Antihypertensive and pleiotropic effects of Phyllanthus emblica extract as an add-on therapy in patients with essential hypertension-A randomized double-blind placebo-controlled trial.

Essential hypertension is an important cause of cardiovascular morbidity and mortality that is compounded by concomitant risk factors like diabetes mellitus and dyslipidemia. Phyllanthus emblica is a rich source of antioxidants, tannins, and vitamin C and is used in treating various ailments in traditional medicine. This study aimed to elucidate the effects of aqueous extract of Phyllanthus emblica on essential hypertension and other protective actions. This randomized controlled trial was conducted on 150 patients with essential hypertension. Participants were randomly assigned to receive Phyllanthus emblica capsule (500 mg) or placebo twice daily, added to their routine medications for 12 weeks. Blood pressure was assessed at baseline, 2, 4, 8, and 12 weeks after beginning treatment or placebo. Other investigations like lipid parameters, oxidant and antioxidant enzyme levels, hs-CRP levels, HbA1C, LFT, RFT, uric acid, and endothelial function were measured at baseline and 12 weeks. Both Phyllanthus emblica and placebo groups were comparable at baseline. Phyllanthus emblica had a good safety profile in patients with essential hypertension. However, the treatment with Phyllanthus emblica failed to produce any additional reduction in systolic and/or diastolic blood pressure levels and did not exhibit improvement in oxidant status, antioxidant capacity, lipid profile, HbA1C, arterial stiffness parameters, or hs-CRP levels.

Do polymorphisms in MDR1 and CYP3A5 genes influence the risk of cytogenetic relapse in patients with chronic myeloid leukemia on imatinib therapy?

Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.

Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia.

Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.

Therapeutic drug monitoring of antiepileptic drugs in a tertiary care hospital in India.

INTRODUCTION: Therapeutic drug monitoring (TDM) helps to optimize the dose of antiepileptic drugs. Only limited information is available about the clinical utility of TDM of antiepileptic drugs in India. Hence, we aimed to study the clinical utility of antiepileptic TDM in a tertiary care hospital in India and to explore the association between the plasma drug levels and the occurrence of breakthrough seizures and drug toxicity. METHODS: All patients taking antiepileptic drugs for whom TDM was done from January 2008 to December 2010 were included in the study. All relevant information was obtained from patient medical records. Trough levels were measured for all drugs using chemiluminescence assay. Drug levels were interpreted as within, below, and above the reference range, as recommended by the International League Against Epilepsy guidelines. RESULTS: Of the 420 samples analyzed during this period, 396 samples were included in this study for analysis. The maximum number of requests was for phenytoin (50%) followed by valproic acid (26%). The most common indication for TDM was dosage adjustment (38%) followed by breakthrough seizures (34%). Among the 135 samples received with breakthrough seizures as indication, more than 50% had drug levels either within or above the reference range. Among the 62 samples referred with clinical symptoms of suspected toxicity, drug levels were above the reference range in only 52% of the samples. CONCLUSIONS: Therapeutic drug monitoring was found to be useful in practice, in tailoring drug dosage in accordance with the needs of individual patient, in distinguishing nonresponders from noncompliants, and in aiding in making critical decisions. However, the "reference range" of these antiepileptic drugs was not reliable in predicting the occurrence of breakthrough seizures and clinical symptoms of suspected drug toxicity.

Efficacy and safety of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia: a randomized controlled trial.

INTRODUCTION: The long half-life of atorvastatin and fenofibrate makes them suitable for alternate day therapy. Hence, we aimed to study the efficacy, safety, and cost-effectiveness of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia. METHODS: Eligible patients with mixed dyslipidemia were randomly allotted into 2 equal parallel groups-alternate day therapy group (group 1) and daily therapy group (group 2). Patients in groups 1 and 2 received fixed dose combination of atorvastatin 10 mg and fenofibrate 160 mg on alternate days and daily, respectively, for 12 weeks. Mean percentage change from baseline in triglycerides (TGLs), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and TC-HDL ratio, incidence of adverse effects, and cost-effectiveness were compared in both the groups. RESULTS: Among 110 patients randomized, 99 completed the study till 12 weeks treatment duration. The TGLs, non-HDL-C, TC, and LDL-C decreased by 56.4%, 49.7%, 36.5%, and 39.2%, respectively, in alternate day therapy group and by 57.5%, 51.2%, 37.5%, and 39.4%, respectively, in daily therapy group. The HDL-C levels increased by 20.1% in alternate day therapy group compared to 21.8% in daily therapy group. No statistically significant difference was seen between both the groups in mean percentage change in lipid parameters from baseline to end of 12 weeks. Incidence of adverse events was reasonably less in alternate day therapy group. CONCLUSION: Alternate day therapy with atorvastatin-fenofibrate combination is an effective and safe alternative to daily therapy in mixed dyslipidemia. Apart from significant cost savings, reasonable reduction in the incidence of adverse events is seen with alternate day regimen. However, larger studies are needed to more reliably confirm our interesting but preliminary results.