Eradication of meticillin-resistant Staphylococcus aureus from human skin by the novel LL-37-derived peptide P10 in four pharmaceutical ointments.

Skin bacterial colonization/infection is a frequent cause of morbidity in patients with chronic wounds and allergic/inflammatory skin diseases. This study aimed to develop a novel approach to eradicate meticillin-resistant Staphylococcus aureus (MRSA) from human skin. To achieve this, the stability and antibacterial activity of the novel LL-37-derived peptide P10 in four ointments was compared.

Pharmacodynamics of Cefepime Combined with Tazobactam against Clinically Relevant Enterobacteriaceae in a Neutropenic Mouse Thigh Model.

The lack of new antibiotics has prompted investigation of the combination of two existing agents-cefepime, a broad-spectrum cephalosporin, and tazobactam-to broaden their efficacy against extended-spectrum beta-lactamase (ESBL)-producing We determined the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination in a murine neutropenic thigh model in order to establish its exposure-response relationships (ERRs). The PK of cefepime were determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al., Antimicrob Agents Chemother 59:3373-3376, 2015, https://doi.

Antimicrobial Peptide P60.4Ac-Containing Creams and Gel for Eradication of Methicillin-Resistant Staphylococcus aureus from Cultured Skin and Airway Epithelial Surfaces.

We previously found the LL-37-derived peptide P60.4Ac to be effective against methicillin-resistant Staphylococcus aureus (MRSA) on human epidermal models (EMs). The goal of this study was to identify the preferred carrier for this peptide for topical application on skin and mucosal surfaces.

The Effect of Tamoxifen Dose Increment in Patients With Impaired CYP2D6 Activity.

Background: The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied.

Methods: Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication.

Dried blood spot analysis for therapeutic drug monitoring of pazopanib.

Dried blood spot (DBS) sampling is potentially a more patient-friendly and flexible alternative to venous sampling of pazopanib. This study determined the agreement between pazopanib DBS and plasma concentrations to facilitate implementation of pazopanib DBS sampling into clinical practice. Paired DBS and plasma samples were collected in 12 patients.

Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study.

Background: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure.

Methods: Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks.

Individualized dosing of tyrosine kinase inhibitors: are we there yet?

Tyrosine kinase inhibitors (TKIs) are registered at a fixed oral dose, despite their large variability in pharmacokinetics (PK). Given that the evidence for a relation between drug exposure and treatment outcome is growing, this one-dose-fits-all approach can unintentionally lead to under- and overexposure. Dose individualization could lower this variability and thereby beneficially effect treatment outcome.

Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma.

Background: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months.

Pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation.

Background: High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients.

Limited sampling model for advanced mycophenolic acid therapeutic drug monitoring after liver transplantation.

Background: The immunosuppressive drug mycophenolate mofetil (MMF), with mycophenolic acid (MPA) as active metabolite, is a nonnephrotoxic alternative to calcineurin inhibitors. Therapeutic drug monitoring (TDM) of MPA may improve clinical benefit from MMF therapy, especially in MMF monotherapy or with reduced dose of a calcineurin inhibitor. Limited data are available on TDM strategies for MPA in orthotopic liver transplantation (OLT).

A validated assay for the simultaneous quantification of six tyrosine kinase inhibitors and two active metabolites in human serum using liquid chromatography coupled with tandem mass spectrometry.

A sensitive, sophisticated and practical bioanalytical assay for the simultaneous determination of six tyrosine kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib, pazopanib, regorafenib) and two active metabolites (N-desmethyl imatinib and N-desethyl sunitinib) was developed and validated. For the quantitative assay, a mixture of three stable isotopes as internal standards was added to human serum, standards and controls. Thereafter, samples were pre-treated using protein precipitation with methanol.

Development of a nose cream containing the synthetic antimicrobial peptide P60.4Ac for eradication of methicillin-resistant Staphylococcus aureus carriage.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are an increasing problem, and current treatment options are suboptimal. Nasal carriage of MRSA is a major risk factor for infection, but nasal eradication strategies are increasingly considered to be insufficiently effective. In this study, a water-in-oil cream formulation was developed for nasal application with an antimicrobial peptide, P60.

