Objective
To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance–based dose in patients with gout.
Methods
Patients with gout who had been ...receiving a stable dose of allopurinol for ≥1 month were recruited. The dose of allopurinol was increased to obtain the target serum urate level of <0.36 mmoles/liter (<6 mg/dl). Patients were seen monthly until the serum urate concentration was <0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months. Data were analyzed using the dosage of allopurinol (mg/day) greater than the recommended dosage, as defined by the Hande criteria.
Results
Ninety patients were enrolled. The mean age of the patients was 58.7 years (range 27–83 years), 87.9% were male, and 81.9% were of European ancestry. Forty‐five patients had a serum urate concentration of ≥0.36 mmoles/liter, and the dose of allopurinol was increased in these patients. Rashes developed in 3 patients, and either allopurinol was discontinued or dose escalation was ceased in these patients. Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation. In 31 (88.8%) of 35 patients who completed the study, the serum urate level was <0.36 mmoles/liter at 12 months. Two of the 5 patients who had a serum urate level ≥0.36 mmoles/liter had undetectable levels of plasma oxypurinol, indicating noncompliance with allopurinol treatment. A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose. Eighteen of 45 patients were receiving furosemide; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of <0.36 mmoles/liter (72% versus 88.5%; P = 0.24). Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration. No serious adverse events were observed.
Conclusion
Increasing the dose of allopurinol above the proposed creatinine clearance–based dose led to a significant reduction in the serum urate concentration. Approximately 89% of patients achieved a serum urate concentration of <0.36 mmoles/liter. In this cohort, toxicity was not increased in patients receiving higher doses of allopurinol, including those with renal impairment.
The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic ...activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.
Context. Strong lenses are extremely useful probes of the distribution of matter on galaxy and cluster scales at cosmological distances, however, they are rare and difficult to find. The number of ...currently known lenses is on the order of 1000. Aims. The aim of this study is to use crowdsourcing to carry out a lens search targeting massive galaxies selected from over 442 square degrees of photometric data from the Hyper Suprime-Cam (HSC) survey. Methods. Based on the S16A internal data release of the HSC survey, we chose a sample of ∼300 000 galaxies with photometric redshifts in the range of 0.2 < zphot < 1.2 and photometrically inferred stellar masses of log M* > 11.2. We crowdsourced lens finding on this sample of galaxies on the Zooniverse platform as part of the Space Warps project. The sample was complemented by a large set of simulated lenses and visually selected non-lenses for training purposes. Nearly 6000 citizen volunteers participated in the experiment. In parallel, we used YATTALENS, an automated lens-finding algorithm, to look for lenses in the same sample of galaxies. Results. Based on a statistical analysis of classification data from the volunteers, we selected a sample of the most promising ∼1500 candidates, which we then visually inspected: half of them turned out to be possible (grade C) lenses or better. By including lenses found by YATTALENS or serendipitously noticed in the discussion section of the Space Warps website, we were able to find 14 definite lenses (grade A), 129 probable lenses (grade B), and 581 possible lenses. YATTALENS found half the number of lenses that were discovered via crowdsourcing. Conclusions. Crowdsourcing is able to produce samples of lens candidates with high completeness, when multiple images are clearly detected, and with higher purity compared to the currently available automated algorithms. A hybrid approach, in which the visual inspection of samples of lens candidates pre-selected by discovery algorithms or coupled to machine learning is crowdsourced, will be a viable option for lens finding in the 2020s, with forthcoming wide-area surveys such as LSST, Euclid, and WFIRST.
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•T. elata larval survival outcomes depend on prey slug species.•Successful pupariation in T. elata is reduced for larvae fed on nematode-exposed slugs.•90% of T. elata neonate larvae ...without prey for four days pupariate successfully.•Neonate and third instar larvae appear to prioritise different predatory strategies.
While the larval stage of Tetanocera elata (Diptera: Sciomyzidae) is a known parasitoid and predator of pestiferous slugs, its biology and predatory behavior as well as its interaction with slug parasitic nematodes requires further investigation. In this study, survival of larvae fed from the neonate stage on Deroceras reticulatum Müller (a previously known prey species) was significantly greater (P = 0.023) than for larvae fed on Deroceras invadens Reise with 100% and 40% survival respectively. However, when fed solely on D. reticulatum which were previously exposed to P. hermaphrodita, only 20% of neonate larvae pupariated successfully. Ninety percent of neonate larvae maintained without food for the first four days and subsequently fed on D. reticulatum pupariated successfully although this decreased to below 50% for ≥6 days without food. Predatory third instar T. elata larvae appeared to select nematode-exposed D. reticulatum over non-exposed slugs with the continued feeding on nematode-exposed slugs also reducing the chances of successful pupariation by 25%. Records of maximum egg-laying by laboratory-reared female adults were greater (487 eggs) than previously recorded for field-caught adults (3 7 3). The implications of these results for the potential use of T. elata as a biological control agent of pestiferous slugs are discussed.
