Comparison of the influence of cyclosporine and tacrolimus on the pharmacokinetics of prednisolone in adult male kidney transplant recipients

Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Clinical Pharmacokinetics of Paclitaxel Monotherapy: An Updated Literature Review.

Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract the maximum concentration (C max), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121 aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m2 and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles. The most widely used dose of cremophor-diluted paclitaxel, 175 mg/m2 given as a 3-h infusion, leads to an interstudy median C max of 5.1 µmol/L [interquartile range (IQR) 4.5-5.7], CL of 12.0 L/h/m2 (IQR 10.9-12.9), and T > 0.05 µmol/L of 23.8 h (IQR 21.5-26.8). Importantly, the significant interindividual variation widely reported in the literature is not reflected in these interstudy estimates of pharmacokinetic parameters. Cremophor-diluted paclitaxel pharmacokinetics are non-linear following short (<6 h) but not long (>24 h) infusions. A similar pattern of non-linearity was observed for nab-paclitaxel, although the number of studies was limited. The pharmacokinetics of paclitaxel monotherapy have been widely studied at numerous dose levels of the Cremophor EL® formulation, but are less well-characterized for the newer nab-paclitaxel formulation. In conclusion, paclitaxel pharmacokinetics are non-linear for short infusion times but not for longer infusions. Whether a similar conclusion can be drawn for nab-paclitaxel formulations requires further study

Docetaxel-induced neuropathy:A pharmacogenetic case-control study of 150 women with early-stage breast cancer

<div><p></p><p><b>Background.</b> Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in <i>GSTP1</i> and <i>ABCB1</i> on DIPN.</p><p><b>Material and methods.</b> DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two polymorphisms in <i>GSTP1</i> and three in <i>ABCB1</i> were selected for the primary analysis, and a host of other candidate genes was explored and compared between 75 patients with clinician-reported DIPN grade ≥ 2 and 75 patients without DIPN.</p><p><b>Results.</b> Patients with the genetic variants <i>GSTP1</i> rs1138272 C/T or T/T (114Ala/114Val or 114Val/114Val) genotype had an adjusted odds ratio of 3.82; 95% confidence interval 1.34–11.09 of developing DIPN. This result was confirmed in both analysis of cumulated docetaxel dose and haplotype analysis. None of the explorative genes investigated were significantly correlated with DIPN. Patients with a BMI ≥ 30 were five-fold more likely to have DIPN than patients with BMI < 25.</p><p><b>Conclusion.</b> We found that <i>GSTP1</i> Ala114Val polymorphism is associated with occurrence of DIPN. This supports the theory that oxidative stress is involved in DIPN pathophysiology. If confirmed, this may be helpful in the risk assessment of DIPN and perhaps help to achieve better management of neurotoxicity.</p></div

The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis

Background. In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. Methods. In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated. Results. Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09). Conclusions. Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer