The antihypertensive effectiveness and usefulness of penbutolol were evaluated by means of a double-blind cross-over study, employing an inactive placebo as control, in patients with essential hypertension unable to be controlled by a thiazide diuretic. The study consisted of a 4-week control period, followed by Treatment Periods I and each 6 weeks in duration. The following results were obtained:
1) Among a total of 113 patients enrolled, 101 were analyzable. Eleven of these patients were evaluated for adverse reactions and safety only.
2) The demographic characteristics of the penbutolol-placebo group and the placebo-penbutolol group were comparable.
3) Blood pressure during Treatment Period I decreased significantly in both the penbutolol and placebo groups compared to the control period. During Treatment Period II, blood pressure in the placebo group did not change significantly compared to the end of Treatment Period I but that in the penbutolol group decreased significantly. Pulse rate during Treatment Periods I and II decreased significantly compared to the control period in the penbutolol group but did not show any change in the placebo group.
4) Since the order and time of treatment was found to influence blood pressure, only data derived from Treatment Period I were subjected to intergroup comparison. Penbutolol was found to be significantly superior to placebo in terms of the global judgment of antihypertensive effect (p<0.05).
5) Although order- and time-related effects were noted, an assessment of efficacy data derived from both Treatment Periods I and II revealed penbutolol to be signifi-cantly superior to placebo with regard to the global judgment of antihypertensive effect, overall improvement, and usefulness (p<0.01).
Intragroup comparison of Treatment Periods I and II demonstrated penbutolol to be significantly superior to placebo for global evaluation of antihypertensive effect, overall improvement and usefulness (p<0.01).
6) Adverse reactions occurred in 4 patients (4.2%, 1 with gastrointestinal disturb-ances and 3 with bradycardia) during penbutolol treatment and 3 patients, (3.1%, 1 with chest compression, shortness of breath and effort palpitation, 1 with malaise, and 1 with dizziness) during placebo treatment. All symptoms appearing during penbutolol treatment disappeared after discontinuing the drug or switching to placebo.
Laboratory examinations did not reveal any severe changes.
These results demonstrated that penbutolol, 40 mg per day in two divided doses, was superior to placebo for antihypertensive effect, overall improvement, and usefulness during concomitant thiazide treatment.

View full abstract

The effects of a hypotensor, indapamide, on diuresis, urinary excretion of electrolytes and cardiohemodynamics were compared clinico-pharmacologically with those of trichlormethiazide by a cross-over method in 7 male adult volunteers indicating borderline hypertension. Indapamide and trichlormethiazide were administered orally for 2 consecutive weeks each in doses of 2 and.4 mg once a day respectively. The day before the initiation of each medication was designed as control observation day. The effect on cardiohemodynamics was evaluated by measuring the blood pressure, pulse rate, cardiac index, stroke index and systemic vascular resistance before and after isometric exercise. The differences for 24-hr urine volume and 24-hr urinary electrolytes excretion were not statistically significant between both drugs. However, the onset of action was slower in indapamide than in trichlormethiazide, and the peak diuretic and electrolyte excretory activities of the former were also weaker than those of the latter. On the other hand, both actions of the former persisted longer than those of the latter. The blood pressure tended to lower 2 weeks after starting each medication. The cardiac and stroke indexes decreased significantly 2 weeks later, and the decrease lasted longer in indapamide group than in trichlormethiazide one.

View full abstract

We studied the safety of butorphanol in different 5 doses (0.5, 1.0, 2.0, 3.0, 4.0mg) administered intramuscularly in healthy Japanese male volunteers.
No remarkable abnormalities were observed in subjective and objective symptoms, vital signs, ECG or laboratory tests. Sedation was observed characteristically in almost every cases. Constipation, specific adverse effect of opiates, was not reported. Respiratory depression was slight and was not dose-dependent. Psychotomimetic reaction such as nightmare or hallucination was not observed. We confirmed butorphanol was the drug of wide safety margins and little adverse effects.
Therefore, we concluded that we can proceed to phase two study with this drug.