Management of gout is frequently suboptimal. The aim of this study was to determine the proportion of patients presenting to Christchurch Hospital for a gout flare and to determine whether management ...for both acute flares and urate lowering was in accordance with international recommendations.
A retrospective audit was undertaken of all admissions to Christchurch Hospital from June 1, 2013, to May 31, 2014, in which gout was coded as a primary or secondary discharge diagnosis. Information including demographics, comorbidities, concomitant medications, treatment of acute gout, and urate lowering was collected.
A total of 235 acute admissions for gout in 216 individuals were identified. Eleven individuals had 2 admissions and 4 individuals had 3 admissions. In 95/235 admissions (40.4%), gout was the primary diagnosis. Gout accounted for 95/77,321 (0.12%) of acute admissions. The treatment of acute gout was prednisone monotherapy in 170/235 (72.3%) of admissions. Serum urate was measured at some point during 123/235 (52.3%) of admissions, with only 19/123 (15.4%) at target urate level (< 0.36 mmol/l). At 60 of the 235 admissions, urate-lowering therapy was already being prescribed. Nine out of 175 patients (5.1%) not treated with urate-lowering therapy at admission commenced allopurinol and 32/174 (18.4%) had commencement of urate-lowering therapy recommended in the discharge plan.
Rates of admission for gout are similar to that observed in other studies. Failure to initiate, change, or recommend alterations in urate-lowering therapy to achieve target urate in people with gout admitted to hospital represents a significant lost opportunity to improve longterm gout management.
Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, ...oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC).
49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited.
Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred.
Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended.
ISRCTN41540878.
Antithrombotic therapy for acute myocardial infarction O'Donnell, Christopher J.; Ridker, Paul M.; Hebert, Patricia R. ...
Journal of the American College of Cardiology,
06/1995, Letnik:
25, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Antithrombotic therapy is clearly beneficial in the treatment of acute myocardial infarction, but the optimal regimen is controversial. Treatment with aspirin leads to substantial and significant ...reductions in rates of mortality, reinfarction and stroke in patients with acute myocardial infarction, and the benefits are additive with those of thrombolytic therapy. It is unclear whether heparin confers additional net benefits over aspirin alone. In patients receiving aspirin and thrombolytic therapy, there is no mortality benefit from adding delayed subcutaneous heparin, no consistent patency benefit from adding immediate intravenous heparin and no reduction in mortality from adding immediate intravenous heparin, at least for patients treated with streptokinase. However, heparin is consistently associated with increased rates of intracranial and other serious bleeding events when used with both aspirin and thrombolytic therapy. Existing data support the need for further large-scale trials of current and newer antithrombotic regimens in acute myocardial infarction to assess the balance of benefits and risks of these regimens compared with that for aspirin alone. In patients not receiving thrombolytic therapy, randomized trial data are currently insufficient to adequately compare the benefits and risks of adding heparin to aspirin alone. The First American Study of Infarct Survival (ASIS-1) will directly compare the balance of risks and benefits of aspirin alone, aspirin plus intravenous heparin and aspirin plus intravenous hirudin in patients with acute myocardial infarction not receiving thrombolytic therapy.
Previous studies have found that treatment with lithium over a 4-week period may increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients and controls. In view of other ...findings indicating that NAA concentrations may be a good marker for neuronal viability and/or functioning, it has been further suggested that some of the long term benefits of lithium may therefore be due to actions to improve these neuronal properties. The aim of the present study was to utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects of both lithium and sodium valproate upon NAA concentrations in treated euthymic bipolar patients. In the first part of the study, healthy controls (n =18) were compared with euthymic bipolar patients (type I and type II) who were taking either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios were determined. In the second part, we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n =9) and compared these to age- and sex-matched healthy controls (n =11), and we quantified the exact concentrations of NAA using an external solution. The results from the first part of the study showed that bipolar patients chronically treated with lithium had a significant increase in NAA concentrations but, in contrast, there were no significant increases in the sodium valproate-treated patients compared to controls. The second part of the study also found no effects of sodium valproate on NAA concentrations. These findings are the first to compare NAA concentrations in euthymic bipolar patients being treated with lithium or sodium valproate. The results support suggestions that longer-term administration of lithium to bipolar patients may increase NAA concentrations. However, the study suggests that chronic administration of sodium valproate to patients does not lead to similar changes in NAA concentrations. These findings suggest that sodium valproate and lithium may not share a common mechanism of action in bipolar disorder involving neurotrophic or neuroprotective effects.
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