The overall objective of the Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment II (SMAART-II) is to deploy a hybrid study design to firstly, demonstrate the efficacy of a polypill (Polycap ®) containing fixed doses of antihypertensives, a statin, and antiplatelet therapy taken as two capsules, once daily orally in reducing composite vascular risk over 24 months vs. usual care among 500 recent stroke patients encountered at 12 hospitals in Ghana. Secondly, SMAART II seeks to develop an implementation strategy for routine integration and policy adoption of this polypill for post-stroke cardiovascular risk reduction in an under-resourced system burdened by suboptimal care and outcomes.

开始日期2024-09-01

申办/合作机构

Northern California Institute for Research & Education

NCT03329599 / Completed临床2期IIT

Stroke Minimization Through Additive Anti-atherosclerotic Agents in Routine Treatment

The overarching objective of the Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment (SMAART) trial is to assess whether a polypill containing fixed doses of (2/3) antihypertensives, a statin and antiplatelet therapy taken once daily orally would result in carotid intimal thickness regression-a surrogate marker of atherosclerosis, improved adherence, and tolerability compared with 'usual care' group on separate individual secondary preventive medications among Ghanaian first time stroke survivors. Our ultimate objective is to design of a future multi center, double-blinded, placebo-controlled, parallel-group, randomized trial comparing the clinical efficacy of the polypill strategy vs 'usual care' in the African context to derive locally relevant, high-quality evidence for routine deployment of polypill for CVD risk moderation among stroke survivors in LMICs. In this current study, we plan to recruit 120 recent ischemic stroke survivors randomized 1:1 to the polypill or usual care arms.

开始日期2019-02-14

申办/合作机构

Northern California Institute for Research & Education

NCT01646437 / Completed临床3期IIT

The International Polycap Study 3 (TIPS-3) is a Randomized Double-blind Placebo-controlled Trial for the Evaluation of a Polycap, Low Dose Aspirin and Vitamin D Supplementation in Primary Prevention

The randomized 2x2x2 factorial design placebo controlled trial will enroll 5000 participants (women 60 years or older and men 55 years or older) without known heart disease or prior stroke and without a clear indication or contraindication to any of the study medications. Eligible and consenting individuals will be randomized to receive either the active study medications or placebo (dummy pills) and will be monitored for an average of 5 years. The study will include people from at 10 countries, will be conducted by an international group of scientists and physicians and will be coordinated by the Population Health Research Institute at Hamilton Health Sciences.

开始日期2012-06-01

申办/合作机构

Population Health Research Institute

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100 项与 NCC x β1-adrenergic receptor 相关的临床结果

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100 项与 NCC x β1-adrenergic receptor 相关的转化医学

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0 项与 NCC x β1-adrenergic receptor 相关的专利（医药）

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项与 NCC x β1-adrenergic receptor 相关的文献（医药）

2021-08-01·Kidney International1区 · 医学

Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

1区 · 医学

Article

作者: Kortenoeven, Marleen L A ; Fenton, Robert A ; Cheng, Lei ; Murali, Sathish K ; Matchkov, Vladimir V ; Little, Robert ; Poulsen, Søren B ; Penton, David ; Loffing, Johannes

