Voltammetric behaviour of drug molecules as a predictor of metabolic liabilities

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t1/2), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short-(2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability

Application of Ni(II)-Assisted Peptide Bond Hydrolysis to Non-Enzymatic Affinity Tag Removal

In this study, we demonstrate a non-enzymatic method for hydrolytic peptide bond cleavage, applied to the removal of an affinity tag from a recombinant fusion protein, SPI2-SRHWAP-His6. This method is based on a highly specific Ni(II) reaction with (S/T)XHZ peptide sequences. It can be applied for the protein attached to an affinity column or to the unbound protein in solution. We studied the effect of pH, temperature and Ni(II) concentration on the efficacy of cleavage and developed an analytical protocol, which provides active protein with a 90% yield and ∼100% purity. The method works well in the presence of non-ionic detergents, DTT and GuHCl, therefore providing a viable alternative for currently used techniques

A prospective surveillance study to determine the prevalence of 16S rRNA methyltransferase-producing Gram-negative bacteria in the UK

OBJECTIVES: To determine the prevalence of 16S rRNA methyltransferase- (16S RMTase-) producing Gram-negative bacteria in patients in the UK and to identify potential risk factors for their acquisition. METHODS: A 6 month prospective surveillance study was conducted from 1 May to 31 October 2016, wherein 14 hospital laboratories submitted Acinetobacter baumannii, Enterobacterales and Pseudomonas aeruginosa isolates that displayed high-level amikacin resistance according to their testing methods, e.g. no zone of inhibition with amikacin discs. Isolates were linked to patient travel history, medical care abroad, and previous antibiotic exposure using a surveillance questionnaire. In the reference laboratory, isolates confirmed to grow on Mueller-Hinton agar supplemented with 256 mg/L amikacin were screened by PCR for 16S RMTase genes armA, rmtA-rmtH and npmA, and carbapenemase genes (blaKPC, blaNDM, blaOXA-48-like and blaVIM). STs and total antibiotic resistance gene complement were determined via WGS. Prevalence was determined using denominators for each bacterial species provided by participating hospital laboratories. RESULTS: Eighty-four isolates (44.7%), among 188 submitted isolates, exhibited high-level amikacin resistance (MIC >256 mg/L), and 79 (94.0%) of these harboured 16S RMTase genes. armA (54.4%, 43/79) was the most common, followed by rmtB (17.7%, 14/79), rmtF (13.9%, 11/79), rmtC (12.7%, 10/79) and armA + rmtF (1.3%, 1/79). The overall period prevalence of 16S RMTase-producing Gram-negative bacteria was 0.1% (79/71 063). Potential risk factors identified through multivariate statistical analysis included being male and polymyxin use. CONCLUSIONS: The UK prevalence of 16S RMTase-producing Gram-negative bacteria is low, but continued surveillance is needed to monitor their spread and inform intervention strategies

Outbreak of pandemic influenza A/H1N1 2009 in Nepal

<p>Abstract</p> <p>Background</p> <p>The 2009 flu pandemic is a global outbreak of a new strain of H1N1 influenza virus. Pandemic influenza A (H1N1) 2009 has posed a serious public health challenge world-wide. Nepal has started Laboratory diagnosis of Pandemic influenza A/H1N1 from mid June 2009 though active screening of febrile travellers with respiratory symptoms was started from April 27, 2009.</p> <p>Results</p> <p>Out of 609 collected samples, 302 (49.6%) were Universal Influenza A positive. Among the influenza A positive samples, 172(28.3%) were positive for Pandemic influenza A/H1N1 and 130 (21.3%) were Seasonal influenza A. Most of the pandemic cases (53%) were found among young people with ≤ 20 years. Case Fatality Ratio for Pandemic influenza A/H1N1 in Nepal was 1.74%. Upon Molecular characterization, all the isolated pandemic influenza A/H1N1 2009 virus found in Nepal were antigenically and genetically related to the novel influenza A/CALIFORNIA/07/2009-LIKE (H1N1)v type.</p> <p>Conclusion</p> <p>The Pandemic 2009 influenza virus found in Nepal were antigenically and genetically related to the novel A/CALIFORNIA/07/2009-LIKE (H1N1)v type.</p

Idiosyncratic deals for older workers: increased heterogeneity among older workers enhance the need for i-Deals

The rapid aging of the workforce throughout the Western world and parts of Asia, including Japan and China, poses many challenges on contemporary organizations (European Commission, 2010 ; Wang & Shultz, 2010 ). The Babyboom generation, consisting of workers born between 1945 and 1965, constitutes a large part of the current workforce. Due to decreased fertility rates, there are fewer younger workers entering the labor market, as a consequence of which the percentage of older workers is rapidly increasing (Truxillo & Fraccaroli, 2013 ). Consequently, organizations are increasingly aware that the employee population is changing, and that strategies to employ, motivate, and retain workers have to be adapted accordingly. It is no longer suffi cient for organizations to focus on employing younger workers (e.g., through designing traineeships for graduates), because the infl ux of younger workers in the labor market is stagnating, which is in particular present in certain sectors, such as technical occupations and health care (Polat, Bal, & Jansen, 2012 ). Hence, organizations increasingly will have to rely on older workers, and try to retain older workers, and motivate them to stay longer in the workforce. Similarly, governments across Europe are also increasing offi cial retirement ages, and making it fi nancially less attractive for older workers to retire early (European Commission)

