In vivo pharmacokinetics of a gentamicin-loaded collagen sponge in acute periprosthetic infection - Serum values in 19 patients

Background The in vivo pharmacokinetics of gentamycin- loaded collagen fleeces in humans have not been described in the current literature. We therefore analyzed in vivo pharmacokinetics of these fleeces when used in the treatment of periprosthetic infections. Patients and methods Gentamycin concentrations were measured in 19 consecutive patients with an acute periprosthetic infection. Each patient received 2-5 fleeces (130 mg gentamycin/fleece). Results Initially, the blood concentration increased to 3.2-7.2 mg/L, depending on the number of fleeces that were applied. The serum peak concentrations resulted in peak/MIC ratios of 2.5-36 for P. aeruginosa, S. aureus, and Klebsiella spp. Subsequently, the serum values decreased almost linearly below 0.3 mg/L in 18 to 62 hours. After 24 hours, the serum levels of gentamicin dropped below 2 mg/L, the toxicity threshold. Interpretation The application of 2 to 5 130-mg gentamycin-loaded collagen fleeces may be useful as an adjuvant treatment for implant-related infections, since no toxic concentrations were measured 24 hours postoperatively

Rhabdomyolysis in Clozapine Overdose

CONTEXT: Clozapine is used for decennia for the treatment of schizophrenia. Agranulocytosis, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis are well-known adverse effects of clozapine, which are sometimes life threatening. Here we report a case of rhabdomyolysis upon an acute overdose of clozapine. CASE: A male patient, 36 years, with elevated creatinine kinase levels (9899 U/l), developed rhabdomyolysis afterafter admission to the emergency department. Approximately 2–4 h earlier he had intoxicated himself with his maintenance oral medication clozapine 125 mg, temazepam 20 mg and lorazepam 1.5 mg. Co-medications, and physical and laboratory examinations did not reveal other risk factors for rhabdomyolysis. According to the Naranjo probability scale there was a probable relation between clozapine dose and symptoms, that developed approximately 2–4 h after the auto-intoxication of 125 mg tablets. At day 5 of hospitalization, clozapine and creatinine kinase levels returned to normal and the patient was discharged with no somatic sequelae. CONCLUSIONS: Elevated creatinine kinase levels in acute clozapine intoxication may be an indicator that rhabdomyolysis may be involved

Drug-drug interactions with tyrosine-kinase inhibitors:A clinical perspective

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice

Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC-MS/MS

Contains fulltext : 218233.pdf (Publisher’s version ) (Open Access)A sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of seven oral oncolytics (two PARP inhibitors, i.e. olaparib and niraparib, and five tyrosine kinase inhibitors, i.e. cobimetinib, cabozantinib, dabrafenib, vemurafenib and regorafenib, plus its active metabolite regorafenib M2) in EDTA plasma was developed and validated. Stable isotope-labelled internal standards were used for each analyte. A simple protein precipitation method was performed with acetonitrile. The LC-MS/MS system consisted of an Acquity H-Class UPLC system, coupled to a Xevo TQ-S micro tandem mass spectrometer. The compounds were separated on a Waters CORTECS UPLC C18 column (2.1 x 50 mm, 1.6 mum particle size) and eluted with a gradient elution system. The ions were detected in the multiple reaction monitoring mode. The method was validated for cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and regorafenib M2 over the ranges 6-1000, 100-5000, 10-4000, 200-2000, 200-20,000, 5000-100,000, 500-10,000 and 500-10,000 mug/L, respectively. Within-day accuracy values for all analytes ranged from 86.8 to 115.0% with a precision of <10.4%. Between-day accuracy values ranged between 89.7 and 111.9% with a between-day precision of <7.4%. The developed method was successfully used for guiding therapy with therapeutic drug monitoring in cancer patients and clinical research programs in our laboratory

Clinical implications of food-drug interactions with small-molecule kinase inhibitors

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice

Extracorporeal treatment of metforminassociated lactic acidosis in clinical practice:A retrospective cohort study

Purpose To assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning. Methods Patients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH 5 mmol/l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP. Results Forty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p <0.01)), metformin (29.4 versus 8.6 mg/l, p <0.01) concentrations, and vasopressor requirement (72% versus 23%, p <0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p <0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria. Conclusions Although there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group. The majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR

Pharmacological aspects of neonatal antidepressant withdrawal

Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse, which could be harmful for both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal withdrawal syndrome, although the exact incidence of this complication is unknown because the definition of the syndrome is not clear and withdrawal reactions are probably underreported. Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary

Prevalence and follow-up of potentially inappropriate medication and potentially omitted medication in older patients with cancer - The PIM POM study

Objectives: To determine the prevalence of Potentially Inappropriate Medication (PIMs) and Potentially Omitted Medication (POMs) in older patients with cancer. Materials and Methods: In this prospective observational study (hospital) pharmacists conducted comprehensive medication reviews in older patients with cancer (aged >= 65 years) receiving parenteral chemotherapy and/or immunotherapy at the Deventer Hospital. PIMs and POMs were identified using the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP), the Screening Tool to Alert doctors to the Right Treatment (START), and pharmacists' expert opinion. Recommendations regarding PIMs and POMs were communicated to the patient's oncologist/haematologist and follow-up was measured. Associations between covariates and the prevalence of PIMs and POMs were statistically analysed. Results: For the 150 patients included, 180 PIMs and 86 POMs were identified with a prevalence of 78%. Using pharmacists' expert opinion in addition to only STOPP/START criteria contributed to 49% of the PIMs and 23% of the POMs. A follow-up action was required in 73% of the 266 PIMs and POMs. Number of medicines and Charlson Comorbidity Index score were both associated with having at least one PIM and/or POM (p = .031 and p = .016, respectively). Conclusion: The prevalence of PIMs and POMs and subsequent follow-up in older patients with cancer is high. A pharmacist-led comprehensive medication review is a good instrument to identify these PIMs and POMs and to optimize patients' treatment. A complete approach, including pharmacists' expert opinion, is recommended to identify all PIMs and POMs in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Dose recommendations for anticancer drugs in patients with renal or hepatic impairment

Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment