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Concept: GlaxoSmithKline


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


BACKGROUND: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). METHODS: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 1 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. RESULTS: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). CONCLUSIONS: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovir.

Concepts: Median, Visual acuity, Aciclovir, Valaciclovir, Retina, Antivirals, GlaxoSmithKline, Eye


The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

Concepts: Generic drug, Drug development, GlaxoSmithKline, AstraZeneca, Drug discovery, Clinical trial, Pharmacology, Pharmaceutical industry


Bladder cancer (BC) is a common malignancy that arises through occupational carcinogen exposure. Here we analyse trends in UK to better understand contemporary occupational BC.

Concepts: Constitutional monarchy, Harold Pinter, GlaxoSmithKline, Decolonization, England, Cancer, English language, United Kingdom


The Global Programme to Eliminate Lymphatic Filariasis (LF) aims to eliminate the disease as a public health problem by 2020 by conducting mass drug administration (MDA) and controlling morbidity. Once elimination targets have been reached, surveillance is critical for ensuring that programmatic gains are sustained, and challenges include timely identification of residual areas of transmission. WHO guidelines encourage cost-efficient surveillance, such as integration with other population-based surveys. In American Samoa, where LF is caused by Wucheraria bancrofti, and Aedes polynesiensis is the main vector, the LF elimination program has made significant progress. Seven rounds of MDA (albendazole and diethycarbamazine) were completed from 2000 to 2006, and Transmission Assessment Surveys were passed in 2010/2011 and 2015. However, a seroprevalence study using an adult serum bank collected in 2010 detected two potential residual foci of transmission, with Og4C3 antigen (Ag) prevalence of 30.8% and 15.6%. We conducted a follow up study in 2014 to verify if transmission was truly occurring by comparing seroprevalence between residents of suspected hotspots and residents of other villages. In adults from non-hotspot villages (N = 602), seroprevalence of Ag (ICT or Og4C3), Bm14 antibody (Ab) and Wb123 Ab were 1.2% (95% CI 0.6-2.6%), 9.6% (95% CI 7.5%-12.3%), and 10.5% (95% CI 7.6-14.3%), respectively. Comparatively, adult residents of Fagali'i (N = 38) had significantly higher seroprevalence of Ag (26.9%, 95% CI 17.3-39.4%), Bm14 Ab (43.4%, 95% CI 32.4-55.0%), and Wb123 Ab 55.2% (95% CI 39.6-69.8%). Adult residents of Ili'ili/Vaitogi/Futiga (N = 113) also had higher prevalence of Ag and Ab, but differences were not statistically significant. The presence of transmission was demonstrated by 1.1% Ag prevalence (95% CI 0.2% to 3.1%) in 283 children aged 7-13 years who lived in one of the suspected hotspots; and microfilaraemia in four individuals, all of whom lived in the suspected hotspots, including a 9 year old child. Our results provide field evidence that integrating LF surveillance with other surveys is effective and feasible for identifying potential hotspots, and conducting surveillance at worksites provides an efficient method of sampling large populations of adults.

Concepts: Statistical significance, Samoa, American Samoa, Adult, Filariasis, GlaxoSmithKline, Malaria, Epidemiology


BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting β(2)-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 μg; 50/25 μg) vs. individual components (FF 100 μg, VI 25 μg) and placebo over 24 weeks. METHODS: Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV(1) (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV(1) (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed. RESULTS: Main findings were: (1) the combination of FF/VI at a strength of 100/25 μg significantly (p < 0.001) improved wm FEV(1) (173 ml) and trough FEV(1) (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 μg; (2) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV(1) (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV(1) (120 ml, p < 0.001); (3) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV(1) (103 ml, p < 0.001) and trough FEV(1) (67 ml, p = 0.017); and (4) no safety signal was observed. CONCLUSIONS: In subjects with moderate-to-severe COPD, FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg. All treatments were well tolerated. GSK study number: HZC112206. NCT01053988.

Concepts: Statistical significance, Weighted mean, Pulmonology, Effectiveness, GlaxoSmithKline, Clinical trial, Randomized controlled trial, Asthma


BACKGROUND: Once-daily combination treatment is an attractive maintenance therapy for COPD. However, the dose of inhaled corticosteroid to use in a once-daily combination is unknown. We compared two strengths of fluticasone furoate (FF) plus vilanterol (VI), the same strengths of the individual components, and placebo. METHODS: Multicentre, randomised, 24-week, double-blind, placebo-controlled, parallel-group study in stable, moderate-to-severe COPD subjects (N = 1224). Subjects were randomised to FF/VI (200/25 μg; 100/25 μg), FF (200 μg; 100 μg), VI 25 μg, or placebo, once daily in the morning. Co-primary efficacy endpoints; 0-4 h weighted mean (wm) FEV(1) on day 168, and change from baseline in trough (23-24 h post-dose) FEV(1) on day 169. The primary safety objective was adverse events (AEs). RESULTS: There was a statistically significant (p < 0.001) increase in wm FEV(1) (209 ml) and trough FEV(1) (131 ml) for FF/VI 200/25 μg vs. placebo; similar changes were seen for FF/VI 100/25 μg vs. placebo. Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1) (32 ml) was not statistically significant (p = 0.224), the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1) (168 ml) was significantly different (p < 0.001). VI 25 μg significantly improved wm and trough FEV(1) vs. placebo (209 ml and 131 ml, respectively). No increase was seen in on-treatment AEs or serious AEs (SAEs), with active therapy vs. placebo. CONCLUSIONS: FF/VI provides rapid and significant sustained improvement in FEV(1) in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study. GSK study number: HZC112207. NCT01054885.