View full abstract

Rifampicin in single oral dose of 450mg was administered to eight healthy subjects and eleven tuberculous patients. Rifampicin in blood and urine samples was measured by high-performance liquid chromatography. Blood and urine samples were collected frequently up to 24 hrs after each dose. Data of rifampicin level in serum (C_t) were fitted by a computer. Biexponential equation, C_t=A (e^-ke·t-e^-ka·t), and the pharmacokinetic parameters were obtained by non linear least squares regression analysis. The data of rifampicin and 25-desacetylrifampicin in urine was fitted by a computer to sigma-minus plot. The first-pass effect was calculated by method of Gibaldi and coworkers.
Vd/F and total body clearance values were higher in the tuberculous patients than in the healthy subjects. Recovery of rifampicin and 25-desacetylrifampicin in urine was lower in the tuberculous patients than in the healthy subjects. First-pass effect (%) washigher in the tuberculous patients than in the healthy subjects.
On these results, it seems reasonable that the increased biliary excretion is due to a process of self-induced enzyme activity, which results in facilitation of the transfer of the antibiotic from blood to bile.

View full abstract

A double-blind controlled clinical trial was carried out in eight patients with typic-al effort angina pectoris to investigate the duration of the hemodynamic effectiveness of beta-blockers. Four treatment regimens (placebo, propranolol 20mg, penbutolol 4 mg, and 20mg) were allotted under double-blind randomized block design. A multi-stage ergometric exercise test was performed at eight hours after administra-tion, and respiratory function and hemodynamic parameters were continuously moni-tored during and after exercise. Statistical analyses were done using ANOVA for the sizes of the parameters and PANOVA for the behavior (the profiles of response curves) of the parameters.
The profiles of these parameters“during and after exercise” indicate interactions between drug and time process. Regarding the sizes of heart rate and double product during and after exercise, statistical differences were observed among the treatment regimens with a significant decrease in the penbutolol 20mg group.Concerning the profiles of heart rate and double product during and after exercise, significant differ-ences were noted among the four treatment regimens with a significant decline in the penbutolol 20mg group.In addition, more distinct differences were recognized among the four treatment regimens with highly significant reductions in the penbuto-lol 20mg grorp, including effectiveness for the size of the parameters. These results suggest that penbutolol 20mg is clinically effective for at least eight hours following oral administration.

View full abstract

Fenbufen, 4-(4-biphenylyl)-4-oxobutyric acid, was compared with diclofenac in a double blind clinical trial of 107 randomly assigned patients with osteoarthritis of the knee joint. The trial was designed to determine the comparative efficacy and safety of the two drugs.
The patients studied were treated with either fenbufen in the dosage of 600mg/day or diclofenac of 75mg/day alone for the period of 6 weeks.
According to evaluation by physicians, the effectiveness was observed 83.3% in fenbufen and 75.0% in diclofenac groups. Of the eleven symptoms of osteoarthritis were selected for the study, fenbufen group demonstrated three statistically better symptoms than diclofenac group, i. e. pain in extension, pain at climbing up and down stairs (p<0.05).
The incidence of drug related side effects was noted 10.5% in fenbufen group and, 25.0% in diclofenac group with statistically significant difference (p<0.05).
Following to overall assessment which considers both efficacy and side effects, it might be concluded that fenbufen is significantly beneficial to patients than diclofenac.

View full abstract

The inhibitory effect of a minor tranquilizer CS-386 (Mexazolam) on development of stress ulcer by a restraint water immersion method was investigated in rats. Development of stress ulcer was suppressed significantly in the groups treated with 10, 30, 50 and 100mg of CS-386 per kg of body weight as compared with the control. The inhibitory effect of CS-386 seemed to be slightly stronger than that of diazepam included for comparison, though diazepam also suppressed stress ulcer to a significant degree. Both CS-386 and diazepam significantly suppressed the elevation of blood gastrin after stress. The experimental results indicate that CS-386 is a promising minor tranquilizer.

View full abstract

The adverse reactions due to single doses of dothiepin 25mg and amitriptyline 25mg were compared in healthy volunteers in double blind, coss-over fashion. The subjects were 7 young (21 to 25 yr of age, average are: 22.7) men. Self-rating, and physiolo-gical and psychological measures were applied, and experiments were performed for 24 hrs after the administrations. Dothiepin 25mg decreased critical flicker frequency and reduced salivary rates significantly less than amitriptyline 25mg. The values of diastolic blood pressure at sitting position were lower after the administrations of dothiepin 25mg than amitriptyline 25mg. The method of evaluating adverse drug reaction was discussed here.

View full abstract

The Mantel-Haenszel statistic is one of the most important statistics related to a 2×2 contingency table and utilized in combining many 2×2 tables as applied to the life-table analysis. The Wilcoxon two-sample statistic, often referred to as the Mann-Whitney statistic, is one of the most well-known statistics related to the data collected by group comparison study and particularly useful when the data are obtained in a 2×c ordered-categorical format.
The poststratified analyses are commonly perfomed of the data obtained in the randomized controlled clinical trials. Many of the analyses are directed toward such an exploratory approach as to force to find out in which strata the test drug is superior to the control.
In this paper we compared the two statistics from the standpoint of subdividing the sum of chi-square statistics into the quadratic forms relevant to the summary and the residual components, and indicated that the two statistics are closely alike in the case of 2-categorical data. Giving weight to the other aspects of stratified analysis than exploring, we discussed the nature of the summary statistic.

View full abstract

The effect of mecobalamin on the regenerating process of myelinated fibers in ex-perimental toxic neuropathy induced by antituberculous drug ethambutol was studied.
Seven rats were given 300mg/kg of ethambutol orally every day for nine months. Then they were divided into two groups. Three rats were administered 1, 000μg/kg of mecobalamin intramuscularly three times a week for the following four months (ex-perimental group). The other four were kept untreated for the same period (EB con-trol group). As untreated controls, four normally fed rats of the same age were also examined.
All rats were sacrificed by perfusion with 2% glutaraldehyde solution. Sciatic nerves at midthigh level and tibial nerves at ankle level were removed and examined by teased-fiber method.
The frequency of myelinated fibers showing axonal degeneration with linear rows of myelin ovoids was not different among experimental, EB control and untreated con-trol groups. However, the frequency of fibers showing regeneration after axonal de-generation was significantly higher in both sciatic and tibial nerves of the ex-perimental group than of the EB control group (p<0.02 and p<0.01) and untreated control group (p<0.001). These fibers had uniformly very short internodal lengths, all of which were less than half of the expected length judging from the standard re-gression line between nerve fiber diameter and internodal length.
The result suggested that mecobalamin has a promoting role in the regeneration af-ter axonal degeneration in experimental ethambutol neuropathy.

View full abstract

A transdermal sustained release formulation. of isosorbide dinitrate (Frandol Tape) has been developed for the purpose of prolonging the preventive effect of isosorbide dinitrate (ISDN) against attacks of angina pectoris.
The plasma levels of ISDN and the two metabolites, isosorbide 2-mononitrate and isosorbide 5-mononitrate, were measured after the application of Frandol Tape (ISDN 40mg) in ten healthy male volunteers. After a single application of the tape to the breast for 24 or 48 hrs, the mean plasma levels of ISDN increased slowly to reach their peaks of 2.6 or 2.7 ng/ml at 6 hrs and declined very slowly to 1.9 ng/ml at 24 hrs or to 1.4 ng/ml at 48 hrs after the application. After removal of the tape, the mean plasma levels of ISDN declined with a half-life of 2.3 hrs.
The area under the plasma level versus time curve (AUC) for ISDN per the amount of ISDN absorbed percutaneously after a transdermal administration was larger than after an oral administration. Probably because ISDN was not susceptible to“first-pass effect” in the cutaneous route. On the other hand, it was suggested that urinary excretion behavior after a transdermal administration was similar to that after an oral administration.
These results demonstrated that Frandol Tape might be an useful transdermal sustained release formulation of ISDN for the prevention of angina pectoris, since the plasma level of ISDN is maintained constantly during the period of application.

View full abstract

Buprenorphine hydrochloride was intramuscularly injected at the usual dose into patients who required frequent use of analgesics, and its analgesic effect and drug dependence potential were studied during the course of treatment and after termination of treatment.
1. A total of 18 patients were studied: 11 patients with cancer-related pain, 3 patients with postoperative pain, 2 patients with postoperative ileus, and 2 patients with other symptoms.
2. The overall improvement in terms of analgesic efficiency was remarkable in 66.7% of the patients studied and moderate in 27.8%, so that the efficacy of the drug was very high.
3. The only side effects observed were slight dizziness in 1 patient and moderate decrease of respiration rate in another.
4. The drug dependence potential was examined in 14 patients who received more than 4 injections of buprenorphine hydrochloride. During the course of treatment, 10 patients (71.4%) requested continuation of the drug and 2 (14.3%) requested an increased dose. After termination of treatment, 2 patients (14.3%) requested resumption of the drug, 2 (14.3%) complained of sleeplessness and 1 (7.1%) complained of nervousness, but these were due to pain. During the course of treatment, 3 patients (21.4%) experienced an exhilarated feeling, but the symptom was mild, and hence, it was not considered to suggest dependency on the drug.
5. Although the number of patients was not large, the dependence potential of buprenorphine hydrochloride was studied in as much detail as possible. However, the results of the present study did not indicate any clinical problems with drug dependence potential.

View full abstract