Drug and Alcohol Rehabilitation: Inducible Nitric Oxide Synthase Haplotype Associated With Hypertension and Responsiveness to Antihypertensive Drug Therapy.
Inducible nitric oxide synthase haplotype associated with hypertension and responsiveness to antihypertensive drug therapy.
Filed under: Drug and Alcohol Rehabilitation
Gene. 2012 Dec 21;
Oliveira-Paula GH, Lacchini R, Coeli-Lacchini FB, Junior HM, Tanus-Santos JE
Hypertension is a multifactorial disorder associated with increased inducible nitric oxide synthase (iNOS) expression and activity. While genetic polymorphisms affect iNOS expression, it is not known whether iNOS gene polymorphisms affect the susceptibility to hypertension and the responses to antihypertensive therapy. This study aimed at assessing whether iNOS polymorphisms ((CCTTT)(n), g.-1026C>A, and g.2087G>A) and haplotypes are associated with hypertension and with responsiveness to drug therapy. We studied 115 well controlled hypertensive patients (HTN), 82 hypertensive patients resistant to optimized antihypertensive therapy (RHTN), and 113 normotensive healthy subjects (NT). Genotypings were carried out using real-time polymerase chain reaction (PCR) and PCR amplification followed by capillary electrophoresis. The software PHASE 2.1 was used to estimate the haplotypes frequencies in each group. Variant genotypes (GA+AA) for the g.2087G>A polymorphism were more commonly found in hypertensive patients (HTN+RHTN) than in normotensives (P=0.016; OR=2.05). We found no associations between genotypes and responsiveness to therapy (P>0.05). The S-C-A haplotype was more commonly found in hypertensive patients (HTN+RHTN) than in normotensives (P=0.014; OR=6.07). Interestingly, this haplotype was more commonly found in the HTN group than in the RHTN group (P=0.012; OR=0.14). Our findings indicate that the g.2087G>A polymorphism in the iNOS gene affects the susceptibility to hypertension. Moreover, while the S-C-A haplotype is associated with hypertension, it is also associated with responsiveness to antihypertensive therapy.
HubMed – drug
Causal co-expression method with module analysis to screen drugs with specific target.
Filed under: Drug and Alcohol Rehabilitation
Gene. 2012 Dec 21;
Yu S, Zheng L, Li Y, Li C, Ma C, Yu Y, Li X, Hao P
The considerable increase of investment in research and development by the pharmaceutical industry over the past three decades has not added the number of approved new drugs. An important issue ignored by drug discovery practice is the multi-dimensional interaction network between drugs and their targets. Thus, it is essential to view drug actions through the lens of network biology. In the curent study, based on the co-expression network of transcription factors and their downstream genes, we proposed a novel approach, called causal co-expression method with module analysis, to screen drugs with specific target and fewer side effects. We presented a causal co-expression method with module analysis and it could be used in analyzing the microarray data of different drug candidates. At first, the differential wiring value (DW) was calculated to find some causal transciption factors (TFs) by combining with differential expression genes in the regulated networks. After the discovery of the causal TFs, co-expression module analysis method was applied to mine molecular pharmacology pathways around these causal TFs at molecular level. We applied our methods to two drug candidates, Argyrin A and Bortezomib, both with anti-cancer activities. We first obtained some differentially expressed transcription factors of cells treated with Argyrin A or Bortezomib. Nearly all these transcription factors are associated with the tumor suppressor protein p27kip1. Furthermore, module analysis showed that Bortezomib inhibited tumor growth not specifically by cell cycle and cell proliferation pathway, but through many basic metabolic processes which result in cell toxicity. In contrast, Argyrin A had influence on cell cycle, and was involved in DNA damage repair at the same time, showing that Argyrin A was a more suitable drug for anti-cancer treatment. Our study revealed that the causal co-expression method with module analysis was effective and can be used as a tool to evaluate drug candidates.
HubMed – drug
Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier.
Filed under: Drug and Alcohol Rehabilitation
J Control Release. 2012 Dec 21;
Beloqui A, Solinís MA, Gascón AR, Del Pozo-Rodríguez A, des Rieux A, Préat V
The aims of this work were (i) to evaluate the potential of nanostructured lipid carriers (NLCs) as a tool to enhance the oral bioavailability of poorly soluble compounds using saquinavir (SQV), a BCS class IV drug and P-gp substrate as a model drug, and (ii) to study NLC transport mechanisms across the intestinal barrier. Three different NLC formulations were evaluated. SQV transport across Caco-2 monolayers was enhanced up to 3.5-fold by NLCs compared to SQV suspension. M cells did not enhance the transport of NLCs loaded with SQV. The size and amount of surfactant in the NLCs influenced SQV permeability, the transcytosis pathway and the efflux of SQV by P-gp. An NLC of size 247nm and 1.5% (w/v) surfactant content circumvented P-gp efflux and used both caveolae- and clathrin-mediated transcytosis, in contrast to the other NLC formulations, which used only caveolae-mediated transcytosis. By modifying critical physicochemical parameters of the NLC formulation, we were thus able to overcome the P-gp drug efflux and alter the transcytosis mechanism of the nanoparticles. These findings support the use of NLCs approaches for oral delivery of poorly water-soluble P-gp substrates.
HubMed – drug
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