Ex Vivo ?CT Analysis of Bleomycin-Induced Lung Fibrosis for Pre-Clinical Drug Evaluation.

Ex vivo ?CT analysis of bleomycin-induced lung fibrosis for pre-clinical drug evaluation.

Eur Respir J. 2013 Mar 21;
Scotton CJ, Hayes B, Alexander R, Datta A, Forty EJ, Mercer PF, Blanchard A, Chambers RC

Research into the pathogenesis underlying the development of idiopathic pulmonary fibrosis (IPF) is hampered by a repertoire of animal models which fail to recapitulate all the features of the human disease. Better use and understanding of what the animal models represent may improve clinical predictability. We interrogated ex vivo micro-Computed Tomography (?CT) as a novel endpoint measure in the mouse model of bleomycin-induced lung fibrosis (BILF), and to evaluate a therapeutic dosing regimen for pre-clinical drug evaluation.A detailed characterisation of BILF was performed using standard endpoint measures (lung hydroxyproline and histology). High resolution ?CT (?13.7 ?m voxel size) was evaluated for quantifying the extent and severity of lung fibrosis.The period from 14 to 28 days following bleomycin instillation represents progression of established fibrosis. A therapeutic dosing regimen during this period was validated using a TGF?R1 kinase inhibitor, and ?CT provided a highly sensitive and quantitative measure of fibrosis. Moreover, fibrotic lesions did not completely resolve, but instead persisted for at least six months following a single insult with bleomycin.Ex vivo ?CT analysis of BILF allows robust evaluation of therapeutic dosing once fibrosis is already well-established, requiring fewer mice than conventional biochemical endpoints. HubMed – drug


Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients.

Eur Respir J. 2013 Mar 21;
Bolhuis MS, Altena RV, Soolingen DV, Lange WC, Uges DR, Werf TS, Kosterink JG, Alffenaar JW

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug-drug interaction between linezolid and clarithromycin resulting in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid.Subjects were included in an open-label, single-center, 1-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods and differences between pharmacokinetic parameters were calculated.Linezolid exposure increased by a median of 44% (interquartile range: 23-102%, P=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients: none experienced severe adverse effects. One patient reported Common Toxicity Criteria Grade 2 gastro-intestinal adverse events.In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug-drug interaction is possibly P-glycoprotein mediated. Due to large inter-patient variability, therapeutic drug monitoring is advisable to determine individual effect size. HubMed – drug


A qualitative study of the barriers to prehospital management of acute pain in children.

Emerg Med J. 2013 Mar 21;
Murphy A, Barrett M, Cronin J, McCoy S, Larkin P, Brenner M, Wakai A, O’Sullivan R

INTRODUCTION: Effective pain management in the prehospital setting is gaining momentum as a potential key performance indicator by many emergency medical service systems, but historically has been shown to be inadequate, particularly in the paediatric population. This study aimed to identify the barriers, as perceived by a national cohort of advanced paramedics (APs), to achieving optimal prehospital management of acute pain in children. METHODS: A qualitative approach was employed to capture data through two focus group interviews. Sixteen APs were invited to participate in this study. Both focus groups were audio recorded, transcribed and analysed using Attride-Stirling’s framework for thematic network analysis. RESULTS: The global theme ‘Understanding Barriers to the Prehospital Management of Acute Pain in Children’ emerged from three organising themes as follows: AP education and training; current clinical practice guidelines for paediatric pain management; realities of prehospital practice. Limited exposure to children in the prehospital setting, difficulty assessing pain intensity in small children, and challenges in administering oral or inhaled analgesic agents to distressed and uncooperative children were highlighted by participants. Short transfer times to the emergency department, and a ‘medical’ cause of pain were also implicated as examples of when children are less likely to receive analgesia from practitioners. CONCLUSIONS: The pathway to improving care must include an emphasis on improvements in practitioner education and training, offering alternatives to assessing pain in preverbal children, exploring the intranasal route of drug delivery in managing acute severe pain, and robustly developed evidence-based guidelines that are practitioner friendly and patient-focused. HubMed – drug


Why do we need drugs to treat the patient with obesity?

Obesity (Silver Spring). 2013 Mar 21;
Bray GA

OBJECTIVE: Obesity is a public health problem, which increases the risk of chronic diseases and mortality. Weight loss can reduce mortality and improve most of the detrimental health consequences of obesity. DESIGN: This paper was developed form 2 presentations to the U.S. Food and Drug Administration (FDA) which has responsibility for reviewing and approving drugs to treat obesity. RESULTS: A weight loss of 5% or more is sufficient to significantly reduce health risks in individuals with impaired glucose tolerance, hypertension, or non-alcoholic fatty liver disease. Slightly more weight loss (16% on average, achieved by surgery) reduces mortality. The goal of medicating for obesity is to help more patients achieve more weight loss. A barrier to drug approval has been the concern that weight loss medications might be used by individuals with little or no health risks, thus mandating a low side effect profile for approval of any drug. This limits the options for patients who have obesity-related health problems that could improve with weight loss. Recently the FDA signaled interest in identifying health benefits in higher risk patients that might justify medications with higher risk; however the potential impact on a large segment of the population has led the FDA to consider requiring a cardiovascular outcome trial for all obesity medications, either prior to or after approval. CONCLUSION: This review argues that drugs are needed for obesity because they enhance behaviorally induced weight loss and that new medications for obesity are needed in the approval process. HubMed – drug


Spectrofluorimetric determination of tobramycin in human serum and pharmaceutical preparations by derivatization with fluorescamine.

Luminescence. 2013 Mar 21;
Tekkeli SE, Onal A, Sa??rl? AO

A simple, sensitive and selective spectrofluorimetric method has been developed for the determination of tobramycin (TOB) in human serum and pharmaceutical preparations. The method is based on the reaction between the primary amino group of TOB and fluorescamine in borate buffer, pH 8.5, to give a highly fluorescent derivative which is measured at 469?nm after excitation at 388?nm. The fluorescence intensity was directly proportional to the concentration over the range 300-1500?ng/mL, with a limit of detection of 65? ng/mL and limit of quantitation of 215? ng/mL. All variables were investigated to optimize the reaction conditions. The method was validated according to International Conference on Harmonization guidelines in terms of specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. Good recoveries were obtained ranging from 97.4 to 100.64%, indicating that no interference was observed from concomitants usually present in pharmaceutical dosage forms. The method was successfully, applied for the analysis of the drug substance in its pharmaceutical preparations and spiked serum samples. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – drug



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