A high performance liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of 10 drug compounds commonly used for antimicrobial therapy in plasma and serum of critically ill patients: Method optimization, validation, cross-validation and clinical application.

Background And Aims: Intensive care antibiotic treatment faces challenges due to substantial pharmacokinetic differences in critically ill patients. Individualized antibiotic dosing guided by therapeutic drug monitoring (TDM) is considered to minimize the risk of treatment failure and toxicity. This study aimed to develop a valid method for simultaneous LC-MS/MS quantification of 10 drugs frequently used in intensive care antibiotic therapy for which TDM-guided dosing is recommended: piperacillin, meropenem, flucloxacillin, cefuroxime, vancomycin, colistin A and B, linezolid, ciprofloxacin and tazobactam.

Targeted and untargeted screening for impurities in losartan tablets marketed in Germany by means of liquid chromatography/high resolution mass spectrometry.

Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al.

Application of advanced high resolution mass spectrometric techniques for the analysis of losartan potassium regarding known and unknown impurities.

Recalls of medicinal products can cause supply bottlenecks. This is often due to the findings of unexpected impurities that pose a health risk to patients. A recent example is losartan potassium which was contaminated with azido-impurities.

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID-19.

Background: The broad-spectrum antifungal isavuconazole is administered to treat invasive aspergillosis and mucormycosis.

Objectives: Isavuconazole plasma concentrations in critically ill ICU patients with or without COVID-19 and invasive fungal infection were determined, and factors for sub-therapeutic drug levels (<1 μg/mL) were evaluated.

Patients And Methods: Isavuconazole plasma levels were measured as part of therapeutic drug monitoring (TDM) in ICUs of a tertiary hospital.

Identification of low-level impurities in drug prototypes of carbocisteine by means of liquid chromatography-high-resolution mass spectrometry and general unknown comparative screening.

High-resolution tandem quadrupole time-of-flight mass analysers enable new automated workflows for untargeted data evaluation of complex samples like drug products. An example of such procedure is the so-called general unknown comparative screening (GUCS), which is used for software-assisted, automated identification of components that are only present in a sample and not in a reference. The GUCS approach has been employed for the first time to detect both degradation products and reaction products in drug products.

Pharmacokinetics of Nirmatrelvir and Ritonavir in COVID-19 Patients with End-Stage Renal Disease on Intermittent Hemodialysis.

Nirmatrelvir/ritonavir is an effective antiviral therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Use is not recommended in patients with end-stage renal disease (ESDR) due to a lack of data. We investigated the pharmacokinetics of nirmatrelvir/ritonavir (150 mg/100 mg twice a day) in four patients with ESRD undergoing hemodialysis.

Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk.

This study aimed to assess the content of caffeine and its metabolites-paraxanthine, theophylline, and theobromine-in breast milk according to selected factors. Samples of human milk were collected from 100 women living in the east-northeast region of Poland. Information on the consumption of beverages and foods containing caffeine was collected using a 3 day food record.

SARS-CoV-2 viral load dynamics in immunocompromised critically ill patients on remdesivir treatment.

The relationship between SARS-CoV-2 quantitative viral load and risk of disease progression, morbidity such as long- COVID or mortality in immunosuppressed, remains largely undefined in COVID-19 patients. Critically ill immunosuppressed patients potentially benefit from remdesivir treatment because of the prolonged course of their infection. Four critically ill immunocompromised patients and the impact of remdesivir on viral dynamics in lower respiratory samples were studied.

Isavuconazole therapeutic drug monitoring in critically ill ICU patients: A monocentric retrospective analysis.

Background: The broad-spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare.

Objectives: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics.

Methylprednisolone Plasma Concentrations During Cardiac Surgery With Cardiopulmonary Bypass in Pediatric Patients.

To our knowledge, methylprednisolone pharmacokinetics and plasma concentrations have not been comprehensively investigated in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass. It is unknown whether there is a significant influence of cardiopulmonary bypass on the plasma concentrations of methylprednisolone and whether this may be an explanation for the limited reported efficacy of steroid administration in cardiac surgery with cardiopulmonary bypass. The study was registered in the Dutch Trial Register (NTR3579; https://www.

The nitrosamine contamination of drugs, part 3: Quantification of 4-Methyl-1-nitrosopiperazine in rifampicin capsules by LC-MS/HRMS.

Upon emergence of nitrosamines in various drugs, e.g in valsartan, metformin and ranitidine, 4-methyl-1-nitrosopiperazine (MeNP) was found in rifampicin in August 2020. Rifampicin is used, amongst others, for post-exposure prophylaxis of leprosy.

Penetration of Isavuconazole in Ascites Fluid of Critically Ill Patients.

Fungal peritonitis is a life-threatening condition which is not only difficult to diagnose, but also to treat. Following recent guidelines, echinocandins and azoles are the recommended antimycotics for the management of intra-abdominal spp. infections, with a favor for echinocandins in critically ill patients.

Physiologically Based Population Pharmacokinetic Modeling Approach for Ciprofloxacin in Bone of Patients Undergoing Orthopedic Surgery.

Ciprofloxacin is highly active against bacteria that commonly cause bone infections. However, the time-course of ciprofloxacin in bone has not been characterized using population pharmacokinetic modeling. Thirty-nine patients received a 1-h infusion of 400 mg of ciprofloxacin before orthopedic surgery.

Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.

Background: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR.

Methods: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.

A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition.

The extent of a drug-drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4-period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients.

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern.

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems.

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not known.

4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU).

In Vitro Recovery of Sufentanil, Midazolam, Propofol, and Methylprednisolone in Pediatric Cardiopulmonary Bypass Systems.

Objectives: To evaluate in vitro drug recovery in cardiopulmonary bypass (CPB) systems used for pediatric cardiac surgery.

Design: Observational in vitro study.

Setting: Single-center university hospital.