1 The pharmacokinetics and biochemical efficacy of losartan, an orally active nonpeptide angiotensin II (AII) receptor antagonist, were evaluated in healthy male volunteers after single and multiple oral administration. 2 Plasma and urinary concentrations of losartan and its active metabolite, E-3174, were determined by a specific high performance liquid chromatographic (h.p.l.c.) method. 3 Plasma concentrations of losartan were proportional to dose over the range of 25 to 200 mg and the terminal half-lives (t',2,,) ranged from 1.5 to 2.5 h. The mean values of Cmax and AUCO-oo increased in a dose-dependent manner. 4 Plasma concentrations of E-3174 were higher than those of losartan at all dose levels.The values of Cmax and AUCO-°o for E-3174 were approximately 2 and 5-8 times higher than those for losartan, respectively. Also the value of t ' , 2 , , was 2 times longer than that of losartan. 5 After multiple dosing for 7 days, the pharmacokinetics of losartan and E-3174 each did not change significantly between day 1 and day 7. 6 Plasma renin activity (PRA) and plasma concentrations of AII increased markedly at all dose levels. Plasma aldosterone levels were slightly reduced, but a similar decrease was also observed with placebo. 7 No clinically significant adverse reaction was observed in any of the volunteers during either study. Blood counts, routine laboratory tests, urine analyses, and electrocardiograms were also not modified by losartan. 8 Losartan appears to be a potent orally active angiotensin II antagonist with a relatively long duration of action.

The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n = 6), or 100 mg (n = 6) or placebo (n = 3) once daily for 7 consecutive days. In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg.dl-1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged. In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg.dl-1) and last administrations (4.42 mg.dl-1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576). The findings suggest that DuP-753 possesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.

Viral eradication reduces both liver stiffness and steatosis in patients with chronic HCV who received direct-acting anti-viral therapy (UMIN000017020).

The effects of Streptococcus thermophilus ST28 on cytokine production by murine splenocytes stimulated with transforming growth factor-β plus interleukin- (IL-) 6 were evaluated. The addition of ST28 significantly repressed IL-17 production compared to ATCC 19258 (type strain). ST28 also decreased the number of Th17 cells in the stimulated splenocytes. The anti-inflammatory effects of ST28 administration were evaluated in mice with colitis induced by dextran sodium sulphate (DSS). Oral treatment of mice with ST28 ameliorated the intestinal lesions by DSS. Upon DSS treatment, IL-17 production in lamina propria lymphocytes (LPLs) was induced, but ST28 significantly decreased its production. ST28 also decreased the percentage of Th17 cells in LPL from DSS-induced colitis. The present results imply that ST28 suppresses the Th17 response in inflamed intestines and would be useful in the treatment of Th17-mediated diseases, such as inflammatory bowel disease.

Effects of calcium antagonists on the ST alternans and associated mechanical altemans during acute coronary occlusion were examined in anesthetized dogs. The heart rate was fixed by atrial pacing. The intravenous administration of 0.2 mg/kg verapamil attenuated the ST alternans as did 0.5 mg/kg diltiazem. Although these drugs significantly attenuated TQ depression during occlusion, the attenuation was observed after a longer period of occlusion and when the degree of TQ depression was comparable to that during the control occlusion. Nifedipine, 0.03 mg/kg, slightly attenuated the ST alternans, but 0.5 mg/kg dipyridamole had no effect. These results support the idea that slow inward currents are involved in the ST altemans. On the other hand, the mechanical altemans was attenuated in six of 11 dogs. It is probable that factors other than the electrical altemans may also contribute to the mechanical altemans. Circulation 68, No. 3, 667472, 1983. ALTERNANS of the ST segment of the electrocardiogram (ST alternans, STA) has been frequently observed in experimental animals'`" and cases of STA also have been observed in patients with ischemic heart disease.5' 8, 9 Because STA is frequently followed by ventricular arrhythmia, many authors have suggested a causal relationship between the two phenomena. of these drugs on the electrical and the mechanical alternans during left anterior descending coronary artery (LAD) occlusion have not been examined. Thus, the purpose of our study was to examine the effects of calcium antagonists on STA and associated mechanical altemans during acute coronary occlusion in dogs. MethodsTwenty-seven mongrel dogs weighing 6.5 to 12.0 kg were anesthetized with 30 mg/kg of intravenous sodium pentobarbital. Under artificial respiration, a left lateral thoracotomy was performed through the fifth left intercostal space and the heart was cradled in the opened pericardium. Standard lead II of the electrocardiogram, an epicardial unipolar electrogram (EPeg), amount of isometric myocardial contraction (contractile force) in the ischemic area, and left ventricular pressure (LVP) were recorded. For measuring LVP a catheter was placed in the left ventricle through the femoral artery. The contractile force was measured by a strain-gauge arch with adjustable feet (HD-IT, Nihon Kohden). The myocardial segment between the two feet of the strain-gauge arch was stretched to about 20% of its diastolic length. The EPeg from the ischemic area was recorded by a tungsten wire with a diameter of 0.2 mm. The electrode for EPeg and the strain-gauge arch were set at the same area in order to examine the relationship between the electrical and the mechanical alternans. The indifferent electrode for EPeg was connected with Wilson's central terminal. The lead II, EPeg, contractile force, and LVP were amplified by a polygraph (RM-85M, Nihon Kohden) and recorded on a mingograph (800-6 Nihon Kohden). To produce transient ischemia, the LAD was occluded below its first diagonal branch for 3 to 10 min. The time int...