The thiazide-sensitive sodium-chloride-cotransporter (NCC) in the kidney distal convoluted tubule (DCT) plays an essential role in sodium and potassium homeostasis. Here, we demonstrate that NCC activity is increased by the β2-adrenoceptor agonist salbutamol, a drug prevalently used to treat asthma. Relative to β1-adrenergic receptors, the β2-adrenergic receptors were greatly enriched in mouse DCT cells. In mice, administration of salbutamol increased NCC phosphorylation (indicating increased activity) within 30 minutes but also caused hypokalemia, which also increases NCC phosphorylation. In ex vivo kidney slices and isolated tubules, salbutamol increased NCC phosphorylation in the pharmacologically relevant range of 0.01-10 μM, an effect observed after 15 minutes and maintained at 60 minutes. Inhibition of the inwardly rectifying potassium channel (Kir) 4.1 or the downstream with-no-lysine kinases (WNKs) and STE20/SPS1-related proline alanine-rich kinase (SPAK) pathway greatly attenuated, but did not prevent, salbutamol-induced NCC phosphorylation. Salbutamol increased cAMP in tubules, kidney slices and mpkDCT cells (model of DCT). Phosphoproteomics indicated that protein phosphatase 1 (PP1) was a key upstream regulator of salbutamol effects. A role for PP1 and the PP1 inhibitor 1 (I1) was confirmed in tubules using inhibitors of PP1 or kidney slices from I1 knockout mice. On normal and high salt diets, salbutamol infusion increased systolic blood pressure, but this increase was normalized by thiazide suggesting a role for NCC. Thus, β2-adrenergic receptor signaling modulates NCC activity via I1/PP1 and WNK-dependent pathways, and chronic salbutamol administration may be a risk factor for hypertension.

2011-05-01·Hypertension1区 · 医学

Association of Hypertension Drug Target Genes With Blood Pressure and Hypertension in 86 588 Individuals

1区 · 医学

Article

作者: Larson, Martin G. ; Psaty, Bruce M. ; Rice, Kenneth ; Johnson, Toby ; Chakravarti, Aravinda ; Caulfield, Mark ; Chasman, Daniel I. ; Launer, Lenore J. ; Rose, Lynda ; van Duijn, Cornelia M. ; Gudnason, Vilmundur ; Johnson, Andrew D. ; Ridker, Paul M. ; Verwoert, Germaine C. ; Ehret, Georg B. ; Levy, Daniel ; Newton-Cheh, Christopher ; Munroe, Patricia B.

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29 136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1 , ADRB2 , AGT , CACNA1A , CACNA1C , and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34 433) and the Women's Genome Health Study (n=23 019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P= 4.7×10 −10 ), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P= 9.5×10 −10 ), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P= 3.3×10 −4 ). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P= 3.8×10 −6 ), as well as diastolic blood pressure ( P= 5.0×10 −8 ) and hypertension ( P= 3.7×10 −7 ). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P= 3.0×10 −5 ). Two loci, ADRB1 and AGT , contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.

2009-12-01·American Journal of Hypertension3区 · 医学

Genetic Factors Are Relevant and Independent Determinants of Antihypertensive Drug Effects in a Multiracial Population

3区 · 医学

Article

作者: Henk-Jan Guchelaar ; Gert A. van Montfrans ; Petra C. van Rijn-Bikker ; Aeilko H. Zwinderman ; Richard P. Koopmans ; Eric J.G. Sijbrands ; Gideon Mairuhu

BACKGROUNDThe success of antihypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to antihypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental, and genetic factors.METHODSA population-based, crossover, open-label randomized treatment study stratified for ethnicity in 102 mildly hypertensive patients aged 35-60 years in an outpatient hypertension clinic (the ROTATE study). Patients underwent five successive 6-week treatment episodes of single-drug treatment in a randomized order with representatives of the major antihypertensive drug classes. The primary outcome measure was the DeltaSBP after 6-week drug therapy.RESULTSParticipants (n = 97) completed 407 treatment episodes. The estimated unpredictable natural variation of SBP within individuals was 65% of the total study variance. The primary analysis model that considered the effects of environmental, demographic, and genetic factors and their interactions to SBP response to antihypertensive drugs, explained 23% of the total variance accounting for 66% of the predictable variance. Ethnicity, low sodium intake, and ADD1 614G-->T polymorphism were the only drug-related predictors. A number of genetic variants (ADD1 614G-->T, ADRB1 145A-->G, ADRB2 79C-->G, CYP11B2 -344C-->T, and SLC12A3 78G-->A) contributed significantly (9%) to the total variance of the SBP response. The contribution of each individual single-nucleotide polymorphism (SNP) ranged from 1.1 to 2.4%.CONCLUSIONSGenetic factors are relevant and independent determinants of antihypertensive drug effects in a multiracial population.