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Despite the availability of a growing range of interventions to assist control of body weight for people with excess weight or obesity, only a small proportion of people achieve their weight loss goals and are able to maintain body weight reductions in the long term. Negative attitudes and beliefs are often found among physicians and others involved in treating obesity and may adversely impact the effectiveness of management. In this international study, healthcare professionals were invited to complete an online survey of their attitudes and practice in the management of excess body weight. A total of 335 clinicians completed the survey of whom approximately half were based in Europe. A key finding from the survey is that, while participants are generally confident in their ability to manage overweight and obesity effectively, they also report that most of their patients are not successful in achieving their weight loss goals. At the same time, participants tended to overestimate the effectiveness of current medical management in maintaining reductions in body weight. Educational initiatives addressing the real-life effectiveness of different weight control interventions may help to close the gap between clinicians' perceptions and reality in the management of excess body weight.

Outcome reporting in bariatric surgery needs a core outcome set (COS), an agreed minimum set of outcomes reported in all studies of a particular condition. The aim of this study was to summarize outcome reporting in bariatric surgery to inform the development of a COS. Outcomes reported in randomized controlled trials (RCTs) and large non-randomized studies identified by a systematic review were listed verbatim and categorized into domains, scrutinizing the frequency of outcome reporting and uniformity of definitions. Ninety studies (39 RCTs) identified 1,088 separate outcomes, grouped into nine domains with most (n = 920, 85%) reported only once. The largest outcome domain was 'surgical complications', and overall, 42% of outcomes corresponded to a theme of 'adverse events'. Only a quarter of outcomes were defined, and where provided definitions, which were often contradictory. Percentage of excess weight loss was the main study outcome in 49 studies, but nearly 40% of weight loss outcomes were heterogeneous, thus not comparable. Outcomes of diverse bariatric operations focus largely on adverse events. Reporting is inconsistent and ill-defined, limiting interpretation and comparison of published studies. Thus, we propose and are developing a COS for the surgical treatment of severe and complex obesity.

Bariatric surgery is increasingly being used to treat severe obesity, but little is known about its impact on patient-reported outcomes (PROs). For PRO data to influence practice, well-designed and reported studies are required. A systematic review identified prospective bariatric surgery studies that used validated PRO measures. Risk of bias in randomized controlled trials (RCTs) was assessed, and papers were examined for reporting of (i) who completed PRO measures; (ii) missing PRO data and (iii) clinical interpretation of PRO data. Studies meeting all criteria were classified as robust. Eighty-six studies were identified. Of the eight RCTs, risk of bias was high in one and unclear in seven. Sixty-eight different PRO measures were identified, with the Short Form (SF)-36 questionnaire most commonly used. Forty-one (48%) studies explicitly stated measures were completed by patients, 63 (73%) documented missing PRO data and 50 (58%) interpreted PRO data clinically. Twenty-six (30%) met all criteria. Although many bariatric surgery studies assess PROs, study design and reporting is often poor, limiting data interpretation and synthesis. Well-designed studies that include agreed PRO measures are needed with reporting to include integration with clinical outcomes to inform practice.

The substrate specificity at the active site of recombinant human synovial fluid phospholipase A2 (hs-PLA2) was investigated by the preparation of a series of short-chain phospholipid analogs and measurement of their enzymatic hydrolysis at concentrations well below the critical micelle concentration. Substrates used in the study included 1,2-dihexanoylglycerophospholipids, 1,2-bis(alkanoylthio)glycerophospholipids, and 1-O-alkyl-2-(alkanoylthio)phospholipids. Turnover was observed for only a few of the 1,2-dihexanoylglycerophospholipids, and the rate of hydrolysis was very low, near the limit of detection of the assay. In contrast, selected 2-(alkanoylthio)-glycerophospholipids were hydrolyzed by hs-PLA2 at much higher rates at concentrations well below their critical micelle concentration (cmc). Thus, the 1,2-bis(hexanoylthio)glycerophosphatidylmethanol exhibits a k(cat)/K(M) = 1800 L mol-1 s-1. Over the calculated log P (cLogP) range of 3-9, cLogP and log(k(cat)/K(M) were linearly related for compounds with straight-chain sn-1 and sn-2 substituents. At comparable cLogP's, the sn-1 ethers and thioesters were hydrolyzed at comparable rates. A negative charge in the phosphate head group was required for enzyme activity. Unsaturation, aromaticity, and branching in the sn-2 substituent reduce turnover dramatically. The same structural modifications in the sn-1 substituent have less effect on turnover. Certain of these substrates, e.g., 1,2-bis(hexanoylthio)glycerophosphatidylmethanol, may be useful in assaying for active site inhibitors of PLA2. The structure--activity relationships established here for substrates should serve as a reference for the structure--activity relationships of substrate-based inhibitors.

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

Recent studies have shown that the compound MX [3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone] can account for up to 57% of the observed acid fraction mutagenicity of chlorinated drinking water. In the present study laboratory investigations showed MX to be very well removed by activated carbon over a wide concentration range. Samples obtained from two water treatment plants following pre‐chlorination showed MX to be present in the range of 38 to 60 ng L−1. MX concentrations were not always correlated with TOC levels, suggesting that the type of organic matter present may play a role in MX formation. GAC appeared to be capable of removing MX precursors.

Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.

Cortisol is metabolized irreversibly by A-ring reductases (5alpha- and 5beta-reductases) and reversibly (to cortisone) by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). In rats, estradiol down-regulates 11betaHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11betaHSD1 activity were measured in healthy young men and women at different phases of the menstrual cycle. Ten men and 10 women with regular menstrual cycles collected a 24-h urine sample, took 250 microg oral dexamethasone at 2300 h, took 25 mg oral cortisone at 0900 h (after fasting), and had blood sampled for plasma cortisol estimation over the subsequent 150 min. Women repeated the tests in random order in menstrual, follicular, and luteal phases. Women excreted disproportionately less A-ring-reduced metabolites of cortisol [median 5alpha-tetrahydrocortisol, 1811 (interquartile range, 1391-2300) microg/day in menstrual phase vs. 2723 (interquartile range, 2454-3154) in men (P = 0.01); 5beta-tetrahydrocortisol, 1600 (interquartile range, 1419-1968) vs. 2197 (interquartile range, 1748-2995; P = 0.03)] but similar amounts of cortisol, cortisone, and tetrahydrocortisone. Analogous differences were observed in urinary excretion of androgen metabolites. Conversion of cortisone to cortisol on hepatic first pass metabolism was not different (peak plasma cortisol, 733 +/- 60 nmol/L in women vs. 684 +/- 53 nmol/L in men; mean +/- SEM; P = 0.55). There were no differences in cortisol or androgen metabolism between phases of the menstrual cycle. We conclude that sexual dimorphism in cortisol metabolite excretion is attributable to less A-ring reduction of cortisol in women, rather than less reactivation of cortisone to cortisol by 11betaHSD1. This difference is not influenced acutely by gonadal steroids. 11BetaHSD1 has been suggested to modulate insulin sensitivity and body fat distribution, but caution must be exercised in extrapolating inferences about its regulation from rodents to man. A-Ring reductases may have an equally important influence on metabolic clearance of cortisol and intracellular cortisol concentrations.

Substrate-mimetic inhibitors of sPLA2 with submicromolar in vitro potency were discovered by use of a novel dual substrate screening strategy. In vivo evaluation of selected inhibitors in the rat carrageenan paw edema model of inflammation, however, indicated that in vitro potency was not a good predictor of in vivo activity. Studies of the metabolic stability of early examples of these inhibitors suggested that the metabolic lability of these compounds was a major contributing factor to the observed weak in vivo activity. In an attempt to achieve improved in vivo activity, we prepared and tested compounds designed to overcome the observed metabolic instability. The design of the new compounds involved two types of changes in the inhibitor molecules. First, the C-2 ester moiety was replaced with an amide function so that direct cleavage by stomach acid and blood esterases at this site was minimized. Second, omega-oxidation of the decanamide moiety was eliminated by substitution of hydrogen with fluorine in this position. Compounds containing fluorine in the terminal positions of the alkyl chain retained sPLA2 inhibitory activity and also possessed improved in vitro metabolic stability and pharmacokinetic parameters relative to nonfluorinated inhibitors in this series. As exemplified by GW 4776, improvements in metabolic stability alone, however, were not sufficient to ensure oral activity. Thus, GW 4776 did not show oral activity in the carrageenan edema model and had only modest activity after i.v. dosing in the same model. In fact, the results for GW 9624 and GW 8219 suggested that factors in addition to potency of sPLA2 inhibition and metabolism affect the observed in vivo activity. Despite the fact that these two compounds varied only by a single oxygen-to-sulfur substitution, one was active whereas the other was not. One possible explanation for the observed variability is a compound-dependent difference in the rate of equilibration into tissue. This possibility is relevant as both the carrageenan paw edema model and the phorbol ester edema model involve a localized inflammation. No measurements were made to assess differences in the distribution of the different inhibitors between the blood and the localized site of inflammation. In summary, a series of bioavailable inhibitors of sPLA2 was prepared using an iterative approach that combined medicinal chemistry, in vitro and in vivo evaluation of biological activity, and metabolic and pharmacokinetic studies. Although some compounds in the series showed in vivo activity, the anti-inflammatory effect observed in animal models was modest and a decision was made to abandon sPLA2 as a molecular target for the development of anti-inflammatory agents.