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Biomedical subjects

Michael A Becker

Publications and source records attributed to Michael A Becker.

14 recordsLinked to original sources
PubMed2006

Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics.

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.

Carrier Proteins↗
PubMed2006

Hyperuricemia and associated diseases.

After introduction of urate-lowering therapy, asympotomatic hyperuricemia was treated with allopurinol or uricosuric agents in the belief that hyperuricemia and/or gout caused chronic kidney disease. Epidemiologic studies in the 1970s, however, failed to confirm the view that hyperuricemia and gout were independent risk factors for chronic kidney disease. As a result, urate-lowering pharmacotherapy is generally not recommended at the present time in the management of asymptomatic hyperuricemia even though recent epidemiological, experimental, and clinical studies have prompted reexamination of a causal role for hyperuricemia (with or without gout) in chronic kidney disease as well as other important disorders including cardiovascular disease, hypertension, and metabolic syndrome. The issue of such a role remains unresolved and this article reviews the current status of the relationship between hyperuricemia and associated disorders.

Animals↗
PubMed2006

Crystal-induced arthropathies: recent investigative advances.

PURPOSE OF REVIEW: To highlight recent investigations that have stimulated renewed interest in crystal-induced arthropathies. RECENT FINDINGS: Specific diet-related and alcohol-related risks for gout have been clarified, and alternative urate-lowering treatments likely to benefit patients with difficult-to-treat gout are in development. Progress toward understanding mechanisms underlying the renal deficits defining most cases of gout includes characterization of a urate-specific renal tubule transporter explaining many aspects of renal uric acid handling and identification of mutations in the UMOD gene, resulting in altered uromodulin protein in the gout-associated disorders familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2. A genetic marker associated with the risk for severe allopurinol toxicity has been reported. Hyperuricemia and gout are increasing in incidence, as is complicated gout, especially among the elderly and patients with cardiovascular and renal comorbidities, organ transplants, or complex concomitant medication regimens. Asymptomatic hyperuricemia is clearly associated with hypertension, chronic kidney disease, cardiovascular disease, and the insulin resistance syndrome, and the pathogenetic significance of these associations is under intensive study. Mutation in the ANKH gene has been found among some patients with sporadic as well as familial calcium pyrophosphate deposition disease. SUMMARY: The results of these clinical, epidemiologic, experimental, and therapeutic investigations presage advances in the management of crystal-induced arthropathies.

Aged↗
PubMed2005

Febuxostat compared with allopurinol in patients with hyperuricemia and gout.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. METHODS: We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. RESULTS: The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). CONCLUSIONS: Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.

Allopurinol↗
PubMed2005

Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase.

The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.

Animals↗
PubMed2005

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.

OBJECTIVE: Gout affects approximately 1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>or=8.0 mg/dl). METHODS: We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28. RESULTS: Greater proportions of febuxostat-treated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups. CONCLUSION: Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.

Adult↗
PubMed2005

Tophaceous gout: quantitative evaluation by direct physical measurement.

OBJECTIVE: The absence of accepted standardized methods for monitoring tophaceous gout limits the ability to track tophus progression or regression. This multicenter study assessed intra- and interrater reproducibility of a simple and direct physical measurement. METHODS: The quantitative evaluation was the area (mm2) of each measurable tophus and was determined independently by 2 raters on 2 occasions within 10 days. Intra- and interrater reproducibilities were determined by calculating mean differences and average percentage differences (APD) in measurements of areas for the same tophus at each of 2 visits and by each rater, respectively. RESULTS: Fifty-two tophi were measured in 13 subjects: 22 on the hand/wrist, 16 on the elbow, and 14 on the foot/ankle. The mean (+/- SD) difference in tophus areas between visits was -0.2 +/- 835 mm2 (95% CI -162 to 162 mm2) and the mean (+/- SD) APD was 29% +/- 33%. The mean (+/- SD) APD between raters was 32% +/- 27%. The largest variations in measurements were noted for elbow tophi and variations were least for well demarcated tophi on the hands. CONCLUSION: This simple and reproducible method can be easily utilized in clinical trials and in practice as a measure of efficacy of urate-lowering treatment in tophaceous gout. Among factors contributing to variability in these measurements were the anatomic site of tophi and rater experience with the method. Restriction of measurements to well circumscribed hand or foot tophi could improve reliability, but major changes, as expected with effective therapy, can clearly be documented with this simple technique.

Crystallization↗
PubMed2004

Sex on the internet: furthering our understanding of men with online sexual problems.

A survey on the MSNBC Web site identified 384 men as having online sexual problems (OSP). Respondents' reasons for online sexual activity (OSA) and their preferred Internet medium were associated with several online and offline consequences and behaviors, including important aspects of real-time relationships and sexual experimentation. Two broad behavior patterns manifested by men with OSP were identified: Men who use the Internet (a) to further their real-time sex lives and (b) as a substitute for their real-time sex lives. Men who facilitate their offline sex lives with the Internet might do so for any number of reasons, many of which are adaptive (e.g., sex education, to purchase sexual materials). Future research should use samples from a variety of affinity Web portals to further examine the factors that differentiate individuals who show no negative effects of OSA from those who do.

Adolescent↗
PubMed2004

Immediate changes in lung compliance following natural surfactant administration in premature infants with respiratory distress syndrome: a controlled trial.

