S-596, a newly developed, α, β-blocking agent, was orally administered to 6 male healthy volunteers and the time course of pharmacokinetics and pharmacodynamics were studied.
Blood pressure and heart rate, at rest, decreased slightly at 2-4 hrs after administration of drug with significant changes. Exercise-induced elevations of systolic blood pressure and tachycardia were suppressed beyond 12 hrs after the administration. Biological half-life of β-blocking activity, based on the declining curves of double products, was 11.2 hrs
Resting mean velocity of circumferential shortning, ejection fraction and cardiac index showed significant decreases for 4 hrs and these maximums at 2 hrs. Pre-ejection period and PEP/ET showed tendency of increments. Peripheral vascular resistance seemed to increase at 2 hrs but returned to initial levels at 4 hrs.
Serum concentration of S-596 reached to the maximum at 2 hrs and the elimination half-life was 7.2 hrs.

View full abstract

Mexiletine is a new antiarrhythmic agent which resembles to lidocaine electrophysiologically and is available for oral use. We investigated pharmacokinetic parameters and clinical effects on ventricular premature contractions (VPCs) of a single dose of mexiletine in 27 patients with frequent VPCs. The maximum concentration (Cmax) and the area under the time-concentration curve (AUC) increased dose-dependently, and the time to the maximum concentration after oral administration was 3.0 hours. There were significant correlations between dosage (mg/kg) and Cmax (r=0.87, p<0.01) or AUC (r=0.91, p<0.01). The biological half life in the elimination phase was 12.6 hours. The percentage of twenty-four hour cumulative urinary excretion of unchanged mexiletine was 7.87%. We investigated the suppressive effects on VPCs in 10 patients, who showed more than 300 VPCs per hour before administration of the drug in Holter dynamic ECG. Mexiletine was effective in suppression of VPCs in 5 patients (50%), in whom the single dosage of mexiletine was more than 200 mg. The minimum effective plasma concentration derived from these 5 patients was 0.59, μg/ml. Serious untoward effects were not observed at all, and PR, QRS, or QTc interval remained unchanged after administration.
In conclusion, oral use of mexiletine is effective and safe to suppress VPCs.

View full abstract

In order to evaluate the efficacy of Ch'an Su containing drug in improvement of acutemountain sickness, the effect on the cardiac output (CO) was examined in 19 experiments with five healthy, 21 to 29 years old, males during exposure to 7, 000 maltitude conditions simulated by a decompression chamber. The subjects were also loaded by exercise with bicycle ergometer during the stay. Five minutes after exercise the single oral administration of the drug (5 mg) or its placebo was taken, then the impedance changes of chest wall, by which the stroke volume (SV) was estimated, and the heart rate (HR) were recorded every 3 or 5 minutes- during the subsequent 20 minutes. CO could be obtained as the product of SV and HR. Although there were considerably large individual differences, the average SV and CO at the 6, 10 and 15 post-drug minutes demonstrated statistically significant increase in comparison with those obtained from the placebo experiments. Further, the data obtained in these increasing periods gave the correlation coefficient of 0.891 for SV to CO relation, while only 0.416 for HR to CO, showing that the CO increase is highly dependent to that of SV. The results suggested that drug acts effectively, and rapidly as well, to improve the cardiac muscle activity against to the hypoxic impairment experienced under extreme high altitude conditions.

View full abstract

“MAPIN” T5, a drug preparation containing Bufonis venenum (The Pharmacopoeia of Japan) as main ingredient was administered to healthy adults, all males ranging 20 to 43 years of age (average 26 years). The dosis was 10 mg po in 5 individuals and 20 mg po in 6 individuals.
1. Within 24 hours after the drug administration no significant changes were observed in pulse rate, body temperature and urine volume. Regarding the blood pressure, diastolic pressure became lowered 5 hours after intake of the drug.
2. There were no significant changes observed in the results of “cardiac function test” before as well as 1 and 2 hours after the drug administration such as isovolumetric contraction time, stroke index, ejection fraction, cardiac index, mean velocity of circumference, pre-ejection period/ejection time and systemic vascular resistance.
3. Continous ECG recording for 6 hours following the drug intake revealed no arrhythmia except coronary sinus rhythm in three cases 1.5 hours after administration 10 or 20 mg of the drug.
4. Laboratory findings of blood and urine were within normal ranges, not only 24 hours after but

