Structure Elucidation of the Daptomycin Products Generated upon Heterologous Expression of the Daptomycin Resistance Gene Cluster .

Recently, a high-level daptomycin (DAP)-resistant strain (TS92) was identified, which mediates a 33% decline of DAP when incubated in Mueller-Hinton (MH) medium. The genetic background of the DAP resistance in TS92 is a newly discovered two-gene operon, named whose expression was reported to impair the structural integrity of DAP, eventually leading to its inactivation. Here, we set out to elucidate the chemical nature of -mediated DAP modification by applying a general unknown comparative screening (GUCS) approach in high-resolution mass spectrometry.

Therapeutic drug monitoring of elexacaftor, tezacaftor, and ivacaftor before, during, and after pregnancy in women with cystic fibrosis: An observational study.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved health and increased life expectancy in many patients with cystic fibrosis (pwCF). Family planning issues have become more important since then. Many women decide to remain on modulator therapy during pregnancy despite insufficient evidence-based recommendations for continuing ETI during pregnancy and lactation.

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.

Investigation of clindamycin concentrations in human plasma and jawbone tissue in patients with osteonecrosis of the jaw: A prospective trial.

The aim of this study was to investigate the jawbone concentration of clindamycin (CLI) in patients with an osteonecrosis of the jaw (ONJ). Patients with medication-related ONJ (MRONJ) and osteoradionecrosis (ORN) with an antibiotic treatment with CLI were included. Plasma, vital and necrotic bone samples were collected.

Antimicrobial effects of clindamycin-loaded platelet-rich fibrin (PRF).

Objectives: Recent research has demonstrated that platelet-rich fibrin (PRF) is an appropriate carrier for ampicillin/sulbactam. The aim of the study was to investigate whether PRF is also a suitable bio-carrier for clindamycin (CLI).

Methods: PRF membranes were produced from 36 patients receiving intravenous therapy with CLI (e.

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.

The solvent- and surface-dependent adsorption of the lipopeptide antibiotic daptomycin: The general necessity of adsorption tests.

The impact of poor or non-reproducible analyte recoveries due to non-specific drug adsorption on various analytical assays is often underestimated. Even internationally approved guidelines for pharmaceutical analysis such as the EMA guideline on bioanalytical method validation, the ICH guideline M10 on bioanalytical method validation and study sample analysis or the FDA bioanalytical method validation guidance do not adequately encourage more detailed investigations. Furthermore, other areas of research in which the concentration of active pharmaceutical compounds plays a crucial role, for example screening for minimal inhibitory concentrations of bacterial isolates, are potentially affected as well.

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.

Harnessing Bile for Drug Absorption through Rational Excipient Selection.

Bile solubilization and apparent solubility at resorption sites critically affect the bioavailability of orally administered and poorly water-soluble drugs. Therefore, identification of drug-bile interaction may critically determine the overall formulation success. For the case of the drug candidate naporafenib, drug in solution at phase separation onset significantly improved with polyethylene glycol-40 hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered saline (PBS) and PBS supplemented with bile components.

Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1.

We analyzed single nucleotide polymorphisms (SNPs) in PKNOX1 (rs2839629) and in the intergenic region between PKNOX1 and CBS (rs915854) by Sanger sequencing in 88 patients with multiple myeloma treated with bortezomib. All patients (n = 13) harboring a homozygous mutation in PKNOX1 (rs2839629) also had a homozygous mutated rs915854 genotype. Homozygous mutated genotypes of rs2839629 and rs915854 were significantly enriched in patients with painful peripheral neuropathy (PNP) (P < 0.

Present in the Aquatic Environment, Unclear Evidence in Top Predators-The Unknown Effects of Anti-Seizure Medication on Eurasian Otters () from Northern Germany.