Predictors of the development of myocarditis or acute renal failure in patients with leptospirosis: An observational study

<p>Abstract</p> <p>Background</p> <p>Leptospirosis has a varied clinical presentation with complications like myocarditis and acute renal failure. There are many predictors of severity and mortality including clinical and laboratory parameters. Early detection and treatment can reduce complications. Therefore recognizing the early predictors of the complications of leptospirosis is important in patient management. This study was aimed at determining the clinical and laboratory predictors of myocarditis or acute renal failure.</p> <p>Methods</p> <p>This was a prospective descriptive study carried out in the Teaching Hospital, Kandy, from 1st July 2007 to 31st July 2008. Patients with clinical features compatible with leptospirosis case definition were confirmed using the Microscopic Agglutination Test (MAT). Clinical features and laboratory measures done on admission were recorded. Patients were observed for the development of acute renal failure or myocarditis. Chi-square statistics, Fisher's exact test and Mann-Whitney <it>U </it>test were used to compare patients with and without complications. A logistic regression model was used to select final predictor variables.</p> <p>Results</p> <p>Sixty two confirmed leptospirosis patients were included in the study. Seven patients (11.3%) developed acute renal failure and five (8.1%) developed myocarditis while three (4.8%) had both acute renal failure and myocarditis. Conjunctival suffusion - 40 (64.5%), muscle tenderness - 28 (45.1%), oliguria - 20 (32.2%), jaundice - 12 (19.3%), hepatomegaly - 10 (16.1%), arrhythmias (irregular radial pulse) - 8 (12.9%), chest pain - 6 (9.7%), bleeding - 5 (8.1%), and shortness of breath (SOB) 4 (6.4%) were the common clinical features present among the patients. Out of these, only oliguria {odds ratio (OR) = 4.14 and 95% confidence interval (CI) 1.003-17.261}, jaundice (OR = 5.13 and 95% CI 1.149-28.003), and arrhythmias (OR = 5.774 and 95% CI 1.001-34.692), were predictors of myocarditis or acute renal failure and none of the laboratory measures could predict the two complications.</p> <p>Conclusions</p> <p>This study shows that out of clinical and laboratory variables, only oliguria, jaundice and arrhythmia are strong predictors of development of acute renal failure or myocarditis in patients with leptospirosis presented to Teaching Hospital of Kandy, Sri Lanka.</p

Moderately overweight and obese patients in general practice: a population based survey

BACKGROUND: Obesity is a main threat to public health in the Western world and is associated with diseases such as diabetes mellitus and coronary heart diseases. Up to now a minority of research studied the relation between obesity and the use of primary health care. In the Netherlands the general practitioner (GP) is the main primary health care provider. The objective of this article is to evaluate GP consultation and prescription of drugs in moderate and severely overweight (obese) persons in the Netherlands. METHODS: Data were used from a representative survey of morbidity in Dutch general practice in 2001. Our study sample consisted of 8,944 adult respondents (18+ years) who participated in an extensive health interview. Interview data were linked to morbidity and prescription registration data from 95 general practices where respondents were listed. Body mass index (BMI) was calculated using self-reported height and weight. Analyses were controlled for clustering within practices as well as for socio-demographic and life style characteristics. RESULTS: Obesity (BMI ≥ 30 kg/m2) was observed in 8.9% of men and 12.4% of women; for moderate overweight (BMI 25-<30 kg/m2) these percentages were 42.2% and 30.4% respectively. Obese men and women were more likely to consult their GP than persons without overweight. This especially holds for diseases of the endocrine system, the cardiovascular system, the musculoskeletal system, the gastro-intestinal system, and skin problems. Related to this, obese men and women were more likely to receive drugs for the cardiovascular system, the musculoskeletal system, alimentary tract and metabolism (including, for example, antidiabetics), and dermatologicals, but also antibiotics and drugs for the respiratory system. For moderately overweight men and women (BMI 25-<30 kg/m2) smaller but significant differences were found for diseases of the endocrine system, the cardiovascular system, and the musculoskeletal system. CONCLUSION: Obesity increases the workload of Dutch general practitioners and the use of prescribed medication. The current increase in the prevalence of obesity will further increase the use of health care and related costs. Since a large majority of Dutch persons visit their GP over the course of one year, GPs' potential role in effective prevention strategies cannot be denied