No abstract

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.

No abstract

To determine whether methylation of the hMLH1 promoter is related to increasing age and gastric carcinogenesis, we examined hMLH1 methylation and expression in 100 gastric cancers. hMLH1 methylation and aberrant protein expression were observed in 9 and 13 cancers, respectively. Normal and intestinal metaplastic tissues adjacent to cancers with hypermethylation did not exhibit any hMLH1 methylation, indicating that it may be specific to gastric cancers. The frequency of hMLH1 methylation significantly increased with age. These results suggest that hMLH1 methylation plays an important role in gastric carcinogenesis in old people.

No abstract

APC and transforming growth factor‐β type II receptor (TGF‐β RII) gene mutations, and microsatcllitc instability have been found in sporadic colorectal carcinomas. To clarify further the early alterations in colorectal carcinogenesis, we investigated these genetic changes in 23 protruding‐ and 24 superficial‐type mucosal colorectal carcinomas. TGF‐β RII gene mutations and microsatellite instability were rarely found in these lesions. Nevertheless, APC was mutated in 16 of the 47 (34.0%) mucosal colorectal carcinomas and was significantly more frequently mutated in protruding‐ (I) and superficial elevated‐type (Ila) (14/32,43.8%) than in other superficial‐type (IIa+IIc, IIb, IIc, and IIc+IIa) (2/ 15,13.3%) mucosal colorectal carcinomas (P<0.04). These results indicate that the APC gene may be involved from the beginning in the tumorigenesis of many early colorectal carcinomas, particularly of the protruding and superficial elevated types. However, there might be a distinct pathway for other superficial‐type colorectal carcinomas, possibly not involving APC as an initial step of tumorigenesis.

No abstract

Although the expression of major matrix components was markedly enhanced, matrix synthesis was enhanced only modestly, and the changes of matrix in human OA menisci were rather modest in the non-degenerated areas.