OBJECTIVE: To compare immediate changes in lung compliance following the administration of two commercially available natural surfactants. METHOD: We conducted a prospective, randomized study of 40 preterm infants with respiratory distress syndrome requiring surfactant. Infants received either Infasurf or Survanta. The primary outcome measure was the change in compliance assessed by bedside pulmonary monitoring. RESULTS: There were no significant changes in dynamic lung compliance within or between the two groups 1 hour after surfactant administration. However, infants given Survanta required more doses per patient (4 vs 2, p=0.05) and were more likely to require >2 doses (57 vs 26%, p=0.05). Infants requiring >1 dose of surfactant had a greater change in airway pressure and improved oxygenation just before the second dose when treated with Infasurf. CONCLUSIONS: We found no significant difference in acute changes in lung compliance. However, treatment with Infasurf seems to be more long lasting than Survanta.

Biological Products↗
PubMed2003

Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman.

Overactivity of phosphoribosylpyrophosphate synthetase (PRS) is an X chromosome-linked disorder of purine metabolism that is characterized by gout with uric acid overproduction and, in some families, neurodevelopmental impairment. We present the case of a 24-year-old Spanish woman with renal colic and hyperuricemia, which first manifested at age 11 years. Results of enzymatic and genetic studies supported the view that accelerated purine nucleotide and uric acid production in this woman resulted from defective allosteric regulation of PRS activity, which is, in turn, a consequence of a mutation in one of the patient's PRPS1 genes: an A-to-T substitution at nucleotide 578, encoding leucine for histidine at amino acid residue 192 of the mature PRS1 isoform. A previous example of disordered regulation of PRS1 activity in a family with a different substitution at the same amino acid residue strengthens this proposed mechanism. This is the first reported instance of PRS overactivity in which the propositus and sole affected family member is a woman.

Adult↗
PubMed2003

A lupus-like syndrome associated with infliximab therapy.

Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-alpha), is efficacious in the treatment of rheumatoid arthritis and Crohn's disease. We report in detail an unusual adverse reaction to infliximab therapy, a drug-induced lupus-like clinical syndrome. A 45-year-old woman with steroid-dependent Crohn's colitis, successfully managed with maintenance infliximab infusions and methotrexate, developed a lupus-like syndrome eight months after her initial infusion. This was characterized by inflammatory arthritis and an urticarial and papulosquamous rash and was accompanied by high titers of antinuclear, double-stranded DNA, glomerular-binding, and histone antibodies and by reduced levels of the C4 component of complement. After discontinuance of infliximab infusions and treatment of symptoms with intermittent courses of prednisone, the patient's arthritis progressively improved, with accompanying decrements in autoantibody titers. One year later, she has minimal joint discomfort and no rash or gastrointestinal symptoms despite also discontinuing prednisone and methotrexate. Infliximab therapy may cause a lupus-like syndrome that is reversible upon discontinuing this agent. These findings support recent evidence identifying TNF-alpha as an inhibitor of autoantibody formation.

Antibodies, Monoclonal↗
PubMed2002

Rheumatoid hyperviscosity syndrome: reversibility of microvascular abnormalities after treatment.

PURPOSE: To report a case of rheumatoid hyperviscosity syndrome involving both retinal and choroidal circulation that resolved after treatment. DESIGN: Interventional case report. METHODS: A 58-year-old woman with clinical and serologic evidence of an inflammatory connective tissue disease without any visual complaints was referred for a funduscopic evaluation. RESULTS: Funduscopic examination revealed marked dilation and beading of the venous system, microaneurysms, and telangiectatic capillary beds in the posterior pole. Fluorescein angiography disclosed delayed choroidal filling, prolonged arteriovenous transit time, and areas of capillary nonperfusion. These findings were accompanied by a severe polyclonal hypergammaglobulinemia and a 10-fold increase in serum viscosity. The ocular findings were reversible after plasmapheresis and steroid treatment. CONCLUSION: Rheumatoid hyperviscosity syndrome can involve both retinal and choroidal circulation. The prominent microvasculopathy is reversible after appropriate treatment.

Administration, Oral↗
PubMed2002

Relationship of neonatal endotracheal tube size and airway resistance.

BACKGROUND: Infants receiving mechanical ventilation require narrow-lumen, small-diameter endotracheal tubes. OBJECTIVE: Compare the resistances of endotracheal tubes used in the neonatal intensive care unit. METHODS: Endotracheal tubes of internal diameter 2.5, 3.0, 3.5, and 4.0 mm were tested with a standard neonatal ventilator and a test lung. An endotracheal tube of each diameter was cut to 12 cm and connected to a flow transducer at one end and the test lung at the other. Serial measurements of resistance were made at various flows (6, 8, 10, and 12 L/min) and ventilator rates (30-90 breaths/min) encompassing the ranges of clinical practice. Analysis of variance was performed for each tube size, comparing resistance to flows and ventilator rates. RESULTS: Resistance was significantly higher with the 2.5 mm tube than with the others. There was also a consistent trend, in all the tube sizes, towards higher resistance as flow was increased. CONCLUSIONS: The higher resistance of the 2.5 mm tube may be detrimental to extremely low birthweight infants kept on mechanical support merely "to grow." The higher resistance may increase the work of breathing and thus increase caloric expenditure and impede growth.

Airway Resistance↗