Morphine induces hyperalgesia without involvement of μ-opioid receptor or morphine-3-glucuronide.

Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia.

Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients.

Background And Objective: Everolimus is a novel macrolide immunosuppressant used in the prevention of acute and chronic rejection of solid organ transplants. Everolimus is being actively investigated worldwide as a non-nephrotoxic alternative for calcineurin inhibitors. Its highly variable pharmacokinetics and narrow therapeutic window make it difficult to maintain an adequate exposure to prevent serious adverse effects.

Phenol levels during intralesional curettage and local adjuvant treatment of benign and low-grade malignant bone tumours.

Background: Phenol is widely used for years as local adjuvant treatment for bone tumours. Despite its use for a long time, no information is available about the local concentration of phenol that is achieved in an individual patient, and the most sufficient and safe procedure to wash out the phenol after using it as local adjuvant.

Questions/purposes: 1.

A simplified oral flucloxacillin absorption test for patients requiring long-term treatment.

Background: Patients with severe methicillin-sensitive Staphylococcus aureus infections are effectively treated with initial continuous intravenous (iv) flucloxacillin followed by oral maintenance therapy. As the absorption of oral flucloxacillin is variable, an oral absorption test (OAT) is used to ensure efficacious therapy. The classical OAT (test A) requires overnight fasting, interruption of iv therapy, and is laborious.

Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal.

Background: Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn.

Methods: This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF.

Liquid chromatography-tandem mass spectrometric assay for the PARP-1 inhibitor olaparib in combination with the nitrogen mustard melphalan in human plasma.

A bioanalytical assay for the new poly(ADP-ribose) polymerase-1 inhibitor olaparib in combination with melphalan was developed and validated. For the quantitative assay, human plasma samples were pre-treated on ice using protein precipitation with 2% (v/v) acetic acid in acetonitrile containing erlotinib and melphalan-d₈ as internal standards. The extract was diluted with water and injected into the chromatographic system.

Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study.

Context: In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14 mg/liter or greater and metabolite formation.

Objective: The study was performed to confirm the correlation of the currently used mitotane (o,p'DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p'DDA) and o,p'DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene) levels for predicting tumor response.

Subjects/methods: Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively.

Mitotane has a strong and a durable inducing effect on CYP3A4 activity.

Objective: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib.

Design: A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study.

Arterial and venous pharmacokinetics of morphine-6-glucuronide and impact of sample site on pharmacodynamic parameter estimates.

Background: In pharmacokinetic-pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of morphine-6-glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect.

Liquid chromatography-tandem mass spectrometry outperforms fluorescence polarization immunoassay in monitoring everolimus therapy in renal transplantation.

Background: There is a need to monitor everolimus blood concentrations in renal transplant recipients as a result of its high pharmacokinetic variability and narrow therapeutic window. However, analytical methods to determine blood concentrations often differ in performance. Therefore, we investigated whether two commonly used therapeutic drug monitoring methods for everolimus were in agreement and to what extent their differences could lead to differences in dosage advice.

Marginal increase of sunitinib exposure by grapefruit juice.

Purpose: The drug label of sunitinib includes a warning for concomitant use of grapefruit juice (GJ) but clinical evidence for this drug interaction is lacking. The aim of this study is to determine the effect of GJ, a potent intestinal cytochrome P450 (CYP) 3A4 inhibitor, on steady-state sunitinib pharmacokinetics (PK).

Methods: Sunitinib PK was evaluated in eight cancer patients receiving sunitinib monotherapy in a "4 weeks on-2 weeks off" dose regimen.

Pancytopenia due to proguanil toxicity in a returning traveller with fever.

A patient known to have renal insufficiency was admitted to the hospital with fever and pancytopenia after returning from a trip to Mali. Pancytopenia was not caused by a tropical infection but was a side effect of atovaquone/proguanil used as malaria chemoprophylaxis. High and prolonged detectable proguanil serum levels can result in bone marrow suppression in patients with renal insufficiency.