Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography–tandem mass spectrometry. A putative quinoneimine–GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl–GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.

BackgroundThere is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications.MethodsThis was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4‐month interval (October–December 2014) were eligible for inclusion. The primary outcome was the 30‐day major complication rate (Clavien–Dindo grade III–V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital‐level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.).ResultsOf 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30‐day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147).ConclusionOverweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.

Purpose The purpose of this study was to identify the common clinical presentations and the evidence on the presence of ageusia and anosmia as an emerging coronavirus disease 2019 (COVID-19) symptom to better inform in both COVID-19 patients and clinicians. Patients and Methods As part of a double-institutional collaboration coordinated by doctors, this study retrospectively collected and analyzed the clinical characteristics of 60 patients with COVID-19 pneumonia between April 1 and April 20, 2020. Pregnant women and patients taking anti-cancer drugs had been excluded from the study. Data from each institution’s electronic medical record had been obtained. Results Sixty patients who had RT-PCR positive for COVID-19 were included in this study; of these patients, all of them had unknown exposure to COVID-19. The mean (SD) age was 45.7 (13.5) years, and 42 were men (70%). Of these patients, 80% had at least ageusia or anosmia. The most common symptoms at the onset of illness were cough (75%), fever (71.3%), myalgia or fatigue (53.3%), anosmia (loss of smell) (40%), ageusia (loss of taste) (28.3%), sore throat (25%), shortness of breath (16.7%), headache (16.7%), and GI symptoms (diarrhea, nausea, vomiting and loss appetite) (16.7%). A total of 68.3% of COVID-19 infected patients had reported either loss of taste or smell, and about 33.3% of them had only loss of smell, while 23.3% of them had impaired taste, and 11.7% of COVID-19 infected patients had both taste and smell loss. Conclusion During the epidemic period of SARS-CoV-2 infection, when presenting patients with ageusia and anosmia, physicians should consider COVID-19 pneumonia as a differential diagnosis to achieve early identification, avoid the delayed diagnosis, and prevention of transmission.

Background: Urinary tract infections (UTIs) are the most common infections in the community and in hospitalized patients. Objectives: To investigate the epidemiology and antimicrobial susceptibility pattern of uropathogens and determine the appropriate empirical antibiotics to treat UTIs in the community and hospitalized patients. Methods: A total of 2,485 urine cultures were performed at Mogadishu Somali Turkish Training and Research Hospital. Through the standard Kirby-Bauer disk diffusion method and commercial disks, antimicrobial sensitivity and resistance were studied based on the Clinical and Laboratory Standards Institute (CLSI) system using Mueller-Hinton agar. The identification of the microorganisms was done using eosin methylene blue agar and blood agar. Results: Escherichia coli was the most predominant pathogen (63.4%) in all age groups, both genders, and in the community and hospital-acquired UTIs, followed by Klebsiella pneumonia (13.3%). Ceftriaxone, trimethoprim/sulfamethoxazole, ampicillin, cefuroxime, and cefixime revealed the highest resistance level (82-100%) against uropathogens. Ciprofloxacin (67.7%) and levofloxacin (54.2%) showed increasing resistance rates against uropathogens. Tigecycline, colimycin, vancomycin, and teicoplanin exhibited the most powerful sensitivity rate (100%). Moreover, fosfomycin, nitrofurantoin, and amikacin manifested a significant sensitivity rate ranging from 86% - 95%. Acinetobacter baumannii was the most prevalent pathogen that belonged to multidrug- and extensively drug-resistant patterns in 69.1% of the samples. Escherichia coli and K. pneumonia showed similar multidrug-resistant patterns in 35.2% of the cases. Conclusions: The results indicated increased trends of antimicrobial resistance rate in trimethoprim/sulfamethoxazole (85.1%) and fluoroquinolones (61%) against E. coli that was higher than the recommended local resistance rate for empirical therapy (< 20% and < 10%, respectively). According to the results, using fosfomycin and nitrofurantoin are suggested for UTI empiric treatment, and other antibiotics should be prescribed carefully.

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