Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review.

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.

Therapeutic Drug Monitoring of Protein Kinase Inhibitors in the Treatment of Non-small Cell Lung Cancer.

Targeted therapy with protein kinase inhibitors (PKIs) represents one of the important treatment options for non-small cell lung cancer (NSCLC). It has contributed to improve patients' survival and quality of life significantly. These anticancer drugs are administrated orally in flat-fixed doses despite the well-known large interpatient pharmacokinetic variability and the possible need for dose individualization. To optimize and individualize dosing of PKIs, and thereby increasing the effectiveness and safety of the treatment, therapeutic drug monitoring (TDM) is the most frequently mentioned method. Unlike other areas of medicine, TDM has been rather exceptional in oncological practise since there is a little evidence or no data for concentration-effect relationships of PKIs. Therefore, the aim of this review is to summarize the pharmacokinetic characteristics of PKIs and provide the evidence supporting the use of TDM for personalised treatment of patients with NSCLC.

Proteomic analysis of the bone marrow microenvironment in extramedullary multiple myeloma patients.

Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the uncontrolled clonal proliferation of bone marrow (BM) plasma cells. The poor prognosis of patients is associated with the presence of extramedullary disease (EMD). Previously, different mechanisms involved in the colonization of BM niches by MM cells and their escape during EMD have been described. Thus, we aimed to investigate the expression of selected cytokines in the BM plasma of MM patients as well as EMD patients to reveal novel molecules involved in EMD pathogenesis. Expression of 120 different cytokines was measured in BM plasma of 13 MM and 11 EMD patients using Proteome Profiler Antibody Arrays. The correlation between statistically significant cytokines and clinicopathological parameters of patients was determined using the Spearman correlation analysis. Finally, protein-protein interactions were analyzed, and GO and KEGG pathways enrichment analysis was performed. In total, 27 cytokines were found to be differently expressed between MM and EMD patients. After the Benjamini-Hochberg correction for multiple testing, the statistical significance of two cytokines downregulated in EMD (EGF, BDNF) and six cytokines upregulated in EMD (NAP-2, ADIPOQ, CRP, MIG, BAFF, and THBS1) was maintained. Correlation analysis proved a significant association between the expression of these molecules and selected clinical-pathological features of MM/EMD patients. Protein association network analysis revealed important protein-protein interactions between THBS1/EGF, MIG/NAP-2, THBS1/NAP-2, EGF/NAP-2, and ADIPOQ/CRP. Finally, identified cytokines were proved to be significantly involved in focal adhesion, PI3K/AKT, and MAPK signaling pathways, and regulation of cell development, localization, proliferation, migration, differentiation, immune system processes, and stress response. Obtained results confirm the key function of the BM microenvironment in the pathogenesis of MM and indicate the essential role of numerous cytokines in disease progression and EMD development. However, the exact mechanisms need to be further clarified.

Involvement of Small Non-Coding RNA and Cell Antigens in Pathogenesis of Extramedullary Multiple Myeloma.

Extramedullary multiple myeloma (EMD) is an aggressive disease; malignant plasma cells lose their dependence in the bone marrow microenvironment and migrate into tissues. EMD is a negative prognostic factor of survival. Using flow cytometry and next-generation sequencing, we aimed to identify antigens and microRNAs (miRNAs) involved in EMD pathogenesis. Flow cytometry analysis revealed significant differences in the level of clonal plasma cells between MM and EMD patients, while the expression of CD markers was comparable between these two groups. Further, miR-26a-5p and miR-30e-5p were found to be significantly down-regulated in EMD compared to MM. Based on the expression of miR-26a-5p, we were able to distinguish these two groups of patients with high sensitivity and specificity. In addition, the involvement of deregulated miRNAs in cell cycle regulation, ubiquitin-mediated proteolysis and signaling pathways associated with infections or neurological disorders was observed using GO and KEGG pathways enrichment analysis. Subsequently, a correlation between the expression of analyzed miRNAs and the levels of CD molecules was observed. Finally, clinicopathological characteristics as well as CD antigens associated with the prognosis of MM and EMD patients were identified. Altogether, we identified several molecules possibly involved in the transformation of MM into EMD.

[Fever of unknown origin: case reports from routine clinical practice and a review].

Fever of unknown origin represents a clinical syndrome characterized by a fever of over 38.3 °C documented on several occasions during a period of at least 3 weeks, etiology of which remains unexplained after obtaining a detailed history, conducting a thorough physical exam, and an array of basic laboratory tests and diagnostic imaging. Most cases of this syndrome are caused by infections, non-infectious inflammatory diseases, and neoplasms. In addition, drug fevers and internal medicine diseases should be included in the differential diagnostic work-up in all patients. This article presents five case reports of fever of unknown origin managed at an outpatient clinic of a tertiary care center for infectious diseases. This case series emphasizes the need for a consistent, broad and interdisciplinary diagnostic work-up. In addition, we present a review of the etiology and clinical management of fever of unknown origin.

Fever of unknown origin.

Fever of unknown origin is a rare clinical syndrome, that represents a significant diagnostic challenge. There have been described more than 200 potential diseases, that can manifest as a fever of unknown origin. These are classically divided into following categories: infections, non-infectious inflammatory diseases, malignancies, and other miscellaneous disorders. Each of the disease type is associated with rather characteristic symptoms, clinical signs and laboratory findings, which are individually non-specific, but may provide helpful clues for a further focused diagnostic work-up. The clinicians task is to be able to identify these hallmark clinical features and to correctly interpret their significance and limitations in the appropriate differential diagnostic context. The aim of this review is to provide up-to-date clinical research evidence and to propose a  concise clue-oriented diagnostic approach.

Perioperative management of metformin: is there something new?

Metformin is the drug of choice in the treatment of type 2 diabetes mellitus. Diabetic patients treated with metformin, who are scheduled for surgery, have always been subjects to discussion regarding the perioperative management of metformin because of the risk of developing lactic acidosis. The article presents the basic informations about this adverse event, describes new approach to the metformin treatment in the perioperative period, and summarizes the recommendations of professional societies and expert groups.

A novel coronavirus (SARS-CoV-2) and COVID-19.

By the end of 2019 the first cases of severe pneumonia of unknown origin were reported in Wuhan, China. The causative agent was identified as a novel b-coronavirus SARS-CoV-2 and the disease was named COVID-19. Since the beginning of 2020, the infection has spread worldwide, which led the WHO to declare COVID-19 a public health emergency of international concern and to characterize the current situation as a pandemic. The transmission occurs mainly via respiratory droplets and the incubation period ranges from 2 to 14 days. Most cases are mild, but some patients develop severe pneumonia with acute respiratory distress, septic shock and multi-organ failure. The most common symptoms include fever, dry cough, myalgia and shortness of breath. Characteristic laboratory findings are normal white blood cell count or mild leukopenia, marked lymphopenia, in severe cases elevated CRP, procalcitonin, LDH, and D-dimer are commonly found. Typical imaging findings include multifocal peripherally distributed ground-glass opacities or consolidations, interlobular septal thickening, crazy paving appearance and cystic changes. The overall case fatality rate is estimated to range from 1 to 3 %, however, it is dependent on age and underlying medical comorbidities. Current potential treatment options include hydroxychloroquine, remdesivir, lopinavir/ritonavir and convalescent plasma.

Clinical pharmacy in the Czech Republic.

Currently there is an effort to move towards more service pharmacy to the physician and the patient in both inpatient and outpatient care. In the Czech Republic they are gradually created conditions for the daily work of clinical pharmacist. They are defined activities of clinical pharmaceutical care, which constitutes the work of emerging clinical pharmacy department. Contribution of the clinical pharmaceutical care has been repeatedly confirmed by both patients and the healthcare system as a whole.

Is safe pharmacotherapy worthwhile?

The safety of pharmacotherapy can be monitored at different levels of the health system and the quality of health care provided can be assessed from different points of view. The Ministry of Health, the health insurance companies, the State Institute for Drug Control, the Institute of Health Information and Statistics, and the health care facilities themselves fulfill their roles. Safety is assessed differently at each level. Based on current knowledge, it follows that the monitoring of adverse effects is not only of safety but also of economic importance for health care facilities. At this point the proactive way of working of clinical pharmacist can play a major role specifically when they get involved in direct care of the patient.

Specialization in clinical pharmacy.

Specialization in clinical pharmacy is necessary to providing clinical pharmacy services in Czech Republic. Clinical pharmacy knowledge has to be further developed within the framework of continuous education system.

Intrapleural alteplase therapy: what are the knowns and unknowns?

In pneumology, enzymatic properties of plasmin are used to disrupt fibrin adhesions and septations formed during pathological conditions of the pleural cavity. In that case, fibrinolytics are administrated locally via a chest tube in the pleural cavity to evacuate pathological effusion. Although the first intrapleural administration of fibrinolytic occurred seventy years ago, there has been no consensus on dosing or a uniform procedure of their application. The aim of the article is to summarize current knowledge of alteplase usage in pneumology and discuss practical aspects of its intrapleural application regarding specific possibilities in the Czech Republic.

Management of metabolic adverse effects of everolimus in patients with renal carcinoma.

Everolimus is administered to patients with metastatic renal cell carcinoma in full daily dose of 10 mg or in reduced daily dose of 5 mg in case adverse effect occurred. These include metabolic adverse effects, mucositis, anorexia, and non-infectious pneumonitis and lead to increase in morbidity and decrease in the quality of life of the patient. Our goal was to evaluate the administration of fenofibrate and metformin in everolimus induced hypertriglyceridemia and hyperglycemia. The role of mTOR in lipid and glucose metabolism was researched in literature. The effect of including fenofibrate and metformin into metabolic adverse effect management guidelines in metastatic renal cell carcinoma patients who are administered everolimus was evaluated. Fenofibrate, metformin, and everolimus have several similar effects on intracellular level, therefore the effect of fenofibrate and metformin in treating everolimus induced metabolic adverse effects in metastatic renal cell carcinoma patients may be limited. The manifestation of metabolic adverse effects in patients treated with everolimus is not identical with metabolic syndrome or type II diabetes in standard population.

Standardization of clinical pharmacist's activities: Methodology.

STUDY OBJECTIVES: Establishing standardized and controlled system of work at a clinical pharmacy department and establishing effective recording of activities of a group of four clinical pharmacist when providing clinical pharmaceutical care (CPC) in a hospital. METHODS: The duration of evaluated period is 5.5 years. The first part was defining the purpose, methods and activities of clinical pharmaceutical care, the next part was designing the software for recording patient's data and CPC activities. To verify the functionality of our system the third part was conducted (from January 1, 2015 to June 30, 2015). RESULTS: CPC activities were defined precisely. During the 6 months period, 3946 patients were reviewed (17% of patients admitted), in this group, 41% patients was labeled as risk (these patients had one or more risk factor). 1722 repeated reviews were performed, 884 drug therapy recommendations were recorded. The calculated average time necessary for one CPC activity is 28 min. CONCLUSION: During the 5 year period, standardized system of work in clinical pharmacy department was established. This system is based on clearly defined activities and it enables external control. Our results supply data for negotiations with health insurance companies.

Dermatitis toxica faciei after boric acid.

An adverse toxic reaction to the topical application of a 2% boric acid solution is described in a 2-year-old girl. Topical boric acid is licensed for use in children above the age of 10 in the Czech Republic. However, it can be bought over the counter and it is very often used in younger children. Due to its fast absorption and slow elimination, there is a high risk of systemic side effects. On the other hand, topical side effects are not reported in the present literature.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

Aim: The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Methods: Therapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. Results: A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. Conclusion: We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

Critical view on antimicrobial, antibiofilm and cytotoxic activities of quinazolin-4(3H)-one derived schiff bases and their Cu(II) complexes.

A series of nine 2,3-disubstituted-quinazolin-4(3H)-one derived Schiff bases and their three Cu(II) complexes was prepared and tested for their antimicrobial activities against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the substances were tested in vitro against Mycobacterium tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 and M. smegmatis ATCC 700084. While anti-enterococcal and antimycobacterial activities were insignificant, 3-[(E)-(2-hydroxy-5-nitrobenzylidene)amino]-2-(2-hydroxy-5-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (SB3) and its Cu(II) complex (SB3-Cu) demonstrated bacteriostatic antistaphylococcal activity. In addition, both compounds, as well as the other two prepared complexes, showed antibiofilm activity, which resulted in a reduction of biofilm formation and eradication of mature S. aureus biofilm by 80% even at concentrations lower than the values of their minimum inhibitory concentrations. In addition, the compounds were tested for their cytotoxic effect on the human monocytic leukemia cell line THP-1. The antileukemic efficiency was improved by the preparation of Cu(II) complexes from the corresponding non-chelated Schiff base ligands.

Liquid biopsy of peripheral blood using mass spectrometry detects primary extramedullary disease in multiple myeloma patients.

Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by infiltration of the bone marrow by malignant plasma cells. Extramedullary disease (EMD) represents a more aggressive condition involving the migration of a subclone of plasma cells to paraskeletal or extraskeletal sites. Liquid biopsies could improve and speed diagnosis, as they can better capture the disease heterogeneity while lowering patients' discomfort due to minimal invasiveness. Recent studies have confirmed alterations in the proteome across various malignancies, suggesting specific changes in protein classes. In this study, we show that MALDI-TOF mass spectrometry fingerprinting of peripheral blood can differentiate between MM and primary EMD patients. We constructed a predictive model using a supervised learning method, partial least squares-discriminant analysis (PLS-DA) and evaluated its generalization performance on a test dataset. The outcome of this analysis is a method that predicts specifically primary EMD with high sensitivity (86.4%), accuracy (78.4%), and specificity (72.4%). Given the simplicity of this approach and its minimally invasive character, this method provides rapid identification of primary EMD and could prove helpful in clinical practice.

Improved Screening of Monoclonal Gammopathy Patients by MALDI-TOF Mass Spectrometry.

Monoclonal gammopathies are a group of blood diseases characterized by presence of abnormal immunoglobulins in peripheral blood and/or urine of patients. Multiple myeloma and plasma cell leukemia are monoclonal gammopathies with unclear etiology, caused by malignant transformation of bone marrow plasma cells. Mass spectrometry with matrix-assisted laser desorption/ionization and time-of-flight detection is commonly used for investigation of the peptidome and small proteome of blood plasma with high accuracy, robustness, and cost-effectivity. In addition, mass spectrometry coupled with advanced statistics can be used for molecular profiling, classification, and diagnosis of liquid biopsies and tissue specimens in various malignancies. Despite the fact there have been fully optimized protocols for mass spectrometry of normal blood plasma available for decades, in monoclonal gammopathy patients, the massive alterations of biophysical and biochemical parameters of peripheral blood plasma often limit the mass spectrometry measurements. In this paper, we present a new two-step extraction protocol and demonstrated the enhanced resolution and intensity (>50×) of mass spectra obtained from extracts of peripheral blood plasma from monoclonal gammopathy patients. When coupled with advanced statistics and machine learning, the mass spectra profiles enabled the direct identification, classification, and discrimination of multiple myeloma and plasma cell leukemia patients with high accuracy and precision. A model based on PLS-DA achieved the best performance with 71.5% accuracy (95% confidence interval, CI = 57.1-83.3%) when the 10× repeated 5-fold CV was performed. In summary, the two-step extraction protocol improved the analysis of monoclonal gammopathy peripheral blood plasma samples by mass spectrometry and provided a tool for addressing the complex molecular etiology of monoclonal gammopathies.

Isolation of quaternary benzo[c]phenanthridine alkaloids from Macleaya microcarpa (MAXIM.) FEDDE: comparison of maceration, Soxhlet extraction and pressurised liquid extraction.

INTRODUCTION: Macleaya microcarpa (Papaveraceae family) has been of considerable interest in recent years as a prospective source of quaternary benzo[c]phenanthridine alkaloids (QBAs) related to many pharmaceutical beneficial effects. For this purpose, a quantitative, efficient and fast method to isolate the QBAs from the plant material is required. OBJECTIVE: To optimise and compare pressurised liquid extraction (PLE) with Soxhlet extraction and maceration in order to estimate extraction conditions for fast and efficient isolation of QBAs contained in the roots of Macleaya microcarpa. METHODOLOGY: The QBAs were extracted by PLE, Soxhlet extraction and maceration at different conditions (solvent, time, etc.). Reversed phase HPLC with diode-array detector was utilised for their determination and quantification. To optimise the PLE procedure, the variable parameters, including temperature (40-150 °C), sample-to-inert material ratio, extraction time (5-30 min) and number of extraction cycles (1-4), were also tested. RESULTS: Quantitative determination of QBAs resulted in 0.2-2.8 mg/g, 0.3-2.5 mg/g and 0.3-3.1 mg/g for PLE, Soxhlet extraction and maceration. To produce the yields mentioned above, PLE required only up to 30 min compared with 21 h for Soxhlet extraction and 49 days for maceration. CONCLUSION: PLE provided an effective and fast extraction of QBAs from M. microcarpa roots and can be recommended as an alternative isolation method to conventional techniques for QBAs from the plant sources.