Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

Outcome of isolated posterior cruciate ligament reconstruction at mean 6.3-year follow up: a consecutive case series

Objectives: There is a paucity of reporting on surgical outcomes of isolated posterior cruciate ligament reconstruction (PCLR). We hypothesize that isolated PCL injuries failing nonoperative treatment achieve good outcomes and are able to return to sport following PCLR.

Methods: A retrospective analysis was performed to identify patients with isolated PCL injuries that underwent reconstruction between 2001 and 2014. Patients with multi-ligamentous injury or another concomitant knee pathology were excluded. Medical records were reviewed for demographic, clinical and operative data. Patients were contacted for administration of a telephone-based questionnaire which included the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form, Lysholm-Tegner scales, Marx activity scale (MAS), return to sport status, and patient satisfaction instruments.

Results: A total of 15 isolated PCL reconstructions in 14 patients with a mean age of 27.5 years (range 17–43) met the study inclusion criteria; mean follow up was 6.3 years (range 1.4–15.2). Pre-operatively, the primary complaint was knee instability in all patients; on physical examination, lack of a firm end point during posterior drawer testing was found in 93% (14/15) of the knees. In total, 12 of 15 knees underwent transtibial, single-bundle PCLR and three of 15 underwent tibial inlay, double bundle PCLR. Graft types included: quadriceps autograft (7/15), Achilles allograft (6/15), and hamstring autograft (2/15). There were no graft failures in our patient cohort. At most recent follow up the mean scores respectively on the IKDC form, Lysholm-Tegner scales and MAS were (standard deviation): 77.3 (16.5), 83.1 (17.9), 6.13 (2.6), and 7.1 (6.0). All fourteen patients were athletes prior to their injury and 79% (11/14) returned to sport and overall patient satisfaction was 9.2/10.

Conclusions: Isolated PCLR provides good outcomes at mean medium-term follow up with restoration of function, high rate of return to sport and overall patient satisfaction.     

Multidimensionality of the PROMIS self-efficacy measure for managing chronic conditions

Quality of Life Research - This study investigated the PROMIS Self-Efficacy Measure for Managing Chronic Conditions (PROMIS-SE) domain distributions and examined the factor structure of the...     

An Improved Method for the Synthesis of the of Indole[2,3-a]Pyrrolo[3,4-c]Carbazole-5,6-Dione N-Glycosides and their Cytotoxic Activity

Pharmaceutical Chemistry Journal - Use of formylindolylacetic acid as a reagent at the stage of preparing the glycosides of bis(indolyl)furan-2,5-diones and dioxane as solvent increased yields from...     

No Influence of the Fat Mass and Obesity-Associated Gene rs9939609 Single Nucleotide Polymorphism on Blood Lipids in Young Males

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is linked to obesity and dyslipidemia, yet the independent influence of this polymorphism on blood lipids remains equivocal. We examined the influence of the FTO rs9939609 polymorphism on fasting and postprandial blood lipids in individuals homozygous for the risk A-allele or T-allele with similar anthropometric and demographic characteristics. 12 AA and 12 TT males consumed a standardized meal after fasting overnight. Blood samples were collected at baseline (−1.5 h), before the meal (0 h), and for five hours postprandially to measure lipid, glucose, and insulin concentrations. Time-averaged total area under the curve (TAUC) values (0–5 h) were calculated and compared between genotypes. Fasting triacylglycerol (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, non-esterified fatty acid (NEFA), glucose, and insulin concentrations were similar between groups (p ≥ 0.293). TAUC for TG was similar in AAs and TTs (95% confidence interval (CI) −0.52 to 0.31 mmol/L/h; p = 0.606). Likewise, TAUC values were similar for NEFA (95% CI −0.04 to 0.03 mmol/L/h; p = 0.734), glucose (95% CI −0.41 to 0.44 mmol/L/h; p = 0.951), and insulin (95% CI −6.87 to 2.83 pmol/L/h; p = 0.395). Blood lipids are not influenced by the FTO rs9939609 polymorphism, suggesting the FTO-dyslipidemia link is mediated by adiposity and weight management is important in preventing FTO-related lipid variations.