The effects of trimoprostil, an analogue of PGE₂, on gastric secretion was studied inhealthy volunteers in comparison with those of cimetidine . Graded doses of 50, 250, 500, and 750g, were used for trimoprostil and 200 mg for cimetidine. Basal secretion wassignificantly depressed at doses larger than 500 μg of trimoprostil but not by 200 mg ofcimetidine. In AOC-tetragastrin stimulated gastric secretion, 500 μg of trimoprostildepressed acid output, but did not affect pepsin output, which was depressed at 750μg, however. On the other hand, cimetidine inhibited gastrin-stimulated gastric acid andpepsin secretion remarkably. Some difference was also recognized between trimoprostiland cimetidine concerning the mechanism of inhibitory effect. Serum concentration oftrimoprostil was measured at 60 min. after oral administration varied dose-dependentlyand dose-related anti-secretory effects were also found. Serum gastrin and pepsinogen 1were not affected either by trimoprostil or cimetidine. These results indicate thattrimoprostil showed inhibitory effects on gastric secretion at doses larger than 500 μgfor acid, and 750 μg for pepsin.

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Hemodynamic effects of short-term (6 weeks) oral urapidil 84.0±7.8mg/day, dilevalol 142±33 mg/day and acebutolol 444±26 mg/day were investigated in 48outpatients with essential hypertension (WHO stage I and II). Hemodynamic studieswere made in the supine position by radioisotope dilution technique using ¹³¹I humanserum albumin to measure total circulating blood volume (TCBV) and ^99mTc in vivolabelled red cells to measure cardiac output and left ventiicular ejection fraction (LVEF).
These three drugs reduced blood pressure (P<0.005) with various changes in heartrate (urapidil, 73±3 to 71±2 bpm, ns; dilevalol, 63±2 to 59±1 bpm, P<0.025, acebutolol, 73±2 to 62±1 bpm, P<0.005). Cardiac index (CI) decreased slightly ithe acebutolol-and dilevalol-treated groups, though the change was not significant inthe latter. Urapidil did not induce a decrease in CI. LVEF tended to increase in thesethree groups, though the changes were not siginificant. Total peripheral resistanceindex (TPRI) tended to decrease in the dilevalol group (2, 885±118 to 2, 504±86dyne·sec·cm^-5·m², P<0.005) andand in the urapidil group (2, 749±193 to 2, 471±163dyne·sec·cm^-5·m², ns), but did not in the acebutolol.
Urapidil, dilevalol, and acebutolol were reported to have beta-blocking activity andintrinsic sympathomimetic activity (ISA) as common pharmacological properties.However, urapidil and dilevalol have alpha-blocking activity, acebutolol did not. Theresults in this study suggest that the less beta-blocking activity the drug has, the lesscardiosuppressive effects it induces, and the effects of cardiac blockade may beantagonized by ISA and afterload reduction for the heart.
Urapidil may induce a decrease in TPRI by vascular alpha-receptor blockingactivity, and its cardiac beta-blockade was not exhibited in this study, though thepossibility may exist that it supressed a reflex-induced tachycardia and increase incardiac pump function. ISA of dilevalol on the vasculature was reported to induceperipheral vasodilation in animal study, and this coincided with the results in this study, however, the decrease in TPRI may be partially influenced by vascular alpha-receptorblockade.

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The present study was undertaken to determine whether the effects of furosemidedepend on the administration time or not. After furosemide 20 mg or distilled water wasadministrated intravenously in 12 human volunteers at 9: 00 or at 21: 00, urine volumeand urinary excretion of sodium, choride, and furosemide were measured. There was nosignificant difference in urine volume and urinary excretion of sodium and chloridebetween when distilled water was given at 9: 00 and when given at 21: 00. Whenfurosemide was administrated at 21: 00, urine volume and urinary excretion of sodium, chloride, and furosemide during 60 min were significantly greater those administrated at9: 00. There was a marked correlation between the urinary output of furosemide and theurine volume, urinary sodium or chloride. These results suggest that the effects offurosemide vary with the administration time and the observed variations are mainlydependent on the amount of furosemide secreted to urine.