View full abstract

Following the first investigation of single dosage of “MAPIN” T 5 in healthy subjects (First report), the effect of the drug was tested by successive daily administration for 7 days in the amount of 20 mg per day (2×10 mg) to 6 male and healthy subjects. Their age was 24.8 years on the average.
The test comprised “cardiac function test”, various laboratory tests and observation of tolerance of the drug.
1. No subjective trouble attending the intake of the drug was observed except for a case where a nausea occurred 1. 5 hours after the drug administration. This, however, was considered to due to an overeating the day before and not to the drug itself.2. Regarding “cardiac function test”, among “systolic time intervals” significant lowering of isovolumetric contraction time and preejection period/ejection time and increase of ejection fraction were observed one hour after the drug intake. These findings are indicative of the existence of cardiotonic effects of “MAPIN” after its oral intake.
3. Among the laboratory tests nothing was to be noted except some elevation in GOT and GP T values of blood though both were within normal limits. This is considered of minor importance but further observation in a more prolonged and continuous administration might be desirable.
4. Detailed study for pharmacokinetics could not be performed this time because the quantitative estimation of concentration of “MAPIN” in the blood was not possible. However the serum samples were preserved in an appropriate refrigerator for future analysis and the results of such analysis in the future will elucidate the fate of the drug in the body.

View full abstract

The present authors had already proposed a criterion for assessing the clinical state of patients with bacterial pneumonia as well as that for evaluating efficacy of antibiotics in the disease. A modified version of this criterion was applied to a recently performed double-blind comparison of cefmenoxime (CMX) and cefotiam (CTM). The two treatment groups, though randomly constructed, were not comparable in their baseline clinical states. Furthermore, the efficacy assessment was affected by the initial state according to the above-mentioned criterion, whereas the relation between the subjective efficacy assessment by the attending physician and the initial state was obscure. In the present paper, we discuss this interesting discrepancy between the two different assessment methods of efficacy and also the results of the statistical analyses by the two methods which adjust for confounding factors; analysis of covariance (ANOCOVA) and logistic regression analysis.

View full abstract

Blood and urine levels of malotilate (NKK-105) (unchanged) and its metabolites after single oral administration of malotilate 100 mg, 200 mg and 400 mg or repeated administration in a single dose of 200 mg three times daily for seven days.were determined for the purpose of elucidating the in vivo behavior of malotilate in normal adults.
After administration, malotilate was absorbed rapidly and well, but its in vivo metabolism was rapid and the blood malotilate level was very low. In blood, malotilate was mostly present as hydrolyzed metabolites (isopropyl hydrogen 1, 3-dithiol-2-ylidenemalonate: M-1) but it cleared up rapidly.In urine, it was excreted as glucuronic acid conjugate of M-1 (M-3).
The blood levels of unchanged malotilate and M-1 was increased along with the doses from 100mg to 400mg.
The rate of excretion of M-3 and isopropyl hydrogen malonate (M-6) into urine remained almost constant irrespective of the doses.
With the two metabolites put together, the rate of urinary excretion was between 37%and 48%.
As to the influence of meal on absorption, the maximum blood level of malotilate and M-1 was slightly higher and the half-life was shorter on postprandial administration than fasting administration, but there was no significant difference in the area under the curve of blood concentration (AUC).
Where malotilate was administered repeatedly three times daily for seven days, changes in the levels showed the same pattern daily, there being no chronological accumulation of blood concentrations of malotilate and M-1.
Chronological changes in the urinary excretion of M-3 and M-6 were hardly observed in both cases.
That is, there is no difference in vivo behavior of malotilate between single administration and repeated administrations. These results suggest that malotilate is almost devoid of the tendency to accumulate in the body.

