after a meal.

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The fluorescence polarization immunoassay (FPIA) method for determination of cyclosporin in whole blood was evaluated and compared with the high-performance liquid chromatography (HPLC) and the radioimmunoassay (polyclonal-RIA) methods. The coefficients of variation for the within-run and between-run precisions were 5% and 7%, respectively, for samples ranging in concentration from 350 to 1, 750 ng/ml. Recoveries were determined by adding cyclosporin at concentrations from 250 to 1, 750ng/ml to patient whole blood ; they were, on the average, 98.1%. The calibration curve was stable throughout a 10-week study period. There was no clinically significant interference for the FPIA assay due to icterus, lipemia, or other commonly used drugs. There was considerable variation of the ratio of the FPIA result to the HPLC result, whereas there was a good correlation between the FPIA and the polyclonal-RIA results (Y=0.9X-27.2, r=0.983, n=45, P<0.005), when evaluated using specimens from renal transplant patients receiving cyclosporin orally. In clinical practice, although higher blood levels of cyclosporin by the FPIA do not always correspond to more abnormal results in the clinical laboratory tests, an elevation of the trough level by the FPIA should be useful as an indicator of the risk of occurrence of tissue toxicity. It was concluded that the FPIA assay for cyclosporin in whole blood showed sufficient reproducibility and reliability to be used for either emergency or routine analysis in clinical practice, and serves as a practical alternative to the polyclonal-RIA.

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Pharmacokinetics and safety of salazosulfapyridine were studied using 18 healthy male subjects. Salazosulfapyridine (SASP), 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) degraded from SASP in large intestine, N⁴-acetyl-SP (Ac-SP), N⁴-acetyl-5'-OH-SP (AcOHSP) and N⁴-acetyl-5'-OH-SP-o-glucuronide (AcSP-Gluc) as SP-metabolites and acetyl-5-ASA (Ac-5-ASA) as metabolite of 5-ASA, were examined by means of HPLC. 1) Single-dose study: In the groups dosed at 500, 1, 000, and 2, 000 mg of SASP respectively, t_max was 5. 69-6. 88 hr, t_1/2 was 3. 23-4. 01 hr, and excretion into urine was 3-8% ; thus, absorption of SASP through gastrointestinal tracts was considered to be low (less than 10%). Between the groups dosed at 1, 000 and 2, 000 mg respectively, an increase of dose-correlative C_max and AUC was not noted, suggesting a possibility that absorption is saturated at the higher level of dosage. The t_max of SP delayed to 12. 45-16. 82 hr, while t_1/2 was 6. 10-7. 69 hr and excretion into urine was 34. 6-71. 5% respectively. In all the groups, concentrations of Ac-SP were higher than those of SP, which showed that all the subjects in this study had very good metabolic reactions. Recovery of 5-ASA from feces was about 45%. Dosage after meals revealed delayed t_max and reduction of C_max and AUC in both SASP and SP. 2) Multiple-dose study: Pharmacokinetic parameters of SASP on the 8th day under the multiple-dose study for 8 days revealed an increase of C_max (8. 17 vs 11.52 μg/ml), and AUC (47.98 vs.83.36 μg/hr/ml) compared with that df the first day, but no change was noted in t_max (5.17 vs. 5.98 hr), t_1/2 (2.90 vs. 3.00 hr), and kei (0.24 vs. 0.25 hr^-1). Steady-state in the serum SASP concentration was reached approximately within 4 days. No accumulation of SP was noted after 8 days of administration. Concentration of total SP metabolites (Ac-SP+AcOH-SP+AcSP-Gluc) indicated values 4 to 5 times higher than that of SP, but 72 hr after the final administration nearly all of them were eliminated out of blood. No special change in clinical laboratory test was noted except two cases exceeding the normal level of GPT upon the test. As the clinical symptoms, gastrointestinal findings such as discomfort in the stomach (1 case) and lower abdominal pain (1 case) as well as mucocutaneous findings such as stomatitis (2 cases) were noted, none of which, however, were serious. From these results of pharmacokinetics, safety, and tolerance of the enteric coated tablet of salazosulfapyridine in Japanese healthy subjects, it is indicated that the next clinical trial can proceed.