Emerging contaminants are produced globally at high rates and often ultimately find their way into the aquatic environment. These include substances contained in anti-seizure medication (ASM), which are currently appearing in surface waters at increasing concentrations in Germany. Unintentional and sublethal, chronic exposure to pharmaceuticals such as ASMs has unknown consequences for aquatic wildlife.

Clinical validation and assessment of feasibility of volumetric absorptive microsampling (VAMS) for monitoring of nilotinib, cabozantinib, dabrafenib, trametinib, and ruxolitinib.

Volumetric absorptive microsampling (VAMS) has emerged as a minimally invasive alternative to conventional sampling. However, the applicability of VAMS must be investigated clinically. Therefore, the feasibility of at-home sampling was investigated for the kinase inhibitors nilotinib, cabozantinib, dabrafenib, trametinib and ruxolitinib and evaluated regarding the acceptance of at-home microsampling, sample quality of at-home VAMS and incurred sample stability.

Development, validation and application of a selective and sensitive LC-MS/MS method for the quantification of daptomycin in a suspension of Mammaliicoccus sciuri in Mueller-Hinton broth.

Reports of therapy failures related to the use of daptomycin (DAP) are steadily increasing. This is mainly due to emerging DAP resistance for which, however, the underlying mechanism is often unknown. To elucidate the mode of action of novel DAP resistance traits it is indispensable to reliably detect and quantify DAP in complex matrices such as bacterial culture media.

A Physiologically-Based Pharmacokinetic Model of Ruxolitinib and Posaconazole to Predict CYP3A4-Mediated Drug-Drug Interaction Frequently Observed in Graft versus Host Disease Patients.

Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor.

Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime.

Carbon monoxide (CO) is a therapeutic gas with therapeutic potential in intestinal bowel disease. Therapeutic efficacy in the gastrointestinal tract (GIT) must be paired with safe and convenient use. Therefore, we designed an oral CO releasing system (OCORS) pairing tunable CO release into the GIT while preventing the release of any other molecule from within the device, causing safety concerns.

A liquid chromatography-tandem mass spectrometry method for the quantification of ampicillin/sulbactam and clindamycin in jawbone, plasma, and platelet-rich fibrin: Application to patients with osteonecrosis of the jaw.

Ampicillin in combination with sulbactam is a widely used drug choice for infection prophylaxis, especially in oral and maxillofacial surgery. Clindamycin serves as an alternative in patients with known allergy to β-lactam antibiotics. To ensure effective prophylaxis, it is important to achieve sufficiently high concentrations of active antibiotic substances in the tissues affected by the surgery.

Bone Concentration of Ampicillin/Sulbactam: A Pilot Study in Patients with Osteonecrosis of the Jaw.

Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam.

Robustness of the honeybee neuro-muscular octopaminergic system in the face of cold stress.

In recent decades, our planet has undergone dramatic environmental changes resulting in the loss of numerous species. This contrasts with species that can adapt quickly to rapidly changing ambient conditions, which require physiological plasticity and must occur rapidly. The Western honeybee () apparently meets this challenge with remarkable success, as this species is adapted to numerous climates, resulting in an almost worldwide distribution.

Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma.

Patients treated with dabrafenib and trametinib for BRAF-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling).

Development and validation of a bioanalytical method for the quantification of axitinib from plasma and capillary blood using volumetric absorptive microsampling (VAMS) and on-line solid phase extraction (SPE) LC-MS.

For therapeutic drug monitoring (TDM) of axitinib, the new volumetric absorption microsampling technology (VAMS™) was applied to obtain capillary blood samples in an ambulatory setting and the results were compared to plasma samples as the gold standard. On-line solid phase extraction (SPE) applying a Turboflow HTLC Cyclone™ 1.0 × 500 mm column was used to reduce costs and working time.

Evaluation of advanced platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam.

Objectives: Mechanisms of wound healing are often impaired in patients with osteonecrosis of the jaw (ONJ). According to the guidelines for the treatment of this disease, early surgical intervention is indicated. However, surgery often faces complications such as wound healing disorders.