Nifedipine GITS/Candesartan Combination Therapy Lowers Blood Pressure Across Different Baseline Systolic and Diastolic Blood Pressure Categories: DISTINCT Study Subanalyses.

DISTINCT was an 8-week, double-blind, randomized study to investigate the antihypertensive efficacy and safety of various nifedipine gastrointestinal treatment system (GITS)/candesartan cilexetil (N/C) dose combinations, vs respective monotherapies or placebo, in patients with diastolic blood pressure (DBP) ≥95 to <110 mm Hg. The current prespecified analysis compared BP reduction in participants with mild vs moderate baseline hypertension (ie, systolic [S]BP <160 mm Hg vs ≥160 mm Hg and DBP <100 mm Hg vs ≥100 mm Hg). A total of 1362 patients were analyzed by descriptive statistics. In all patient subgroups investigated, the NC combinations (ie, N: 20, 30, or 60 mg; C: 4, 8, 16, or 32 mg daily) provided greater SBP and DBP lowering and higher rates of BP control (defined as BP <140/90 mm Hg) than respective monotherapies or placebo, with greatest absolute BP reductions observed in the moderately elevated SBP or DBP subgroups. A trend to dose-response relationship was observed in each subgroup. In each SBP and DBP subgroup, treatment-related vasodilatory events (flushing, headache, or edema) were less frequent for patients receiving NC combination therapy than N monotherapy. These analyses support the use of calcium antagonist and angiotensin receptor blocker combination therapy in patients with both mild and moderate hypertension, for whom effective BP normalization and good drug tolerance would greatly reduce the risk of cardiovascular events.

Molecular complexity of sexual development and gene regulation in Plasmodium falciparum.

The malaria parasite, Plasmodium falciparum, has a complex life cycle which alternates between the vertebrate host and the invertebrate vector. Various morphological changes as well as stage-specific transcripts and gene expression profiles that accompany parasite's asexual and sexual life cycle suggest that gene regulation is crucial for the parasite's continual adaptations to survive the changing environments as well as for pathogenesis. Development of sexual stages is crucial for malaria transmission and relatively little is known about the role of specific gene products during asexual to sexual differentiation and further development. Therefore, in order to have a full understanding of the biology of the malaria parasite, gene regulation on a genome-wide global level must be understood, an area remaining to be elucidated in P. falciparum. Parasite features, such as A-T bias, difficulties in cloning, labor-intensive culture and purification of specific stages of the parasite, all contribute to the difficulties to investigate many aspects of parasite biology. However, despite these challenges, limited studies have revealed a number of parallelisms with eukaryotic transcription. For example, the parasite's genes are organised in a similar fashion, contain promoter elements and upstream activation sequences, as shown by structural searches and functional assays, and some of the basal machinery and general transcription factors have been found in Plasmodium. The completion of the full genome sequence of P. falciparum and other species of Plasmodium has resulted in the search for specific transcription factors through genome mining. Although genome mining may identify some of the factors, search for these factors solely by primary sequence homology would result in a non-comprehensive list for transcription factors present in the genome. Here, we present further discussion on putative transcription factors like activities detected in the asexual and sexual stages of P. falciparum.

Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results.

OBJECTIVES: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) aimed to determine the dose-response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension. METHODS: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP. RESULTS: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose-response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [-23.8/-16.5 mmHg; P < 0.01 versus placebo (-5.3/-6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.). CONCLUSION: N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy.