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Concept: Beecham

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To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.

Concepts: The Canon of Medicine, Systematic review, Randomized controlled trial, Avicenna, Major depressive disorder, Paroxetine, GlaxoSmithKline, Beecham

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Bacterial resistance and antibiotic drug effectiveness can be related to administering generic products with a subtherapeutic dose or poor in vivo drug release. The aim of this study was to investigate whether locally marketed amoxicillin tablets have the required chemical and physical attributes, including in vitro bioequivalence performance. Five generic products (T1, T2, T3, T4, and T5) containing combination of amoxicillin trihydrate and potassium clavulanate as 1 g strength present in immediate release tablets were compared to the reference listed drug product Augmentin® ® for weight variation, friability, resistance to crushing, and chemical content of amoxicillin. Difference (ƒ1) and similarity (ƒ2) factors were calculated to assess in vitro bioequivalence requirements. The tablets from different products have shown compliance with the pharmacopeial requirements of the performed tests. The measured resistance to crushing of tablets did not influence the dissolution time. Three generic products released more than 85% of amoxicillin by the first 15 min as did the reference product and were considered as bioequivalent products. T1 and T4 had ƒ1 values of 16.5% and 25.4% respectively and their ƒ2 values were 44.5 and 34.6 respectively, indicating failure to meet in vitro bioequivalence requirements. Tablet formulations can play an important role in achieving bioequivalence. Independent investigations such as this study serve as an important tool to reveal possible inferior or noncompliant products that may find their way to the market.

Concepts: Antibiotic, Generic drug, Beta-lactam antibiotic, Clavulanic acid, Beta-lactamase, Tablet, Amoxicillin, Beecham

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The basophil activation test (BAT), has been proposed as a possible assay for the diagnosis of immediate-type allergy to beta-lactams (BLs). The aim of this study was to assess the utility of BAT in the diagnosis of amoxicillin (AMX) or AMX-clavulanate (AMX-C) IgE-mediated hypersensitivity in children and adults.

Concepts: Immune system, Allergy, Psychometrics, Beta-lactam antibiotic, Beta-lactamase, Beecham

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Amoxicillin-clavulanate (AC) is one of the most common causes of drug induced liver injury (DILI). The association between AC-DILI and HLA alleles and the detection of drug-specific T cells in patients with AC-DILI indicate that the adaptive immune system is involved in the disease pathogenesis. In this study, mass spectrometric methods were employed to characterize the antigen formed by AC in exposed patients and the antigenic determinants that stimulate T cells. Amoxicillin formed penicilloyl adducts with lysine residues on human serum albumin (HSA) in vitro, with K190 and K199 being the most reactive sites. Amoxicillin-modified K190 and K199 have also been detected in all patients, and more extensive modification was observed in patients exposed to higher doses of amoxicillin. In contrast, the binding of clavulanic acid to HSA was more complicated. Multiple adducts were identified at high concentrations in vitro, including those formed by direct binding of clavulanic acid to lysine residues, novel pyrazine adducts derived from binding to the degradation products of clavulanic acid, and a cross-linking adduct. Stable adducts derived from formylacetic acid were detected in all patients exposed to the drug. Importantly, analysis of hapten-protein adducts formed in cell culture medium revealed that the highly drug-specific T-cell responses were likely driven by the markedly different haptenic structures formed by these two drugs. In this study the unique haptenic structures on albumin in patients formed by amoxicillin and clavulanic acid have been characterized and shown to function as chemically distinct antigens which can stimulate separate, specific T-cell clones.

