A phase I study of EST, a newly synthesized specific thiol protease inhibitor developed as a drug for muscular dystrophy, was performed in healthy adult male volunteers to investigate its safety and pharmacokinetics. EST was administered orally in single doses of 100 mg during fasting, or of 100 mg or 200 mg after a meal. The following results were obtained.
The clinical tests and observation of the subjective and objective signs and symptomsfound no change due to EST.
EST was detected as E-64-c (effective form of EST) in serum and urine after oral administration. The absorption of EST was slower when administered after a meal than during fasting. The AUC (area under the serum concentration curve) and urinary excretion rate were greater following administration after a meal, which indicates a tendency to better bioavailability of EST.
As for the comparison of 100 mg and 200 mg administration after a meal, a distinct dosedependency was observed in the serum concentration and urinary excretion.

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A simple and sensitive method for quantifying 2-chlorophenyl-N-desmethyldiazepam (CND), which is the major metabolite in plasma after administration of mexazolam, has been developed using gasliquid chromatography equipped with electron capture detector (GC-ECD). After extraction with benzene from 2ml of plasma specimens, CND could be quantitated to a lower limit of 0.1 ng/ml. A single oral dose of mexazolam was administrated to ten healthy subjects in order to reveal the pharmacokinetics of mexazolam. The time course of CND in plasma followed the equation of a twocompartment model with an appearance lag time. The mean peak plasma level, 6.80±0.68 ng/ml, was attained at 2.01±0.55 hours after administration of mexazolam, and the apparent elimination half life was 76.4±6.35 hours. The speculated plasma CND profiles reached approximately 90 % of the steady state levels on the 11th day after the initiation of repetitive doses of mexazolam. The calculated average plasma level at steady state, Ca^ss_sv following the hypothetical dosage schedule (3 mg of mexazolam administrated per day), was about 65 ng/ml.

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A transdermal therapeutic system (TTS) containing nitroglycerin (NTG) was applied to 11 healthy male volunteers. The application doses used in this study were of two .different dosage strengths (TTS-NTG 25 mg/10 cm² and TTS-NTG 50 mg/20 cm²).
Plasma NTG concentration was measured by using gas chromatography-mass spectrometry (GC-MS), with ¹⁵N-NTG as internal standard.
Plasma concentration rose clearly at 1-2 hours after application of the system, and the concentration maintained a steady level .all throughout the application.
Mean plasma levels over the interval of time 2-24 hours after application of TTS NTG 50 mg/20 cm² were approximately 2-fold that of TTS-NTG 25 mg/10 cm².
In the data of the subjective symptoms, headache and/or head heaviness were reported much more frequently than other symptoms, and these symptoms grew in intensity with increase of the dosage strength.

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The most common side effects occurring with chenodeoxycholic acid (CDCA) therapy are diarrhea and elevations of serum transaminases. However, the frequency of these adverse reactions have varied among studies. It is the purpose of this study to estimate the frequency of adverse drug reactions and the predisposing factors that seem to affect the development of adverse drug reactions. Twenty-three papers on gallstone dissolution therapy, appearing between 1976 and 1982 in Japan, were examined.
Of 401 patients surveyed, 299 (74.6 %) were females and 102 (25.4 %) were males. The mean age of females and males was 47.5 and 47.2 years respectively (range 17-78 years). In both sexes, no age-related differences in the incidences of diarrhea and abnormal liver function were observed. Likewise, no significant sex differences were found in the incidences of diarrhea and abnormal liver function. Diarrhea occurred in 12.5 % of the patients receiving less than 400 mg/day, and 33.1% in those receiving over 400 mg/day, and abnormal liver function was also more frequent in the patients receiving over 400 mg/day.
There were significant differences in both adverse drug reactions corresponding tothe daily doses. Diarrhea occurred in 8.2% of the patients receiving 200 mg 2 times daily after the morning and evening meals, 15.9% of the patients receiving 100 mg 3 times daily after each meal, and 33.3% of the patients receiving 200 mg 3 times daily after each meal. The incidence of diarrhea was significantly higher in the dose group receiving 200 mg 3 times daily than in the other groups. The incidence of abnormal liver function in the three different dose groups showed a trend similar to that of diarrhea. When CDCA was administered daily in two divided doses, the incidence of abnormal liver function was significantly lower than that obtained after administration in three divided doses. It is considered that the frequency of side effects of CDCA is related to both the daily dose and the dose timings.

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The efficacy of oral theophylline as a 10% alcoholic solution at a dose of 2 mg/kg/12 hr was examined in 15 premature infants with idiopathic apnea . With a plasma theophylline concentration of 6.3±0.8 μg/ml (mean ± S .E.) or total methylxanthine as a theophylline (theophylline + caff eine) concentration of 7.8±1.2 μg/ml, all in fants experienced complete cessation of apneic spells. Mild adverse effects such as tachycardia and vomitting were observed in 2 infants with plasma theophylline concentration of 8 to 9 μg/ml. Since both the effective and the toxic concentration of theophylline varied from infant to infant, the optimum concentration of theophylline should be adjusted individually.
In a pharmacokinetic study, the plasma half-life of theophylline in 5 infants was 23.5±2.3 hr and the apparent volume of distribution in 4 infants was 0.81±0.041/kg. The plasma elimination rate constants of theophylline increased with postnatal age or postconception age (gestational age + postnatal age) and correlated significantly with postconception age. A dosage adjustment is needed in long-term therapy of apnea in premature infants according to their postconception age.

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The bioavailability of theophylline following administration of two pediatric sustained release tablets (Theona-P^® and Theo-Dur^®), two crushed sustained release tablets (crushed Theona-P^® and crushed Theo-Dur^®), and newly developed sustained release granules (E-0686-023, investigational drug) was studied in four volunteers by measuring salivary concentrations. The pharmacokinetic parameters t_max and MRT (mean residence time) for crushed Theona-P^® and crushed Theo-Dur^® were significantly shorter compared to Theona-P^®, Theo-Dur^®, and E-0686 granules, but the AUC_0-∞ values were not different among them. The results show that each preparation is equivalent in the extent of bioavailability but not in the rate of bioavailability. More frequent administration is required when crushed Theona-P^® or crushed Theo-Dur^® are taken, and sustained release granules are desirable in children with chronic asthma who cannot swallow tablets.

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Azthreonam (SQ26, 776), a new, completely synthetic, monocyclic β-lactam antimicrobial agent, was administered to 29 healthy, Japanese male volunteers by intravenous bolus infusion, intravenous drip infusion, and intramuscular injection as single doses, and intravenous bolus infusion as multiple dose. The pharmacokinetics of single intravenous doses of 500 mg, 1000 mg and 2000 mg were best described by a linear open two-compartment model. The mean peak serum levels were proportional to the doses but the mean serum half-life was essentially independent of the dose administered (t_1/2=1.5-1.8h).
The urinary excretion within 24h ranged from 60-70% of the dose administered as intact azthreonam. Usually, intravenous doses were primarily excreted in the 8h urine. The pharmacokinetics of an intramuscular dose of 1000 mg fitted a linear open one compartment model with a mean peak serum level of 66μg/ml at 1h after dosing, and the urinary excretion rate was 80% of the dose administered within 24h. In the multiple dose regimen with 1000 mg of azthreonam administered intravenously to six healthy male subjects every 12h for 5 days, the mean peak serum levels and urinary excretions did not suggest any evidence of drug accumulation. The results of physical examinations and laboratory tests indicated azthreonam was well tolerated with only moderate reversible elevation of CPK values in all subjects at 24h after intramuscular administration.

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Aprindine hydrochloride, a relatively new Class I antiarrhythmic agent, is known for its effectiveness in treating cardiac rhythm disorders, especially in ventricular arrhythmias. We investigated the pharmacokinetic parameters, clinical effects on ventricular premature contractions (VPCs), and minimal effective plasma levels in 29 patients with frequent VPCs after administration of a single 100 to 150 mg oral dose of aprindine. The plasma concentration curve of a single oral dose of aprindine was described best by a two-compartment open model in the majority of patients studied.
The mean value for the maximum plasma level (C_max) and the time to C_max (T_max) were 0.77μg/ml and 2.9 hours, respectively. The mean plasma half-life (T_1/2β) was 26.5 hours. The number of VPCs per hour was significantly reduced after admini stration of aprindine for 2 to 11 hours continuously in 24 patients in whom analyzable Holter dynamic ECG recordings were made both before and after drug administration. The drug was judged to be effective according to our clinical evaluating criteria in 14 of the 24 patients (58%), with decreases in the VPC/hr rate of at least 80% shown for 2 or more hours consecutively during the period 2 to 11 hours after administration of aprindine. The mean effective time was 7.8 hours. The minimal effective plasma level was defined as the concentration at the end of the period of effectiveness and ranged from 0.13 to 0.68 μg/ml (mean 0.38 μg/ml).

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To investigate the hemodynamic effects of isosorbide-5-mononitrate (ISMN), 11 patients with effort angina pectoris were studied.
Hemodynamic and echocardiographic measurements were observed at rest and during angina-limited supine multi-stage bicycle ergometer exercise testings before and 120 min after oral administration of 20 mg of ISMN. Compared with the control exercise test, the mean ST-segment at peak exercise showed less depression after ISMN (P<0.001). At rest there were significant decreases in systolic and diastolic blood pressures after ISMN (P<0.001 and P<0.05, respectively). Both at rest and peak exercise there were significant decreases in pulmonary capillary wedge pressure (both P<0.0001), left atrial volume (both P<0.001), and left ventricular end-diastolic volume (both P<0.05), while cardiac index, pressure-rate-product, and systemic vascular resistance remained unchanged. The average peak value for plasma ISMN concentration was 460 ng/ml at 90 min after dosing, and the elimination half-life was 7 hours.
These data would indicate that the antianginal effects of ISMN, which is appropriate for its prolonged duration of action, are mainly related to diminishment of myocardial oxygen requirements due to left ventricular preload reduction as a common mechanism.

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