Polymorphism in Gene for ABCC2 Transporter Predicts Methotrexate Drug Survival in Patients with Psoriasis.

Background and Objectives: Methotrexate is widely prescribed for the treatment of moderate-to-severe psoriasis. As drug survival encompasses efficacy, safety, and treatment satisfaction, such studies provide insights into successful drug treatments in the real-life scenario. The objective was to define methotrexate drug survival and reasons for discontinuation, along with factors associated with drug survival, in a cohort of adult patients with moderate-to-severe plaque psoriasis. Materials and Methods: Data on methotrexate treatment were extracted from our institutional registry. Drug survival was estimated by Kaplan-Meier analysis, and predictors of drug survival were analyzed by Cox proportional hazards regression. Results: We included 133 patients treated with methotrexate. Due to significant effects of the year of treatment initiation, drug survival analysis was performed for 117 patients who started methotrexate in 2010 or later. Median methotrexate drug survival was 11.0 months. Overall, 89% of patients discontinued treatment, with over half of these (51%) due to lack of efficacy. Significantly longer drug survival was seen for patients who discontinued treatment due to lack of efficacy versus drug safety (p = 0.049); when stratified by sex, this remained significant only for women (p = 0.002). The patient ABCC2 rs717620 genotype was significantly associated with drug survival in both univariate log-rank and multivariate Cox regression analyses, with variant T allele associated with longer drug survival (hazard ratio, 0.606; 95% confidence interval, 0.380-0.967; p = 0.036). Conclusions: We have identified the novel association of patient ABCC2 rs717620 genotype with methotrexate drug survival. This pharmacogenetic marker might thus help in the management of psoriasis patients in daily practice.

Polymorphisms in GNMT and DNMT3b are associated with methotrexate treatment outcome in plaque psoriasis.

Methotrexate is used as first-line treatment of moderate to severe psoriasis. Despite the marked variability in treatment outcomes, no pharmacogenetic markers are currently used for personalised management of therapy. In this retrospective study, we investigated the effects of genetic predisposition on efficacy and toxicity of low-dose methotrexate in a cohort of 137 patients with moderate to severe plaque psoriasis. We genotyped 16 polymorphisms in genes for enzymes involved in the folate-methionine pathway and in methotrexate transport, and analysed their association with treatment efficacy and toxicity using classification and regression tree analysis and logistic regression. The most pronounced effect observed in this study was for GNMT rs10948059, which was identified as a risk factor for inadequate efficacy leading to treatment discontinuation. Patients carrying at least one variant allele had ~7-fold increased risk of treatment failure compared to patients with the wild-type genotype, as shown by the classification and regression tree analysis and logistic regression (odds ratio [OR], 6.94; p = 0.0004). Another risk factor associated with insufficient treatment responses was DNMT3b rs2424913, where patients carrying at least one variant allele had a 4-fold increased risk of treatment failure compared to patients with the wild-type genotype (OR, 4.10; p = 0.005). Using classification and regression tree analysis, we show that DNMT3b rs2424913 has a more pronounced role in patients with the variant GNMT genotype, and hence we suggest an interaction between these two genes. Further, we show that patients with the BHMT rs3733890 variant allele had increased risk of hepatotoxicity (OR, 3.17; p = 0.022), which is the most prominent reason for methotrexate discontinuation. We also show that variants in the genes for methotrexate transporters OATP1B1 (rs2306283/rs4149056 SLCO1B1 haplotypes) and ABCC2 (rs717620) are associated with increased risk of treatment failure. The associations identified have not been reported previously. These data suggest that polymorphisms in genes for enzymes of the methionine cycle (which affect cell methylation potential) might have significant roles in treatment responses to methotrexate of patients with psoriasis. Further studies are warranted to validate the potential of the pharmacogenetic markers identified.

Curriculum Mapping of the Master's Program in Pharmacy in Slovenia with the PHAR-QA Competency Framework.

This article presents the results of mapping the Slovenian pharmacy curriculum to evaluate the adequacy of the recently developed and validated European Pharmacy Competences Framework (EPCF). The mapping was carried out and evaluated progressively by seven members of the teaching staff at the University of Ljubljana's Faculty of Pharmacy. Consensus was achieved by using a two-round modified Delphi technique to evaluate the coverage of competences in the current curriculum. The preliminary results of the curriculum mapping showed that all of the competences as defined by the EPCF are covered in Ljubljana's academic program. However, because most EPCF competences cover healthcare-oriented pharmacy practice, a lack of competences was observed for the drug development and production perspectives. Both of these perspectives are important because a pharmacist is (or should be) responsible for the entire process, from the development and production of medicines to pharmaceutical care in contact with patients. Nevertheless, Ljubljana's graduates are employed in both of these pharmaceutical professions in comparable proportions. The Delphi study revealed that the majority of differences in scoring arise from different perspectives on the pharmacy profession (e.g., community, hospital, industrial, etc.). Nevertheless, it can be concluded that curriculum mapping using the EPCF is very useful for evaluating and recognizing weak and strong points of the curriculum. However, the competences of the framework should address various fields of the pharmacist's profession in a more balanced way.

A novel, self-shielded modular radiosynthesis system for fully automated preparation of PET and therapeutic radiopharmaceuticals.

OBJECTIVE: With the vast development of theranostics and, recently, (68)Ga-radiolabeled molecules, there is also a need for novel, smaller, flexible, safe, and efficient modular automated synthesis systems in different clinical settings. The aim of our study was to determine the shielding properties of the modular self-shielded automated radiosynthesis box and determine its suitability for routine preparation of different radiopharmaceuticals to be used for diagnosis and therapy. METHODS: To evaluate shielding properties, shielding factors were determined using two different radiation sources: (137)Cs and (68)Ga. The dose rates were measured at critical points at the surface and 1 m distance from the surface. Three different methods were used to concentrate and purify (68)Ga generator eluate. Performance of the system was tested by evaluating several radiolabeling applications using (68)Ga, (177)Lu, and (90)Y. RESULTS: Dose rates measured at the surface did not exceed 9 µSv/h for (68)Ga and 20 µSv/h when using (137)Cs. On average, dose rates at the surface were reduced for factors of 1665 and 906, respectively. Different DOTA peptides were labeled successfully with (68)Ga with radiochemical purities more than 94% using three different radiolabeling methods. (177)Lu-DOTATATE and (90)Y-DOTATATE were synthesized reproducibly with a radiochemical purity of more than 99% and more than 97%, respectively. CONCLUSION: A self-shielded radiosynthesis box is a unique solution for nuclear medicine departments that lack space for installation of standard automated synthesis systems set in large and heavy dedicated PET synthesis boxes. Shielding properties are sufficient for safe clinical use for both PET and ß(-) radioisotopes. Because of its modular design and the simple adaptability of system parameters, the system can be used for the preparation of different clinically used radiopharmaceuticals and is also useful for research purposes.

Low CD8 T cells in neonates and infants prior to surgery, and health-care-associated infections: prospective observational study.

BACKGROUND: Major surgery suppresses the cell-mediated immune response in children and adults. Data on preoperative and postoperative T-cell counts in pediatric surgical patients and their relationship to health-care-associated infection (HAI) are not yet known. METHODS: A prospective observational study was carried out in a level III multidisciplinary neonatal and pediatric intensive care unit. Before and after, and in the first 3 days after surgery, lymphocyte subsets in peripheral blood were measured in 28 neonates and infants on flow cytometry. HAI were classified according to CDC/NHSN criteria. RESULTS: Six out of 28 neonates and infants (21.4%) developed HAI (group I-HAI), while 22 out of 28 (78.6%) remained infection free (group II-non-HAI). In group I with HAI, the preoperative median cytotoxic T-lymphocyte (CD8-T-cell) level was found to be below normal, and remained very low throughout the study period. In addition, the median and interquartile CD8 T-cell range (358 cells/µL; 304-424 cells/µL) were twice as low compared to group II without HAI (822 cells/µL; 522-933 cells/µL; P = 0.013). No differences were found between the two groups with regard to patient demographics and clinical data. CONCLUSION: Neonates and infants who underwent a major surgical procedure and who had a very low preoperative CD8 T-cell level, developed HAI postoperatively.