Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity.

Immune Checkpoint Inhibitor-related Pancreatitis: A Case Series, Review of the Literature and an Expert Opinion.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies, but are associated with serious adverse events like pancreatitis. Current guidelines are limited to the first step in treating acute ICI-related pancreatitis with steroids but lack treatment advices for steroid dependent pancreatitis. We describe a case series of 3 patients who developed ICI-related pancreatitis with chronic features such as exocrine insufficiency and pancreatic atrophy at imaging.

Protist.guru: A Comparative Transcriptomics Database for Protists.

During the last few decades, the study of microbial ecology has been enabled by molecular and genomic data. DNA sequencing has revealed the surprising extent of microbial diversity and how microbial processes run global ecosystems. However, significant gaps in our understanding of the microbial world remain, and one example is that microbial eukaryotes, or protists, are still largely neglected.

Fungi.guru: Comparative genomic and transcriptomic resource for the fungi kingdom.

The fungi kingdom is composed of eukaryotic heterotrophs, which are responsible for balancing the ecosystem and play a major role as decomposers. They also produce a vast diversity of secondary metabolites, which have antibiotic or pharmacological properties. However, our lack of knowledge of gene function in fungi precludes us from tailoring them to our needs and tapping into their metabolic diversity.

Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients.

Hearing screening outcome in neonatal intensive care unit graduates from a tertiary care centre in Singapore.

Background: We aimed to analyse the outcome of universal newborn hearing screening (UNHS) and high-risk hearing screening in neonatal intensive care unit (NICU) graduates in a tertiary care unit.

Methods: The hearing screen programme comprises a 2-stage automated auditory brainstem response protocol followed by a high-risk hearing screen at 3-6 months. This study is a retrospective study of NICU graduates born between April 2002 and December 2009.

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.

is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible.

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model.

COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib.

Recrudescence, Reinfection, or Relapse? A More Rigorous Framework to Assess Chloroquine Efficacy for Plasmodium vivax Malaria.

Background: Plasmodium vivax resistance to chloroquine (CQ) has been reported worldwide, although the World Health Organization clinical drug efficacy studies protocol does not permit classification of patient outcomes.

Methods: We enrolled 40 patients with P. vivax malaria in northeastern Cambodia, where >17% treatment failures were previously reported.

Development and validation of liquid chromatography tandem mass spectrometry method quantitative determination of polymyxin B1, polymyxin B2, polymyxin B3 and isoleucine-polymyxin B1 in human plasma and its application in clinical studies.

Polymyxin B (PB) is an antibiotic consisting of a cyclic heptapeptide and a tripeptide side chain used in treatment of infections caused by Gram-negative bacteria. Commercial formulations of PB contain multiple structurally related components with major constituents of PB1, PB2, PB3 and ile-PB1. To understand the pharmacokinetics of these major components, we have developed and validated a LC-MS/MS method to quantify PB1, PB2, PB3 and ile-PB1 in human plasma.

Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial.

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial.

Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) ( n  =   8), rifampicin (10 mg/kg) ( n  =   14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid ( n  =   14).

Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.

Background: Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.

Methods: Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen.

Post-hemodialysis dosing of 1 vs. 2 g of ceftazidime in anuric end-stage renal disease patients on low-flux dialysis and its pharmacodynamic implications on clinical use.

Ceftazidime is a cost-effective antimicrobial against Gram-negative pathogens associated with sepsis in end-stage renal disease (ESRD) hemodialysis patients with potential for wider use with the advent of ceftazidime-avibactam. Dosing ceftazidime post-hemodialysis appears attractive and convenient, but limited in vivo data on pharmacodynamic efficacy (PE) attainment, defined as >70% of the interdialytic period drug concentrations exceed susceptible pathogens minimal inhibitory concentrations (MICs) (%TMIC), warrants further assessment. We therefore evaluated PE and tolerability of 1 against 2 g regime in anuric ESRD patients on low-flux hemodialysis.

Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults.

Objectives: Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions.

Methods: Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days.

Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function.

Development and validation of liquid chromatography tandem mass spectrometry method for simultaneous quantification of first line tuberculosis drugs and metabolites in human plasma and its application in clinical study.

Rifampicin (RIF) and isoniazid (INH), first line drugs for the treatment of tuberculosis, are known to cause hepatotoxicity as a serious adverse side effect. To further understand the pharmacokinetic parameters of these two drugs, we have developed and validated a rapid, sensitive and selective LC-MS/MS method for simultaneous quantification of RIF, INH and their metabolites 25-desacetylrifampicin (DRIF), acetylisoniazid (AcINH) and isonicotinic acid (INA). Analytes were extracted from 20 μl of plasma using solid-phase extraction (SPE) followed by chromatographic separation on Zorbax SB-Aq column (50 mm × 4.

Prediction scores or gastroenterologists' Gut Feeling for triaging patients that present with acute upper gastrointestinal bleeding.

Introduction: Several prediction scores for triaging patients with upper gastrointestinal (GI) bleeding have been developed, yet these scores have never been compared to the current gold standard, which is the clinical evaluation by a gastroenterologist. The aim of this study was to assess the added value of prediction scores to gastroenterologists' Gut Feeling in patients with a suspected upper GI bleeding.

Methods: WE PROSPECTIVELY EVALUATED GUT FEELING OF SENIOR GASTROENTEROLOGISTS AND ASKED THEM TO ESTIMATE: (1) the risk that a clinical intervention is needed; (2) the risk of rebleeding; and (3) the risk of mortality in patients presenting with suspected upper GI bleeding, subdivided into low, medium, or high risk.

Hearing Loss in Newborns with Cleft Lip and/or Palate.

Introduction: This study aims to review the results of hearing screens in newborns with cleft deformities.

Materials And Methods: A retrospective audit of 123 newborns with cleft deformities, born between 1 April 2002 and 1 December 2008, was conducted. Data on the results of universal newborn hearing screens (UNHS) and high-risk hearing screens, age at diagnosis, severity/type of hearing loss and mode of intervention were obtained from a prospectively maintained hearing database.

Pharmacokinetics of ertapenem in outpatients with complicated urinary tract infections.

Objectives: Ertapenem is a broad-spectrum carbapenem antibiotic used to treat severe bacterial infections. In view of its dosing convenience, it is increasingly used as outpatient therapy. The objective of this study was to determine the pharmacokinetics and renal disposition of ertapenem in outpatients with complicated urinary tract infections.

Reassessment of the predictive value of the Forrest classification for peptic ulcer rebleeding and mortality: can classification be simplified?

Background And Study Aims: This study aimed to reassess whether the Forrest classification is still useful for the prediction of rebleeding and mortality in peptic ulcer bleedings and, based on this, whether the classification could be simplified.

Patients And Methods: Prospective registry data on peptic ulcer bleedings were collected and categorized according to the Forrest classification. The primary outcomes were 30-day rebleeding and all-cause mortality rates.

CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.

We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1-day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry.

Simultaneous determination of probe drugs, metabolites, inhibitors and inducer in human plasma by liquid chromatography/tandem mass spectrometry and its application to pharmacokinetic study.

Cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferase 1A1 (UGT1A1) are important enzymes responsible for the metabolism of many xenobiotics. To investigate their induction and inhibition properties, administering probe drugs and monitoring their concentration in plasma under the effects of inducers/inhibitors is the gold standard method. A rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of midazolam, raltegravir (probe drugs for CYP3A4 and UGT1A1), their major metabolites, 1'-hydroxymidazolam, 1'-hydroxymidazolam glucuronide and raltegravir glucuronide, rifampicin (inducer), ritonavir and ketoconazole (inhibitors).

[Conservative treatment of acute diverticulitis].

Scientific evidence concerning the treatment of acute diverticulitis is scarce. We describe 2 patients with this condition in this article. The first, a 64-year-old man, came to the emergency room because he had experienced persistent abdominal pain for the previous 4 days.