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Carvedilol (DQ-2466) is a new β-blocker with vasodilating properties. In order to investigate the hemodynamics and safety of carvedilol after single oral administration, in a placebo controlled manner, each group of 5 healthy male volunteers was treated with ascending doses of 20, 40, or 60 mg. The following results were obtained: (1) Both systolic and diastolic blood pressures at rest decreased significantly from 2 hr to 24 hr after administration of carvedilol at each dose level (P<0.05-0.001). Maximum decreases of systolic and diastolic blood pressures were achieved at 3-4 hr after administration. The changes of systolic blood pressure (SBP Δ%) were 4. 2, 14. 6, 16. 2, and 16. 6% in placebo, 20, 40, and 60 mg group, respectively, at 3 hr after dosing. The changes of diastolic blood pressure (DBP Δ%) were 0.5, 16. 1, 13. 3, and 18. 8% in placebo, 20, 40, and 60 mg group, respectively, at 4 hr after dosing. There was no significant difference in the changes of pulse rate (PR Δ%) at rest between carvedilol administration group and placebo admistration group.(2) Stroke index (SI) and cardiac index (CI), which were determined by echocardiography, were not affected in the 20 mg group.SI and CI slightly decreased in the 40 mg group in comparison with the placebo group.There was a tendency of decrease in these parameters in the 60 mg group.Total peripheral vascular resistance (TPVR) decreased significantly at 4 and 29 hr after 20 mg dosing.(3) The increase of systolic blood pressure on treadmill exercise was significantly reduced with dose-dependency in carvedilol administration groups for 9 hr after dosing.(4) There were no abnormal laboratory findings. No subjective symptoms were observed in the placebo and the 20 mg group.One of 5 subjects in the 40 mg group 4 of 5 subjects in the 60 mg group showed slight dizzy feeling, heavy-headedness, nausea, and dizziness.(5) In conclusion, carvedilol appears to maintain marked hypotensive effects up to 24 hr after single oral administration of 20 mg, which was the lowest dose in this study. At less than 40 mg, there were no clinically significant subjective symptoms. This suggests that maximum daily dose should be less than 40 mg in the future investigation for multiple dosing.

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Following the investigation of single oral doses of carvedilol (DQ-2466) in healthy male volunteers, multiple dosing studies of 2 and 14 days were conducted to evaluate the hemodynamics and safety of the drug. In the 2-day multiple dosing study, daily doses of 20 mg and 40 mg were tested each for 4 regimen groups (i. e. 10 mg, 20 mg twice daily, 20 mg, 40 mg once daily). With respect to 14-day multiple dosing, a 20 mg once daily regimen was used. The following results were obtained: 1) Decrease of systolic and diastolic blood pressures at rest was enhanced on day 2 both for the once and the twice daily regimen in the 2-day multiple dosing. In the 14-day multiple dosing, decrease of systolic and diastolic blood pressures at rest was gradually enhanced up to day 7, and the decreased blood pressures were stabilized thereafter. Circadian variation of blood pressures was studied on the day of placebo (day 0), days 1, 7, and 14. The systolic and diastolic blood pressures on days 7 and 14 were roughly 10mm Hg and 7-8mmHg lower during the day, respectively, than those on the day of placebo (day 0). 2) Pulse rate at rest was shown to have a tendency of decrease on day 2 in the 40 mg once daily group, but there were no consistent changes in the other dose groups in the 2-day multiple dosing. In the 14-day multiple dosing, the decrease of pulse rates at rest was slight, 5 beats/min. 3) In the once daily dosing for 2 days, the increase of heart rate on treadmill exercise was significantly reduced for 29 hr after the dosing on day 2 with dose-dependency. 4) Echocardiographic examination at rest revealed no significant changes in the hemodynamic parameters obtained in the 2-day multiple dosing study. In the 14-day multiple dosing, cardiac index (CI) was significantly decreased on day 2 and day 3, but there were no remarkable changes in CI on the other days. Total peripheral vascular resistance (TPVR) did not change during the study. 5) There were no clinically significant abnormal laboratory findings in the 2-day and 14-day multiple dosing studies. Transient slight dizzy feeling was noted in 2 of 5 subjects both in the 20 mg twice daily and the 40 mg once daily regimen of the 2-day multiple dosing. In the 14-day multiple dosing, 3 of 5 subjects showed slight palpitation, slight dizziness, and slight nausea on day 7 and thereafter. 6) In conclusion, it is suggested that carvedilol can be administered in the patients of hypertension and angina pectoris at 20 mg or lower doses once daily.

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Carvedilol is a newly developed β-blocking agent with vasodilating activities. The pharmacokinetics of carvedilol has been studied in healthy subjects following the single and multiple oral administration of the drug. In the single oral study, it was clear that the disposition of carvedilol is adequately described by a two-compartment model with first order absorption. Carvedilol was rapidly absorbed within 1.6 hr following oral dosing. The half-lives ranging from 6 to 14 hr are estimated. The study indicated that carvedilol follows linear pharmacokinetics with a slight deviation from linearity in the range of 5 to 60 mg dose. The deviation is attributed to about 4-fold inter-individual variation observed for AUC. Carvedilol is not excreted into urine, suggesting that the drug is eliminated from plasma primarily by metabolism. It is considered that the wide interindividual variation is attributed to variaton in hepatic first-pass metabolism of carvedilol. The plasma level of carvedilol glucuronide was about 2-fold greater than that of carvedilol and desmethyl carvedilol was 5 times lower than that of carvedilol. During the multiple oral administration of carvedilol for 14 days at a daily dose of 20 mg, plasma profiles showed no accumulation of the drug. The predicted steady-state for carvedilol is attained on day 11, and Css (max) and Css (min) values for the drug are calculated to be 46.4 and 2.1 ng/ml, respectlvely.

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A simple method for acetylator phenotyping with caffeine was studied. Three hundred milligrams of caffeine was given orally to 39 consanguineously unrelated healthy Japanese subjects and urine was collected over 24 hr. 5-Acetylamino-6-formylamino-3-methyluracil (AFMU) is formed by acetylation ; four other major metabolites [1-methylxanthine (1X), 1-methyluric acid (1U), 1, 7-dimethylxanthine (17X), and 1, 7-dimethyluric acid (17U)] are formed by oxidation. Their urinary concentration was measured by HPLC. The frequency histogram of 24 hr urinary molar. excretion ratio of AFMU to 1 X (AFMU/1 X) showed a bimodal distribution as well as AFMU to total major metabolites [AFMU/ (1X+1U+17X+17U+AFMU)]. Five of 39 subjects (12.8%) were determined to be slow acetylators by AFMU/ (1X+1U+17X+17U+AFMU) and were identical to those of slow acetylator considered by AFMU/1X. A similar bimodality was also shown in the distribution of AFMU/1X using pooled 2 hr urine (2 to 4 hr after ingestion of caffeine). Concordance for slow acetylators was also observed between AFMU/1X using pooled 2 hr urine and AFMU/ (1X+1U+17X+17U+AFMU) using pooled 24 hr urine. These results indicate that an individual acetylator phenotype could be determined by AFMU/1X of pooled 2 hr urine.