View full abstract

Carteolol, a new beta-adrenergic blocking drug with intrinsic sympathomimetic activity, and pindolol were compared in 18 normal men in terms of heart rate, blood pressure, double products, cardiac output, stroke index, cardiac work and systemic vascular resistance.
Carteolol decreased the resting heart rate (p<0.01) to a greater extent than pindolol. At the same supine exercise level there was no difference in the exercise heart rate between both drugs. Carteolol did not significantly decrease the resting and exercise systolic blood pressure, while pindolol decreased both blood pressures (p<0.05). The double products decreased with carteolol on exercise; with pindolol double products decreased at rest as well as on exercise (p<0.05). The resting cardiac output was not changed significantly with pindolol, but decreased with carteolol (p<0.01). At each exercise level both drugs decreased the exercise cardiac output to the same extent (p<0.01). Pindolol did not appreciably decrease the stroke index in contrast to carteolol which reduced the resting stroke index (p<0.05). Both pindolol and carteolol reduced the resting and exercise cardiac work with no significant difference between them. Systemic vascular resistance was not significantly changed at rest as well as on exercise with pindolol and increased with carteolol at rest (p<0.01) and on exercise (p<0.001).
It may be concluded that the efficacy of carteolol lies somewhere between that of pindolol and propranolol as to its intrinsic symapathomimetic action.

View full abstract

The pharmacokinetics of amikacin (4 mg/kg) was studied in healthy volunteers (n=5) by inravenous drip infusion and intramuscular injection. After intravenous infusion for 1 hr, the antibiotic followed a two compartment model, and after intramuscular injection it followed a one compartment model.
Concentrations of amikacin were assayed microbiologically, radioimmunologically and radioenzymatically. After intravenous infusion the maximum concentration (Cmax) was obtained at the end of infusion and was higher than that obtained at 45 min after intramuscular administration. The route of administration did not significantly modify the pharmacokinetic parameters of amikacin except Cmax and the time obtained Cmax (Tmax). Urinary excretion was slightly higher in intravenous infusion than that in intramuscular administration. There were good correlations among three different assays of amikacin concentration.
The serum concentrations of amikacin in repeated intravenous drip infusion twice a day werecoincided with concentrations simulated using pharmacokinetic parameters obtained by single administration.
Decreased renal excretion of amikacin was observed in bedridden elderly patients.

View full abstract

In a double blind controlled trial, 24 hour DCG records were obtained from 70 patients with ventricular premature contraction (VPC), twice during run-in observation and once at the end of 2 weeks treatment with metoprolol or propranolol.
Each record was summarized in a form of 6-point counts, each point consisting of 4 hours'VPC counts. Then the differences between the pre-and postmedication data of corresponding time points were taken to obtain differential data, which were subjected to principal component analysis (PCA), cluster analysis (CA) and periodic regression analysis (PRA).
The 6-point VPC counts were presented as a set of pre- and postmedication plottings to 5 raters (cardiologists) who independently assessed the degree of improvement in VPC counts on a 6-ordered-categorical scale. The reliability of judgment was 76%. According to the extent of disagreement in the rating, these data were classified into 2 groups of good and poor agreement, and analyzed by means of stepwise regression analysis (SRA) to clarify the policy of judgment.
The results of PCA of the differential data indicated that the size factor (the difference in the total VPC counts) occupied 73% of the overallvariance and that the shape factors (the pattern of the differential plotting) of day-midnight and morning-evening contrasts held 64% of the nonsize variance.
PRA of the differential data gave similar results to those of P CA. With the aid of CA, it was suggested the decrease in VPC counts dominant during day time, although not so clear.
The results of SRA of raters' judgments showed that the judgment policy was largely influenced by the size factor, whose coefficient of determination was 50-60% and further to be modified to some extent by the baseline counts in the control period. In the “good agreement” group the policy seemed to be based on the difference or ratio in the total VP C counts. In the “poor” agreement group, however, the policy was complex, and included shape factors.

View full abstract

Effects of methylcobalamin (MCB) on the myelinated axon regeneration were studied in rats. Free sciatic nerve grafts harvested from both gluteal regions were transplanted respectively into the gap created in the contralateral sciatic nerve under an operating microscope. Totally 39 rats were subjected to this study: 15 rats were involved in intraabdominal administration of MCB, 500 μg/kg, daily after operation, while 24 rats were used as control observation for the period of 8 th postoperative weeks. Each rat was sacrificed periodically and the grafts were processed for morphometric studies.
Regenerated axons grew earlier in grafts administrated with MCB than in control grafts. The density of regenerated myelinated fibers was higher in the grafts with MCB than in control. Diameters of myelinated fibers became larger in grafts with MCB than in control at early postoperative stage. There was no differences in regenerated axons at the late stage, more than six weeks, between in grafts administrated with MCB and in control grafts.
We suggest that MCB will make an activation of Schwann cell and help a smooth regeneration of axons.

