Blood pressure-lowering efficacy of olmesartan relative to other angiotensin II receptor antagonists: an overview of randomized controlled studies

The aim of the present work was to review published studies investigating the dose-related efficacy on blood pressure (BP) of olmesartan and of other commercially available angiotensin II type I receptor blockers (ARBs). Patient population comprises mild to moderate hypertensive adult patients. We selected studies with comparable design and dose ranges. Dose-effect relationship plots were fitted for diastolic (DBP) and systolic (SBP) BP to the simplified E(max) model. We also examined controlled studies of olmesartan vs. other individual ARBs. Our overview was based on 7280 patients, of which 5769 received an ARB and 1511 received placebo. Except for losartan, the data fitted correctly to the E(max) model, with correlation coefficients ranging from 0.77 to 0.99. BP-lowering efficacy defined as E(max) was superior with olmesartan, (DBP/SBP mmHg: -9.0/-12.4) when compared with candesartan (-6.7/-11.3), irbesartan (-6.5/-11.2) and valsartan (-6.3/-8.9). Head-to-head comparisons of olmesartan to each of the other ARBs used at per-label 'recommended doses', support the finding of a greater BP-lowering effect of olmesartan. This overview suggests that clinically relevant differences in maximal efficacy, as well as in efficacy of per-label recommended doses can be evidenced among individual ARBs. Olmesartan efficacy was consistently at the highest end of the range of efficacy of ARBs studied.     

Lesion characteristics, NIH stroke scale, and functional recovery after stroke

OBJECTIVE: We examined the relationships between the National Institute of Health Stroke Scale (NIHSS) and physical, cognitive, and social participation outcomes across subpopulations of stroke survivors on the basis of cortical involvement and lesion lateralization. DESIGN: Families in Recovery from Stroke Trial participants were classified with respect to lesion lateralization (n = 274) and cortical involvement (n = 158). NIHSS scores (average 13 days after stroke) were used to predict Physical Performance Test times (PPT), limitations in activities of daily living (Augmented Barthel Index (ABI)), Instrumental Activities of Daily Living (IADL), cognitive function, depressive symptoms (Center for Epidemiologic Studies Depression scale [CES-D]), and productive, recreational, self-care, and social role activities 3 and 6 mos later. We compared the relationship between NIHSS and each outcome in stroke subgroups classified by lesion lateralization and cortical involvement. RESULTS: NIHSS predicted physical performance, activities of daily living, and IADL independence. The association between NIHSS and both PPT and IADLs was less steep for patients with cortical lesions than for patients with exclusively subcortical lesions. NIHSS predicted physical performance, activities of daily living, or IADLs similarly for right- and left-hemisphere strokes, but hemisphere modified the association between NIHSS and CES-D and cognitive measures. CONCLUSIONS: The NIHSS may predict outcomes in subpopulations of stroke survivors with subcortical lesions better than in patients with cortical involvement. NIHSS predicted CES-D in patients with right-sided lesions but not in those with left-sided lesions. In contrast, NIHSS had little association with cognitive outcomes among patients without left-side involvement.     

The contribution of intestinal UDP-glucuronosyltransferases in modulating 7-ethyl-10-hydroxy-camptothecin (SN-38)-induced gastrointestinal toxicity in rats

Life-threatening diarrhea afflicts a considerable percentage of patients treated with irinotecan, an anticancer agent with effects elicited through its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The primary detoxification pathway for SN-38 is glucuronidation. The purpose of this study was to evaluate the role that intestinal UDP-glucuronosyltransferases (UGTs) have from hepatic UGTs in modulating this diarrhea. To investigate this, Gunn rats devoid of UGT1A activity were injected with recombinant adenoviral vectors expressing UGT1A1, 1A6, and 1A7, resulting in reconstituted hepatic UGT expression comparable to a heterozygote. Hepatic microsome studies indicated that 4 to 7 days after adenoviral injection, transfected Gunn rats (j/jAV) had SN-38 glucuronide (SN-38G) formation rates three times higher than control heterozygote rats (j+AV). The adenovirus did not impart any glucuronidating capacity to the intestine in j/jAV rats, whereas j+AV rats possessed intestinal UGT function. After the administration of 20 mg/kg/day irinotecan i.p. to j/jAV rats 4 days after adenovirus injection, diarrhea ensued before the fourth irinotecan dose. j+AV rats were spared the diarrhea, and the toxicity was mild compared with the j/jAV rats, as measured by diarrhea scores, weight loss, and histological assessments of the cecum and colon. The pharmacokinetics of irinotecan, SN-38, and SN-38G indicate that the systemic exposure of SN-38 and SN-38G was higher and lower, respectively, in j/jAV rats. Despite this, the biliary excretion of irinotecan and metabolites was similar. Because intestinal UGTs are the main discriminating factor between j/jAV and j+AV rats, their presence seems to be critical for the gastrointestinal protection observed in j+AV rats.     

Targeting the AKT protein kinase for cancer chemoprevention

The AKT protein kinase transduces signals from growth factors and oncogenes to downstream targets that control crucial elements in tumor development. The AKT pathway is one of the most frequently hyperactivated signaling pathways in human cancers. Available data are reviewed herein to support targeting the AKT kinase for cancer prevention. This review will present data to show that AKT is up-regulated in preneoplastic lesions across a broad range of target tissues, briefly describe drug development efforts in this area, and present evidence that down-regulation of AKT signaling may be a viable strategy to prevent cancer.     

Psychotropic medication use for behavioral symptoms of dementia

Behavioral disturbances associated with dementia are common and burdensome. Although no psychotropic medications are currently approved by the US Food and Drug Administration (FDA) to treat such behavioral symptoms, a variety of drug classes are commonly used for these purposes. Atypical antipsychotic medications may be somewhat effective and are generally considered the pharmacologic treatments of choice; however “black box” warnings have recently been added to their labels by the FDA, warning of significantly increased risks of short-term mortality. Older conventional antipsychotic medications may also be somewhat effective but appear to pose risks that can be at least as great as those of the newer atypical drugs. Although antidepressants, benzodiazepines, mood stabilizers, acetylcholinesterase inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists may be considered, particularly in patients with specific types of symptomatology, even less is known about their effectiveness and safety. Also, although various psychotropic medications used for behavioral disturbances in dementia patients may be somewhat effective, they have been increasingly associated with important safety risks.     

The Landmark Surgical Trials of the National Surgical Adjuvant Breast and Bowel Project

In this paper we provide a summary of several of the completed and ongoing surgical trials of the National Surgical Adjuvant Breast and Bowel Project, one of the cancer cooperative trials groups supported by the US National Cancer Institute.