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The effects of coenzyme Q₁₀ (CoQ₁₀) on blood rheology were studied in patients with ischemic heart disease. Twenty milligrams of CoQ₁₀ was administrated per os three times daily (total dose 60 mg per day) for two months. Whole blood viscosity was measured at the shear rates of 37.5, 75, 150 and 375 sec^-1 with a conplate type viscometer. Whole blood viscosity at each shear rate was decreased after administration of CoQ₁₀. Casson viscosity and yield shear stress were calculated using the Casson plot method from the blood viscosity at each shear rate. Yield shear stress was significantly lowered after administration of CoQ₁₀, while Casson viscosity was not significantly changed. Both the hemolysis starting point and hemolysis end point represented by mOsm were determined by means of the coil plant centrifuge method. These parameters, which reflect osmotic fragility of erythrocytes, showed significant decreases after administration of CoQ₁₀. After the blood was diluted with a phosphate buffer solution, passage time through the Nuclepore membrane with a pore size of 5 μm was measured 10 min after the in vitro administration of CoQ₁₀ of 5 μg. This passage time was significantly shortened after administration of CoQ₁₀. There were no significant changes in hematocrit and fibrinogen after administration of CoQ₁₀. These results show that administration of CoQ₁₀ improves hemorheology in ischemic heart disease, and thus suggests that oxygen transport to heart muscle is increased by treatment of CoQ₁₀.

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To assess the clinical efficacy of L-camititine in chronic heart failure, we measured echocardiographic left ventricular dimensions, peak oxygen consumption (peak V_o2), and anaerobic threshold (AT) before and after a long-term administration of L-carnitine (1, 800 mg/day, 12 weeks) in 18 patients with left ventricular dysfunction (I to III in New York Heart Association fuhctional classification). Peak V_o2 and AT were determined by the continuous respiratory gas analysis during a symptom-limited maximal bicycle exercise test. The patiehts were divided into 2 groups according to the presence of exercise-induced ST depression (>0.1 mV) in the control exercise test: 9 patients with ST depression (Group I) and 9 patients without ST depression (Group II). In Group I, exercise-induced ST depression was significantly improved by the chrohic admihistratioh of L-carnitine (0.17±0.03 mV to 0.12±0.03 mV, mean±SE, P<0.05). Coincidentally both peak V_o2 and AT significantly increased after L-carnitine administration when compared to those before administration in Group I (21.3±2.5, 17.2±27 to 24.3±2.3, 20.2±2.3 ml/min·kg, re spectively, mean±SE, P<0.05). In Group II there was no sighificant change in electro cardiographic findings, peak V_o2, or AT by the drug administration. The intemal dimensions and the fractional shortening of the left ventricle were not altered by the L-carnitineadministration in both grotips. Thus, we conclude that L-carhitine can increase exercise capacity in patients with chronic heart failure when they are attended with exercise-induced ST depression, possibly by improving abnormalities in the myocardial fatty acidenergy metabolism during exercise.

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To investigate the effect of Amrinone (AMR) on left ventricular regional wall motion, we performed contrast ventriculography before and after administration of AMR in patients with myocardial infarction. Three patients had anterior myocardial infarction, one had inferior infarction, and one had posterior infarction. All patients had abnormal regional wall motions corresponding with the territory of electrocardiographic abnormal ities. In four of the five patients the regional wall motions of the infarct area were improved by administration of AMR (1mg/kg). The results suggest that the positive inotropic effect of AMR may influence not only normal myocardium but also stunned myocardium.

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This is a report of cyclosporine (CYA) therapy with trough level monitoring in whole blood and individual pharmacokinetic studies by high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) in 19 renal transplant recipients. The correlation coefficient for the values obtained by HPLC and FPIA was 0.90. However, the values with FPIA based on polyclonal antibodies were approximately twice those with the HPLC method. The patients were given two equal doses (8: 00 am, 8: 00 pm) of CYA orally. The morning trough level/night trough level (M/N) ratio of CYA with the initial dose was significatly higher than that of the maintenance dose (HPLC, P<0.05 ; FPIA, P<0. 001). In the individual pharmacokinetic studies in 4 patients, the C_max and AUC following the night CYA dose were smaller than with the morning dose in all patients.

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