Dilevalol

Idiosyncratic adverse drug reactions are drug reactions that occur rarely and unpredictably among the population. These reactions often occur after a drug is marketed, which means that they are strongly related to the genotype of the population. The prediction of such adverse reactions is a major challenge because of the lack of appropriate test models during the drug development process. In this study, we chose withdrawn drugs because the reasons why they were withdrawn and from which countries or regions is easily obtained. We selected Dilevalol and its chiral drug (Labetalol) as the investigatory drugs, as they have been withdrawn from a European market (Britain) because of serious hepatotoxicity. First, we searched for and obtained the Dilevalol-induced- liver-injury related protein, multidrug resistance protein 1 (MDR1), from the Comparative Toxicogenomics Database (CTD). Then, we searched and extracted 477 non-synonymous single nucleotide polymorphisms (nsSNP) on MDR1 in the dbSNP database. Second, we used the VarMod tool to predict the functional changes of MDR1 induced by these nsSNPs, from which we extracted the nsSNPs that significantly change the functions of this protein. Third, we built the three-dimensional structures of those variant proteins and used AutoDock to perform a docking study, choosing the best model to determine the sites of nsSNPs. Finally, we used the data from the 1000 Genomes Project to verify the dominant population distribution of the risk SNP. We applied the same strategy to the post-marketing drug-induced liver injury drugs to further test the feasibility of our method.

Not only is there a limited number of studies on the effects of vasodilator β-blocker (VBB) therapy on kidney function - specifically, glomerular filtration rate (GFR), serum creatinine (sCr) and proteinuria - but of those that have been reported, the results are mixed. This meta-analysis seeks to assess the efficacy of VBBs on selected renal parameters in hypertensive patients.

We conducted a meta-analysis of any prospective trial that provided both baseline and follow-up of at least 4 weeks of VBB therapy - carvedilol, labetalol, dilevalol, nebivolol and celiprolol in patients with hypertension. We used Ovid MEDLINE, EMBASE and PubMed, all without date restrictions. We included 39 studies totaling 3987 patients.

Although VBBs did not significantly change GFR or sCr levels after at least 4 weeks of therapy, they did significantly decrease protein excretion by -0.12 SD units [95% confidence interval (CI) -0.19 to -0.04; P < 0.01]. VBBs did not alter renal blood or plasma flow, but renal vascular resistance (RVR) decreased by -20.03 mmHg min/l (95% CI -28.92 to -11.15; P < 0.01). In the analysis which compared VBBs with non-VBBs, the only significant difference was the greater decrease in RVR in the VBB group by -38.44 mmHg min/l (95% CI -60.57 to -16.31; P < 0.01).

VBBs do not affect GFR or sCr levels, but decrease protein excretion. This class of β-blockers, however, is not superior to non-VBBs in reducing proteinuria. VBBs decrease RVR significantly more than non-VBBs.