Concepts: Immune system, Protein, B cell, Adaptive immune system, Antigen, Major histocompatibility complex, Clavulanic acid, Beecham

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The combination of β-lactams and β-lactamase inhibitors has been shown to have potent in vitro activity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent β-lactam/β-lactamase inhibitor combination against MDR-TB, we selected nine β-lactams and three β-lactamase inhibitors, belonging to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the β-lactams used herein, biapenem showed the best effect against MDR-TB, the MIC50 value of which was 8 μg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with the MIC50 value of 4 μg/ml. For meropenem, there were 76 (62.8%), 41 (33.9%) and 22 (18.2%) out of 121 MDR-TB strains exhibited the synergistic effect when combined with sulbactam, tazobactam and clavulanate, respectively. Further statistical analysis revealed that significantly more strains showed a synergistic effect for the combination of meropenem with sulbactam, compared to its combination with tazobactam or clavulanate, respectively (P<0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in blaC gene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with Ser111Arg substitution in BlaC, the better synergistic effect was observed in the meropenem/clavulanate and amoxicillin/clavulanate combinations as compared with a synonymous SNP group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in presence of clavulanate.

Concepts: Tuberculosis, Multi-drug-resistant tuberculosis, Mycobacterium, Mycobacterium tuberculosis, Beta-lactam antibiotic, Beta-lactamase, 2007 tuberculosis scare, Beecham

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Professor Sian Harding talks to Caroline Telfer, Assistant Commissioning Editor. Professor Sian Harding obtained her PhD in Pharmacology from King’s College, London (UK) in 1981. She became Professor of Cardiac Pharmacology at the National Heart and Lung Institute, a division of the Imperial College Faculty of Medicine, in 2002. Her work has been funded by the British Heart Foundation, the Wellcome Trust, the Medical Research Council, the Biochemical and Biophysical Research Council, the The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Pfizer, GlaxoSmithKline and SmithKline Beecham. Harding is former president of the European Section of the International Society for Heart Research and has organized international cardiovascular science meetings for this society, as well as for the European Society of Cardiology. She is the principal investigator for the first UK gene therapy trial aimed at improving cardiac contractility, organized jointly at Harefield and Papworth Hospitals. Harding is a member of the Nuffield Council on Bioethics and the Medical Research Coucil Regenerative Medicine Research Committee, and Director of a recently awarded British Heart Foundation Cardiovascular Regenerative Medicine Centre. She has been elected Fellow of the American Heart Association, European Society of Cardiology, International Society for Heart Research, Society of Biology and British Society of Pharmacology.

Concepts: Medicine, Gene, Cardiology, Heart, United Kingdom, Bioethics, GlaxoSmithKline, Beecham

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Abstract Objectives. The aim of the study was to evaluate the effect of three desensitizing toothpastes on bonding of resin cements to dentin. Materials and methods. The occlusal surfaces of 72 maxillary third molars were ground to obtain flat dentin surfaces and then divided into three groups according to three desensitizing toothpastes used: Sensodyne Rapid Relief (GlaxoSmithKline, SmithKline Beecham Ltd., Slough, UK), Signal Sensitive Expert (Unilever Sanayi ve Ticaret Türk A.Ş., Ümraniye, İstanbul, Turkey) and Colgate Sensitive Pro-Relief (Colgate Palmolive, New York, NY). Following bonding of the resin cement (Clearfil™ SA Cement, Kuraray Co, Osaka, Japan) to dentin, the specimens were light cured for 40 s with a LED (Elipar S10, 3M Espe, St. Paul, MN). The strength measurements were accomplished with a micro-shear testing machine (Bisco, Schaumburg, IL) at a cross-head speed of 0.5 mm/min until the failure occurs. Failure modes were examined using a stereomicroscope and scanning electron microscope. The data were analyzed with one-way analysis of variance (ANOVA) and Tukey HSD test (α = 0.05). Results and conclusion. ANOVA revealed that the application of desensitizing toothpastes had significant effects on bond strength of the resin cement tested to dentin (p < 0.05). Mixed failures were observed in all of the groups. Clinical significance. The use of a desensitizing toothpaste before cementation might alter the bond strength of adhesively luted restorations.

Concepts: Electron, Variance, Analysis of variance, Scanning electron microscope, Toothpaste, GlaxoSmithKline, Colgate-Palmolive, Beecham