Concepts: Mean, Improve, GlaxoSmithKline, Better, Randomized controlled trial, Fluticasone propionate, Clinical trial, Asthma


Antibiotic prophylaxis in dogs undergoing surgical procedures frequently involves the administration of a product without a veterinary licence. Two drugs commonly used for this purpose are the clavulanate amoxicillin Augmentin and the cefuroxime Zinacef. This prospective observational study aims to compare the incidence of adverse events associated with these two antibiotics in a clinical setting. The authors hypothesised that a higher incidence of adverse effects would be observed with Augmentin. Sixty-five dogs were included in the study and adverse events were recorded using a modified scoring system. A significantly higher incidence of adverse events to Augmentin (8/22; 36 per cent) was observed compared with Zinacef (1/43; 2 per cent) (P=0.0003). The majority of these adverse events involved cutaneous signs and/or hypotension. These findings might be taken into consideration when selecting one of these intravenous antibiotics for prophylaxis in anaesthetised dogs undergoing surgery.

Concepts: Adverse drug reaction, Observational study, Medicine, Beta-lactam antibiotic, Surgery, Clavulanic acid, GlaxoSmithKline, Antibiotic


Routine application of antimicrobials is the current treatment of choice for rainbow trout fry syndrome (RTFS) or bacterial coldwater disease (BCWD) caused by Flavobacterium psychrophilum. In this study, the antimicrobial susceptibilities of 133 F. psychrophilum isolates, 118 of which were from the UK, were evaluated by broth microdilution and disc diffusion methods following VET04-A2 and VET03-A guidelines of Clinical and Laboratory Standards Institute (CLSI), respectively. Isolates were categorized as wild type (fully susceptible, WT) or non-wild type (NWT) using normalized resistance interpretation (NRI)-determined cut-off values (COWT ). Broth microdilution testing showed that only 12% of UK isolates were WT to oxolinic acid (MIC COWT  ≤ 0.25 mg/L) and 42% were WT for oxytetracycline (MIC COWT  ≤ 0.25 mg/L). In contrast, all the isolates tested were WT (MIC COWT  ≤ 2 mg/L) for florfenicol, the main antimicrobial for RTFS control in the UK. Disc diffusion-based COWT values were ≥51 mm for 10 μg amoxicillin, ≥44 mm for 30 μg florfenicol, ≥30 mm for 2 μg oxolinic acid and ≥51 mm for 30 μg oxytetracycline. There was a high categorical agreement between the classifications of the isolates by two testing methods for florfenicol (100%), oxytetracycline (93%) and oxolinic acid (99%).

Concepts: United Kingdom of Great Britain and Ireland, Antimicrobial, History of the United Kingdom, GlaxoSmithKline, English language, Decolonization, Rainbow trout, United Kingdom


A comprehensive model with all effective phenomena in drug release such as diffusion, swelling and erosion was considered. In this work, a mathematical model was developed to describe drug release from controlled release HPMC matrices as a favorable system in pharmaceutical industries. As a novel study, the impact of the MCC presence as a filler in tablet preparation process was considered in the mathematical model. In addition, we found that the volume expansion of these polymeric matrices did not follow the ideal mixing rule and we derived an equation for estimating the volume of hydrated matrix. Furthermore, some equations were derived to estimate the parameters of model (Kerosion, Deq) as well as the change in matrix volume based on the amount of polymer and filler in formulation. This investigation gave deeper insight into underlying drug release mechanisms. According to the results, Kerosion increases linearly and Deq increases exponentially with the increase in the amount of MCC in formulation. Application of this comprehensive mathematical model enables us to predict the behavior of HPMC-MCC based matrices. Furthermore, this model is able to represent the formulation for the desired drug release profile which is useful to design new controlled release matrix as well as improving the system geometry and dimensions of tablets. The presented model was validated by two independent tests: a) predicting the behavior of matrix with certain MCC/HPMC ratio upon exposure to the release medium; b) designing formulation of Bupropion hydrochloride extended release tablet.

Concepts: GlaxoSmithKline, Engineering, Abstract algebra, Physics, Estimation, Pharmaceutical formulation, Pharmacology, Mathematics