Searching for a prodrome for rheumatoid arthritis in the primary care record: a case-control study in the Clinical Practice Research Datalink

Background: Rheumatoid arthritis (RA) has articular and non-articular manifestations. Early, intensive treatment has substantial benefit for both. This requires patients be identified as soon as symptoms develop. Objectives: To determine whether selected signs and symptoms can be identified in the primary care records of patients prior to a formal diagnosis of RA being made and, if so, how early they can be identified. Methods: A case-control study was constructed within the UK Clinical Practice Research Datalink (CPRD). 3577 individuals with 'definite' RA, were matched to 14287 individuals without inflammatory arthritis. An index date was established (i.e. date general practitioner (GP) first appeared to suspect RA). Rates of consultation and consultations for suspected early RA symptoms were compared in cases and controls in the two years prior to the index date using conditional logistic regression, adjusted for number of consultations. Results: The mean (standard deviation) age of participants was 58.8 (14.5) years and 66.8% were female. Rates of any consultation were significantly higher in RA cases than in controls for at least two years prior to the index date. Cases were more likely to have a pre-diagnosis coded consultation for joint, and particularly hand symptoms (aOR 11.44 (9.60, 13.63)), morning stiffness (8.10 (3.54, 18.5)), carpal tunnel syndrome (4.57 (3.54, 5.88)) and other non-articular features. Conclusions: In patients who develop RA, GP consultation rates are higher for at least two years prior to the first recorded suspicion of RA. This study highlights symptoms that should raise a GP’s index of suspicion for RA

Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study

Aim To investigate the safety and efficacy of bupropion sustained release (bupropion SR) in promoting abstinence from smoking in subjects with cardiovascular disease (CVD). Methods Six hundred twenty-nine subjects with CVD who smoked ≥10 cigarettes/day were randomised in a double-blind, multicentre study to receive bupropion SR (150mg twice daily) or placebo for 7 weeks, with a follow-up of 52 weeks. Primary efficacy endpoint: continuous abstinence from smoking from weeks 4 to 7. Secondary endpoints: continuous abstinence (weeks 4-12, 4-26 and 4-52) and weekly point prevalence abstinence. All participants received brief motivational support. Safety was evaluated throughout the study. Results Continuous smoking abstinence rates from weeks 4 to 7 were significantly higher in subjects receiving bupropion SR compared with placebo (43 vs. 19%, odds ratio [OR]=3.27, 95% confidence interval [CI] 2.24-4.84; \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $P{<}0.001$ \end{document}). Continuous abstinence rates from weeks 4 to 26 and 4 to 52 continued to be more than double for bupropion SR compared with placebo (27 vs. 11%; 22 vs. 9%, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $P{<}0.001$ \end{document}). Weekly point prevalence abstinence was significantly higher for participants who received bupropion SR compared with placebo at weeks 3, 7, 26 and 52 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $(P{<}0.001)$ \end{document}. In both groups, there were no clinically significant changes in blood pressure and heart rate throughout the treatment phase. Overall, 6% of the participants \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $(n=36)$ \end{document} discontinued study medication due to an adverse event (bupropion SR, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=17$ \end{document}; placebo, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=19$ \end{document}). Conclusions After 7 weeks of bupropion SR treatment, more than twice as many smokers with CVD had quit smoking at 1 year compared with placebo. The safety profile of bupropion SR was similar to that previously observed in general smoking population

Total synthesis and biological evaluation of the tetramic acid based natural product harzianic acid and its stereoisomers

Financial support for this project was provided by Cancer Research UK (Grant No. C21383/A6950)The bioactive natural product harzianic acid was prepared for the first time in just six steps (longest linear sequence) with an overall yield of 22%. The identification of conditions to telescope amide bond formation and a Lacey-Dieckmann reaction into one pot proved important. The three stereoisomers of harzianic acid were also prepared, providing material for comparison of their biological activity. While all of the isomers promoted root growth, improved antifungal activity was unexpectedly associated with isomers in the enantiomeric series opposite that of harzianic acid.Publisher PDFPeer reviewe

Dissolution of ionizable water-insoluble drugs: The combined effect of pH and surfactant

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate ( J total ) of PX was measured in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl sulfate (SLS) using the rotating disk apparatus. Solubility ( c total ) was also measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX ↔ H + + PX − ) and two micellar solubilization equilibria (PX + micelle ↔ [PX] micelle , PX − + micelle ↔ [PX − ] micelle ) were considered in the convective diffusion reaction model. J total and c total of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed that observed experimental data were well described with the proposed model ( r 2 = 0.86, P < 0.001 for J total and r 2 = 0.98, P < 0.001 for c total ). The p K a value of 5.63 ± 0.02 estimated from c total agreed well with the reported value. The micellar solubilization equilibrium coefficient for the unionized drug was estimated to be 348 ± 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients of the species PX, PX − , and [PX] micelle were estimated from the experimental results as (0.93 ± 0.35) × 10 −5 , (1.4 ± 0.30) × 10 −5 , and (0.59 ± 0.21) × 10 −5 cm 2 /s, respectively. The total flux enhancement is less than the total solubility enhancement due to the smaller diffusion coefficients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and surfactant and for establishing in vitro – in vivo correlations, IVIVC, for maintaining bioequivalence of drug products. © 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 268–274, 2000Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34499/1/14_ftp.pd

Mixing and matching siderophore clusters: structure and biosynthesis of serratiochelins from Serratia sp. v4

Studying the evolutionary history underlying the remarkable structures and biological activities of natural products has been complicated by not knowing the functions they have evolved to fulfill. Siderophores - soluble, low molecular weight compounds - have an easily understood and measured function: acquiring iron from the environment. Bacteria engage in a fierce competition for acquiring iron, which rewards the production of siderophores that bind iron tightly and cannot be used or pirated by competitors. The structures and biosyntheses of 'odd' siderophores can reveal the evolutionary strategy that led to their creation. Here, we here report a new Serratia strain that produces serratiochelin and an analog of serratiochelin. A genetic approach located the serratiochelin gene cluster, and targeted mutations in several genes implicated in serratiochelin biosynthesis were generated. Bioinformatic analyses and mutagenesis results demonstrate that genes from two well known siderophore clusters, the Escherichia coli enterobactin cluster and the Vibrio cholerae vibriobactin cluster, were shuffled to produce a new siderophore biosynthetic pathway. These results highlight how modular siderophore gene clusters can be mixed and matched during evolution to generate structural diversity in siderophores.This work was supported by the National Institutes of Health (Grants GM82137 to R.K., and AI057159 and GM086258 to J.C.). M.R.S. acknowledges support from the NIH Pathway to Independence Award (Grant 1K99 GM098299-01). S.C. and M.J.V. acknowledge support from the Portuguese Foundation for Science and Technology (PhD Grant SFRH/BD/38298/2007 to S.C.; Project PTDC/EBB-EBI/104263/2008 to M.J.V.)