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The study was designed to evaluate the effect of intravenously injected methylcobalamin on the degeneration of myelinated fiber produced by adriamycin in rats. Sixty male, 3-week-old, Sprague Dawley rats were used. Fifteen rats were not treated with drugs (group 1). The other forty-five rats were intravenously administered with adriamycin10 mg/kg (0.4 ml/100g of body weight) on the first day of the experiment. They werefurther divided into 3 groups of 15 rats each (groups 2, 3, and 4). Group 2 wasintravenously administered with physiological saline 2ml/kg/day b. i. d. for 3 weeks. Ina similar manner as in group 2, groups 3 and 4 were administered with methylcobalamin50 and 500 μg/kg/day, respectively. After termination of the 3-week experiment, all ratswere sacrificed and the sural nerve was obtained from the distal thigh. Themorphometric evaluation was made in each sural nerve, numbered at random to mask thegroup of origin.
The frequency of axonal degeneration in myelinated fibers was significantly higher ingroups 2, 3 and 4 compared with group 1. This value was significantly smaller in group 4than in group 2 (P<0.01).
The total number of myelinated fibers was significantly smaller in groups 2, 3, and 4compared with group 1. This value was significantly greater in group 4 than group 2 (P<0.01).
Furthermore, the radioassayed concentration of vitamin B₁₂ was significantlyincreased in both the sciatic nerve and lumber spinal cord in groups 3 and 4 comparedwith group 2.
These data suggest that intravenous administration of methylcobalamin 500μg/kgplayed a protective role against axonal degeneration and subsequent loss of myelinatedfibers in experimental adriamycin neuropathy in rats.
The effect of intravenous methylcobalamin described above is similar to that ofsubcutaneous mehylcobalamin on experimental adriamycin neuropathy presened in ourprevious report.

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In order to investigate the antianginal effects of a new calcium antagonist, nilvadipine, a randomized double-blind cross-over study controlled with placebo wascarried out in 15 patients with stable effort angina pectoris. Multistage treadmillexercise testing was performed before, and at 2, 4, and 7 hours after a single oraladministration of 6 mg nilvadipine or placebo. The exercise testing was terminated atmoderate anginal pain.
The treadmill exercise duration showed no statistically significant time effects ororder effects either before or after administration of the test drugs. Before administration, there were no significant differences in exercise duration, time to onset of STsegment depression≥0.1 mV, pressure-rate products, or ST deviation between nilvadipine and placebo.
Nilvadipine significantly prolonged exercise duration at 2, 4, and 7 hours after dosing, and time to onset of ST-segment depression≥0.1 mV at 2 and 4 hours after dosing.However, there were no significant differences in ST deviation at peak exercise betweennilvadipine and placebo.
Nilvadipine significantly reduced resting systolic blood pressure at 2 and 4 hoursafter dosing. At peak exercise, nilvadipine significantly increased heart rate at 2 and 7hours, and pressure-rate product at 2 hours after dosing, respectively.
These results indicate that nilvadipine significantly increases exercise tolerance inpatients with stable effort angina pectoris up to 7 hours after a single oral administrationof 6 mg. It is concluded that nilvadipine is a clinically useful antianginal agent.

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BKU (a sustained release formulation of urapidil) 15, 30, and 60 mg and prazosin1 mg were orally administered consecutively at 1-week intervals to 6 healthy malevolunteers to compare their pharmacokinetic and pharmacological profiles.
Both the time to maximum plasma concentration (t_max) and the biological half-lifet(_1/2) were longer for BKU than for prazosin. Supine blood pressure decreasedsignificantly after BKU, but not after prazosin. Supine pulse rate increased significantlyafter both drugs. A significant decrease of blood pressure was induced by change ofposition from supine to 50° tilt after both drugs, although no such alteration was inducedbefore drug administration. The exercise-induced elevation of systolic blood pressurewas diminished and the rise of heart rate was enhanced after both drugs.
It is concluded that the pharmacokinetic profiles and mode of action of BKU aresimilar to prazosin except for longer t_max and t_1/2 in BKU.

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NT-1 is a transdermal tape containing 5 mg nitroglycerin and is expected to havesustained efficacy of nitroglycerin.
In order to compare the antianginal effects of 5mg NT-1 and 10 mg NT-1 on exercisetolerance, a ramdomised double-blind cross-over study was carried out in 19 patientswith stable effort angina pectoris. Multistage treadmill exercise testing was performedin all patients before and at 2 hours after a single topical application of 5 mg NT-1 or 10mg NT-1. It was also performed in 12 out of the 19 patients, as a open study, before andat 2 hours after a single topical application of a placebo tape. The exercise testing wasterminated at moderate anginal pain.
Before topical application, there were no significant differences in treadmill exerciseduration, heart rate, systolic blood pressure, or ST deviation between 5 mg NT-1 or 10mg NT-1. At 2 hours after the application, systolic blood pressure at rest was morereduced with 10 mg NT-1 than with 5 mg NT-1. However, there were no significantdifferences in treadmill exercise duration, heart rate, systolic blood pressure at peakexercise, or ST deviation between 5 mg NT-1 and 10 mg NT-1. At 2 hours after a singletopical application of NT-1, the mean plasma level of nitroglycerin was twice as highwith 10 mg NT-1 as with 5 mg NT-1.
In all 12 patients who were subjected to the placebo open study, treadmill exerciseduration was significantly longer with NT-1 than with placebo, irrespective of dosagestudied. However, there were no significant differences in systolic blood pressure, pressure-rate product, or ST deviation at peak exercise between NT-1 and placebo.
These results indicate that the topical application of NT-1 significantly increasesexercise tolerance in patients with stable effort angina pectoris, and that the antianginaleffects of 5 mg NT-1 are approximately equal to those of 10 mg NT-1.

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