View full abstract

Sixteen patients with mild to moderate essential hypetension were treated with cardioselective beta-blocker (atenolol or metoprolol). Atenolol, 50 mg once daily, was given for 4-12 weeks to 9 patients (Group A, mean age 66.2 years) and metoprolol, 20 mg three times daily, for 12 weeks to 7 patients (Group M, mean age 70.7 years). Hemodynamic measurements, which were obtained before and 5 min after intravenous infusion of isoproterenol (ISP) (0.02μg/kg/min), were performed in all subjects before and after the treatment with oral cardioselective beta-blocker therapy.
In Group A, systolic blood pressure (SBP) and diastolic blood pressure (DBP) fell significantly (p<0.025), SBP: 171±5.7 to 159±6.3 mmHg, DBP: 99±3.8 to 90±5.2 mmHg. In Group M, SBP tended to fall but DBP was unchanged. Heart rate (HR) decreased in Group A (74±4.7 to 57±2.8/min, p<0.005) more than in Group M (69±5.0 to 62±4.5/min, p<0.05). Cardiac index (CI) was unchanged in Group A, but decreased significantly in Group M (3.36±0.27 to 2.78±0.28 l/min/M², p<0.005). Stroke index, mean transit time incresaed in Group A, but were unchanged in Group M. Systemic vascular resistance, peripheral venous pressure, total blood volume were unchanged in both Group A and Group M.
In response to ISP stimulation, increasing rate of HR was +49.9% and +35.8% before and after the treatment in Group A, respectively. Heart rate increased by +48.9% and +44.3% before and after the treatment in Group M, respectively. Increasing rate of CI was +71.5% and +30.8% before and after the treatment in Group A, respectively. CI increased by +52.5% and +48.4% before and after the treatment in Group M. Therefore, beta-blocking effects on HR and CI to ISP stimulation were not observed in both Group A and Group M as compared with those to ISP stimulation after the treatment with non-cardioselective beta-blocker (oxprenolol) that we observed previously. In oxprenolol therapy, increasing rate of HR was +44.3% and +13.2% before and after the treatment, and that of CI was +52.4% and +1.1% before and after the treatment. Intravenous atropine did not alter the response to ISP after the treatment of atenolol suggesting that the reflex vagal control was not involved in this response.
It was concluded that oral cardioselective beta-blocker therapy in essential hypertension was effective in reduction of blood pressure and HR, but showed no beta-blocking to ISP stimulation. This unexpected response is not attributed to reflex vagal suppression due to stilmulation of vascular beta-2 receptor by ISP, but may reveal the direct stimulation of cardiac beta-2 receptor by ISP.

View full abstract

In order to clarify the interrelationships between hemodynamic changes and pharmacokinetics following oral administration of a single dose of nifedipine (5 and 10 mg capsules), blood pressure (BP), heart rate (HR) and plasma concentration of nifedipine were measured in 5 healthy volunteers (NT) and in 5 patients with essential hypertension (EHT).
Acute oral administration of nifedipine caused a rapid dose dependent reduction of BP in EHT, whereas no significant fall of BP was found in NT. No significant change of HR after nifedipine administration was observed in both EHT and NT. The results may suggest that the BP reduction is caused mainly by an attenuated sensitivity of the baroreceptor mechanism in EHT.
Plasma concentration of nifedipine promptly rose reaching the maximum level after .1 hour in both groups. The mean value of maximum plasma concentration in healthy volunteers was 55.4 ng/ml receiving 5 mg nifedipine and 124.5 ng/ml receiving 10 mg nifedipine respectively. 67.1 ng/ml and 132.4 ng/ml in EHT was measured after 5 mg and 10 mg. No significant difference of the maximum plasma concentrations in nifedipine or other pharmacokinetic parameters was observed between the two groups.
The minimum plasma concentration of nifedipine required for an effective BP fall (over 13 mmHg reduction in mean arterial pressure) in EHT is about 12 ng/ml and this hypotensive effect lasted 6 hours after the administration of 10 mg nifedipine.
These findings indicate that nifedipine is effective in lowering BP without an increase of HR in EHT, and also suggest that effective plasma concentration of nifedipine may be about 12 ng/ml.

View full abstract