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American Family Physician Dec 2014Gout is characterized by painful joint inflammation, most commonly in the first metatarsophalangeal joint, resulting from precipitation of monosodium urate crystals in a... (Review)
Review
Gout is characterized by painful joint inflammation, most commonly in the first metatarsophalangeal joint, resulting from precipitation of monosodium urate crystals in a joint space. Gout is typically diagnosed using clinical criteria from the American College of Rheumatology. Diagnosis may be confirmed by identification of monosodium urate crystals in synovial fluid of the affected joint. Acute gout may be treated with nonsteroidal anti-inflammatory drugs, corticosteroids, or colchicine. To reduce the likelihood of recurrent flares, patients should limit their consumption of certain purine-rich foods (e.g., organ meats, shellfish) and avoid alcoholic drinks (especially beer) and beverages sweetened with high-fructose corn syrup. Consumption of vegetables and low-fat or nonfat dairy products should be encouraged. The use of loop and thiazide diuretics can increase uric acid levels, whereas the use of the angiotensin receptor blocker losartan increases urinary excretion of uric acid. Reduction of uric acid levels is key to avoiding gout flares. Allopurinol and febuxostat are first-line medications for the prevention of recurrent gout, and colchicine and/or probenecid are reserved for patients who cannot tolerate first-line agents or in whom first-line agents are ineffective. Patients receiving urate-lowering medications should be treated concurrently with nonsteroidal anti-inflammatory drugs, colchicine, or low-dose corticosteroids to prevent flares. Treatment should continue for at least three months after uric acid levels fall below the target goal in those without tophi, and for six months in those with a history of tophi.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Diagnosis, Differential; Diet Therapy; Disease Management; Glucocorticoids; Gout; Gout Suppressants; Humans; Patient Acuity; Risk Factors; Secondary Prevention; Uric Acid
PubMed: 25591183
DOI: No ID Found -
Pharmacological Reviews Apr 2020The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important... (Review)
Review
The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease. SIGNIFICANCE STATEMENT: The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.
Topics: Animals; Humans; Metabolic Diseases; Monocarboxylic Acid Transporters; Structure-Activity Relationship; Tissue Distribution; Transcription, Genetic
PubMed: 32144120
DOI: 10.1124/pr.119.018762 -
Arthritis & Rheumatology (Hoboken, N.J.) Jun 2019To estimate the current prevalence rates and decadal trends of gout and hyperuricemia in the US, as well as the prevalence of urate-lowering therapy (ULT) among gout...
OBJECTIVE
To estimate the current prevalence rates and decadal trends of gout and hyperuricemia in the US, as well as the prevalence of urate-lowering therapy (ULT) among gout patients, using 2007-2016 data from a nationally representative survey of American men and women (the National Health and Nutrition Examination Survey [NHANES]).
METHODS
Using data from 5,467 participants in the NHANES 2015-2016, we estimated the most recent prevalence rates of gout and hyperuricemia. When the NHANES was conducted, all participants were asked about their history of gout (as diagnosed by a health professional) and medication use. Hyperuricemia was defined as having a serum urate level of >7.0 mg/dl in men and >5.7 mg/dl in women. We examined decadal trends in these estimates using data from the NHANES 2007-2016 and investigated ULT usage trends using the NHANES 2007-14 (the most recent data available to date).
RESULTS
In 2015-2016, the prevalence of gout was 3.9% among adults in the US (9.2 million people), with 5.2% [5.9 million] in men and 2.7% [3.3 million] in women. Mean serum urate levels were 6.0 mg/dl in men and 4.8 mg/dl in women, and hyperuricemia prevalence rates were 20.2% and 20.0%, respectively. The prevalence rates of gout and hyperuricemia remained stable between 2007 and 2016 (P for trend > 0.05). The prevalence of ULT use among patients with gout was 33% in 2007-2014 and remained stable over time (P for trend > 0.05).
CONCLUSION
In this nationally representative survey sample of adults in the US, the prevalence rates of gout and hyperuricemia remained substantial, albeit unchanged, between 2007 and 2016. Despite these rates, only one-third of gout patients were receiving ULT.
Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Nutrition Surveys; Prevalence; Probenecid; United States; Uric Acid; Uricosuric Agents; Young Adult
PubMed: 30618180
DOI: 10.1002/art.40807 -
Nature Communications Mar 2022Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like...
Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like abdominal aortic aneurysms (AAA) is unknown. Here we demonstrate that Panx1 on endothelial cells, but not smooth muscle cells, orchestrate a cascade of signaling events to mediate vascular inflammation and remodeling. Mechanistically, Panx1 on endothelial cells acts as a conduit for ATP release that stimulates macrophage activation via P2X7 receptors and mitochondrial DNA release to increase IL-1β and HMGB1 secretion. Secondly, Panx1 signaling regulates smooth muscle cell-dependent intracellular Ca release and vascular remodeling via P2Y2 receptors. Panx1 blockade using probenecid markedly inhibits leukocyte transmigration, aortic inflammation and remodeling to mitigate AAA formation. Panx1 expression is upregulated in human AAAs and retrospective clinical data demonstrated reduced mortality in aortic aneurysm patients treated with Panx1 inhibitors. Collectively, these data identify Panx1 signaling as a contributory mechanism of AAA formation.
Topics: Adenosine Triphosphate; Aortic Aneurysm, Abdominal; Connexins; Endothelial Cells; Humans; Inflammation; Macrophages; Myocytes, Smooth Muscle; Nerve Tissue Proteins; Retrospective Studies
PubMed: 35315432
DOI: 10.1038/s41467-022-29233-4 -
Therapeutic Advances in Musculoskeletal... 2022Gout is characterized by monosodium urate (MSU) crystal deposits in and within joints. These deposits result from persistent hyperuricaemia and most typically lead to... (Review)
Review
Gout is characterized by monosodium urate (MSU) crystal deposits in and within joints. These deposits result from persistent hyperuricaemia and most typically lead to recurrent acute inflammatory episodes (gout flares). Even though some aspects of gout are well characterized, uncertainties remain; this upcoming decade should provide further insights into many of these uncertainties. Synovial fluid analysis allows for the identification of MSU crystals and unequivocal diagnosis. Non-invasive methods for diagnosis are being explored, such as Raman spectroscopy and imaging modalities. Both ultrasound and dual-energy computed tomography (DECT) allow the detection of MSU crystals; this not only provides a mean of diagnosis, but also has furthered gout knowledge defining the presence of a preclinical deposition in asymptomatic hyperuricaemia. Scientific consensus establishes the beginning of gout as the beginning of symptoms (usually the first flare), but the concept is currently under review. For effective long-term gout management, the main goal is to promote crystal dissolution treatment by reducing serum urate below 6 mg/dL (or 5 mg/dL if faster crystal dissolution is required). Current urate-lowering therapies' (ULTs) options are limited, with allopurinol and febuxostat being widely available, and probenecid, benzbromarone, and pegloticase available in some regions. New xanthine oxidase inhibitors and, especially, uricosurics inhibiting urate transporter URAT1 are under development; it is probable that the new decade will see a welcomed increase in the gout therapeutic armamentarium. Cardiovascular and renal comorbidities are common in gout patients. Studies determining whether optimal treatment of gout will positively impact these comorbidities are currently lacking, but will hopefully be forthcoming. Overall, the single change that will most impact gout management is greater uptake of international rheumatology society recommendations. Innovative strategies, such as nurse-led interventions based on these recommendations have recently demonstrated treatment success for people with gout.
PubMed: 35923650
DOI: 10.1177/1759720X221114098 -
Clinical Infectious Diseases : An... Jan 2023Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge.
METHODS
Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21).
RESULTS
Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum β-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator.
CONCLUSIONS
Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated.
CLINICAL TRIAL REGISTRATION
NCT03357614.
Topics: Adult; Humans; Ertapenem; Bacteriuria; Urinary Tract Infections; Anti-Bacterial Agents; Pyelonephritis; