The exercise tolerance and plasma concentration of a long acting isosorbide dinitrate (ISDN) NRR were studied in 6 patients with stable effort angina after 6 hr of therapywith 20 mg of NRR using symptom-limited multistage ergometer exercise. The results weresummarized as follows.
(1) The initiation time of chest pain was significatly prolonged (P<0.05) with animproved work tolerance after a single oral dose of NRR 20 mg.
(2) A peak of mean plasma concentration of ISDN was reached at 4 hr after a singleoral dose of NRR 20 mg, and its concentration level over 20 ng/ml persisted for 2-6 hr.Moreover, 42% of the peak plasmaconcentration of ISDN was noted at 8 hr after dosing.
(3) Against the same work load and double product ST depression was significantlyimproved after administration as compared to that before dosing.
(4) The effect of NRR 20 mg on work tolerance lasted for 6 hr.
These results suggest that NRR is effective for 6 hr and that more than 42% of thepeak plasma ISDN concentration remains for 8 hr after a single oral dosing.

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In order to discuss the safty of epidural anesthesia with continuous infusion method, therelationship between serum concentration of mepivacaine and time laps during continuousepidural infusion was observed in 44 patients who underwent laparotomy.
Continuous epidural infusion was started at the rate of ko (mg/hr) at τ (min) after initialepidural injection with about 200 mg mepivacaine HC1. Patients were divided into fourgroups by τ/k0 as follows: 20/100, 20/120, 30/150, and 60/150.
Significant difference of serum mepivacaine concentration in four groups during continuousepidural infusion was not observed. Mean serum mepivacaine concentration of each groupat 4-5 hr after initial injection (3-4 hr after a start of continuous infusion) was about 5-6, μg/ml. Thus it was suggested that serum concentration of mepivacaine was at the safety levelduring surgery for 5 hr with continuous epidural infusion of 100-150 mg/hr mepivacaine HC1.
In the group where τ=60, additional bolus epidural injection was necessary for half ofthe patients before and after a start of continuous epidural infusion. Therefore, continuousinfusion ought to be started by 60 min after initial injection (200 mg) in our methods.

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This study was undertaken to assess the interaction between alcohol and betablocker onthe body equilibrium function. Six healthy male subjects ingested alcohol (1 ml/kg) within10 min after administration of a beta-blocker. The equilibrium disturbance following ingestion of alcohol was evaluated as an increase in area of the center of gravity (ACG), because the ACG after alcohol ingestion had been shown to increase in parallel with theblood concentration of alcohol. Either treatment with metoprolol (40 mg) or pindolol (10mg) augmented the increase in ACG by alcohol, but atenolol (50 mg) did not affect it.Alcohol induced decline in critical flicker fusion (CFF) threshold. The decline in CFFinduced by alcohol was also augmented after administration of metoprolol and pindolol, butnot atenolol. Each beta-blocker itself had no effect on ACG nor CFF. Blood levels ofalcohol were unaffected by treatments with beta-blockers, though metoprolol tended toshorten the elimination of alcohol. These results indicated that lipophilic beta-blockers, metoprolol and pindolol, augmented the alcohol-induced equilibrium disturbance, conceivablyby their interaction with alcohol at brain. In contrast, atenolol, a hydrophilic betablocker, did not influence the effect of alcohol on the central nervous system.

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Effects of pre-operative administration of ranitidine on pH and volume of gastric juicewere evaluated in 42 patients undergoing elective surgery under general anesthesia. Allpatients were randomly divided into two groups: placebo group (group P), and ranitidinegroup (group R).Patients in group P received placebo (lactose) and served as controls.Patients in group R received ranitidine 300 mg orally at 9: 00 p.m.on the day before surgeryand 50 mg iv immediately after induction of anesthesia (9: 15a.m.). The pH and volumeof gastric juice were measured during induction of anesthesia and every one hour duringsurgery in both groups by continuous sampling of gastric juice utilizing a low-pressuremethod. Plasma ranitidine levels were measured by high performance liquid chromatographyin 5 patients of group R and compared with those of oral administration alone in 6 patientsand of iv administration alone in 6 patients. The gastric pH just after induction of anesthesiawas lower than 2. 5 in 67% of group P and 4% of group R (P<0.05). The gastric volumeover 25ml was seen in 17% of group P and none of group R. There were significantelevations in gastric pH at induction and 1, 2, 3, 5, and 6 hr following induction ofanesthesia in group R compared with group P. The total volume of gastric juice during 4-5hr surgery were 20 ml in group R and 37 ml in group P respectively (P<0.05). Theplasma ranitidine levels 3 hr after iv administration were 186 ng/ml in group R and 128ng/ml in patients of iv administration group alone (P<0.05), and 78ng/ml in patients oforal administration group alone. It is essential to keep gastric pH over 2.5 and gastricvolume less than 25 ml in order to prevent aspiration pneumonitis during anesthesia.Therefore, our data indicate that pre-operative administration (oral plus intravenous) ofranitidine is sufficiently effective to prevent aspiration pneumonitis related to acidity and volume of gastric juice during anesthesia.

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This study was designed to investigate the effectiveness, hemodynamic effects, and serummexiletine concentration in senile hypertensives with repetitive ventricular arrhythmias.Mexiletine, 100mg t. i. d. was administered in 10 senile hypertensives. Blood pressure, echocardiogram, 24-hr ambulatory ECG were obtained before and after medication. Serummexiletine concentration was measured by HPLC (High Performance Liquid Chromatography). Cardiac output, mean velocity of circumferential fiber shortening were calculatedfrom LVDd, LVDs, HR, ejection time by echocardiogram. The effcacy of mexiletine wasassessed by 24-hr ECG with comnuter analysis.
No repetitive ventricular arrhythmias were found in all patients by administration ofmexiletine. Number of ventricular arrhythmias decreased from 925 to 120 per day. Althoughthey have low cardiac performance, no significant change was found in hemodynamics. Theaverage of serum mexiletine concentration was 0.75 μg/ml (equal to that of adult). Seriousuntoward effects were not found in all patients.
In conclusion, orally administered mexiletine was very effective in the treatment ofrepetitive ventricular arrhythmias in senile hypertensives with conventional doses similarto that in middle-aged subjects and also, HPLC was thought to be superior to gas chromatography because of its rapidity, accuracy, and lower cost.

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The inducing effect of carbamazepine (CBZ), an antiepileptic agent, on hepatic drug-metabolizing enzymes in children, receiving CBZ with and without phenobarbital (PB), has been studied. The ratio of 6β-Phydroxycortisol (6β-OHF) to 17-hydroxycorticosteroids (17- OHCS) in urine was measured to evaluate individual oxidative drugmetabolizing capacity.
The ratio in the group receiving CBZ was 0. 113 ± 0. 048 (mean ± S. D.) and the group receiving PB was 0. 080 ± 0. 028, showing significant elevation from the steady level (0. 031 ± 0. 008) which was the ratio in the normal group.
In the group receiving CBZ and PB simultaneously, the ratio (0. 182 ± 0. 074) was over six times that in the normal group ; moreover, it was significantly higher than those in the groups receiving CBZ and PB alone.
These results indicate that intensity of enzyme-inducing effect of CBZ, in children, is comparable to that of PB and even more increased by the combined use of PB.

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The effect of methylcobalamin on the autonomic nerve structure in the spontaneously diabetic BB rat was studied electron microscopically with quantitative analysis. The diabetic BB rats were divided into two groups, one of which was treated with daily intramuscular injection of methylcobalamin (500 μg/kg) for 8 wk from the third month after the onset of diabetes, and the other was treated with saline for the same duration. Age- and sexmatched normal Wistar rats served as normal controls. Blood glucose levels of the diabetic rats were maintained at more than 300 mg/dl throughout the observation period in both groups, but the body weight of the treated group significantly increased in comparison with no increase in the nontreated group.Electron microscopically, axonal degenerative structures exemplified as Schwann cell ingrowth, membranous profiles, and type 2 fibers, were significantly reduced in the treated group.Axonal dystrophic changes, the most representative structural hallmark of diabetic autonomic neuropathy, were also reduced in number in the treated group although it was insignificant when compared with non-treated group.Morphometric analysis revealed near normalization of unmyelinated nerve fiber density, fiber number, and mean fiber size in the treated group.The histogram of fiber caliber spectrum displayed a significant shift to the left in the non-treated group, while that of the treated group remained as almost normal with a significant rise in the population of small fibers. Thus, eight-week treatment with methylcobalamin on the diabetic BB rat showed a beneficial effect on the autonomic nerve morphology and therefore it was suggested that this treatment regimen can be applicable to clinical use.

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Pharmacokinetic and pharmacological effects and safety profile of doxazosin mesilate, a new quinazoline α1-adrenoceptor blocking agent, were studied in six Japanese healthy adult male volunteers. Doxazosin 0.5 mg, 1 mg, or 2 mg was orally administered at two-week intervals.
The pharmacokinetic data were well fitted to a two-compartment model. Peak plasma concentrations of doxazosin were dosed-ependent and attained at 1 .6-1.7 hr after dosing. Mean terminal elimination half-lives were 15. 62±5. 12 hr for the 1 mg and 10. 14±3.32hr for the 2 mg.
Blood pressure and pulse rate were determined in the sitting, supine, and 50° tilt positions. The maximal reduction of blood pressure was observed during 4-8 hr after adminis-tration, with a corresponding increase in heart rate.
With the postural change from supine to 50° tilt position, the fall of systolic blood pressure was more pronounced in the tilt posture than in the supine position at 4-6 hr after dosing.
During exercise with a bicycle ergometer, the exerciseinduced increases in heart rate and systolic blood pressure were attenuated with doxazosin.
Three hours after administration, one of the six volunteers complained of dizziness while taking 0.5 mg and 2 mg tablets. Except for elevated serum triglyceride noticed, in one volunteer, notable abnormalities were not observed in laboratory findings .

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The anti-platelet aggregating action of minidose aspirin and its combined effect with dilazep were examined in healthy male volunteers. A quantitative and dose-dependent decrease in platelet aggregability was observed on a single oral administration of 30 mg, 100 mg and 300 mg of aspirin and also on the repeated oral administration of 10 mg and 30 mg three times a day for 5 days. Administration of 100 mg of dilazep in combination with 30 mg or 100 mg of aspirin produced an anti-platelet effect equivalent to a 3-fold dose of aspirin alone. In the repeated administration test, the t. i. d. admin-istration of aspirin 10 mg+ dilazep 100 mg was confirmed to be close to the ideal in the balance between anti-platelet action and the reduced production of PGI₂

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The pharmacokinetics of tobramycin were studied in two groups of elderly people. Sixteen aged people (65-97 years old) participated in the study after giving informed verbal consent. They were divided into two groups: group I consisted of the age group 65-79, and group II consisted of 80-97 years old.
Tobramycin was administered intravenously with an infusion pump over lhr. Blood samples (3 ml) were collected at 7 time points via an indwelling catheter placed in the forearm. Serum creatinine, beta-2-microglobulin, and tobramycin concentrations weremeasured. The values obtained were compared between the two groups. Serum creatinine showed no significant differences in the 2 groups, whereas beta-2-microglobulin was significantly higher in group II (3. 35 ± 0.95) than in group I (2.25 ± 0.48). The elimination rate constant of tobramycin was determined from 7 postinfusion serum concentrations using linear regression on a natural logarithm concentration-versus-time graph. Half-life was calculated by dividing the elimination rate constant into 0.693. The half-lives of these 2 groups were 2.5± 0.47 (hr) and 4.2± 1.2 (hr) respectively and they were significantly different. The serum beta-2-microglobulin concentration correlated with the half-life of this drug in all subjects. Due to the large degree of interpatient variability observed, individualization of tobramycin doses using serum concentration monitoring may help to rapidly achieve desired steady-state levels.

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