Pharmacokinetics of penicillin G in preterm and term neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age 90% for MICs ≤2 mg/L with doses of 25,000 IU/kg/q12h. In neonates, regardless of GA, PK parameters of penicillin G are similar. The dose of 25,000 IU/kg/q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 hours of life

ATP-binding cassette (ABC) transporters in normal and pathological lung

ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) are highly expressed in bronchial epithelium. This review aims to give new insights in the possible functions of ABC molecules in the lung in view of their expression in different cell types. Furthermore, their role in protection against noxious compounds, e.g. air pollutants and cigarette smoke components, will be discussed as well as the (mal)function in normal and pathological lung. Several pulmonary drugs are substrates for ABC transporters and therefore, the delivery of these drugs to the site of action may be highly dependent on the presence and activity of many ABC transporters in several cell types. Three ABC transporters are known to play an important role in lung functioning. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis, and mutations in ABCA1 and ABCA3 are responsible for respectively Tangier disease and fatal surfactant deficiency. The role of altered function of ABC transporters in highly prevalent pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) have hardly been investigated so far. We especially focused on polymorphisms, knock-out mice models and in vitro results of pulmonary research. Insight in the function of ABC transporters in the lung may open new ways to facilitate treatment of lung diseases

The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone

PURPOSE: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug-naive patients experiencing a first episode of psychosis. ----- METHODS: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-restriction fragment length polymorphism analysis (for alleles *3,*4,*6) and long-distance PCR (for duplications and allele *5), while real-time PCR analysis was used for the ABCB1 G2677T/A and C3435T variants. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-performance liquid chromatography. ----- RESULTS: The number of patients with the CYP2D6 wild type (wt)/wt, wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G, G/T and T/T variants was 29, 42 and 12, respectively; those with the 3435CC, C/T and T/T variants was 25, 37 and 21, respectively. The CYP2D6 genotype had a strong effect on the steady-state dose-corrected plasma levels (C/D) of risperidone, its 9-OH metabolite and the active moiety, while the ABCB1 2677 T/T and 3435 T/T genotypes has similarly strong effects on the active moiety C/D. The CYP2D6 poor metabolizers had a significantly higher risperidone C/D and active moiety C/D and lower 9-OH risperidone C/D. The ABCB1 3435 T allele and the ABCB1 2667 T-3435 T haplotype carriers were more frequent among subjects without extrapyramidal syndromes. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data. ----- CONCLUSION: Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T may be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remain unclear

Thiopurine S-methyltransferase activity in Nigerians: phenotypes and activity reference values

Abstract Objectives This study assessed the activity of thiopurine S-methyltransferase (TPMT) in Nigerians with a view to providing data on susceptibility to thiopurine toxicity, and as well generate reference activity values for clinical use. Results TPMT activity, expressed as the amount of 6MMP in ng/mL after 1 h incubation at 37 °C per haemoglobin (U/g Hb), varied between 2.34 and 63.50 U/g Hb in the study population. Poor metabolic phenotypes, characterised by an activity values below 8.41 U/g Hb, were observed in 20% of the study subjects. Intermediate metabolizers had activity values between 8.41 and 16.13 U/g Hb. Fast and very fast metabolizers were characterised by activity values of 16.20–56.22 and > 56.22 U/g Hb, respectively. These findings suggest that a potentially huge discordance between TPMT phenotype and genotype exist in Nigerians, and emphasizes the superiority of a prior determination of TPMT metabolic phenotype in ensuring the safety of thiopurine drug administration in the population

European Reference Network for rare adult solid cancers, statement and integration to health care systems of member states: a position paper of the ERN EURACAN

International audienc

VP3-2022: Pembrolizumab (pembro) versus placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: Randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study

BACKGROUND & nbsp;Pembro is a standard of care for advanced NSCLC. PEARLS/ KEYNOTE-091 (NCT02504372) evaluated adjuvant pembro vs placebo for patients (pts) with completely resected early-stage NSCLC.& nbsp;METHODS & nbsp;Eligible pts with completely resected stage IB (T > 4 cm), II, or IIIA NSCLC per AJCC v7 followed by adjuvant chemo as indicated per guidelines, ECOG PS 0-1, and any PD-L1 expression were randomized 1:1 to pembro 200 mg or placebo Q3W for 18 doses (w1 year). Dual primary end points are DFS in the all-comers and PD-L1 TPS > 50% populations. Secondary end points are DFS in the TPS > 1% population, OS in the all-comers, TPS > 50% and > 1% populations, and safety. Data are from the protocol-specified second interim analysis (IA2; 20 September 2021, data cutoff).& nbsp;RESULTS & nbsp;1177 pts were randomized to pembro (N = 590) or placebo (N = 587), including 168 and 165, respectively, who had TPS >= 50%. Baseline characteristics were generally balanced between arms. Median time from randomization to data cutoff for IA2 was 35.6 mo (range 16.5-68.0). DFS was significantly improved with pembro in the all-comers population (median 53.6 vs 42.0 mo; HR 0.76; 95% CI 0.63-0.91; P = 0.0014); the significance boundary was not crossed for the TPS >= 50% population (median not reached in either arm; HR 0.82; 95% CI 0.57-1.18; P = 0.14). With only 209 events, the significance boundary for OS in the all-comers population was not crossed (18-mo rate 91.7% vs 91.3%; HR 0.87; 95% CI 0.67-1.15; P = 0.17). Median number of doses was 17 for pembro vs 18 for placebo. AEs were grade >= 3 in 34.1% of pts in the pembro arm vs 25.8% in the placebo arm and led to discontinuation in 19.8% vs 5.9%; treatment-related AEs led to death in 0.7% vs 0%.& nbsp;CONCLUSIONS & nbsp;Adjuvant pembro provided a statistically significant, clini-cally meaningful DFS improvement following complete resection and, when indicated, adjuvant chemo in pts with stage IB (T >= 4 cm)-IIIA NSCLC, regardless of PD-L1 expres-sion. The pembro safety profile was as expected. DFS in the PD-L1-defined populations and OS will be tested at future analyses according to the analysis plan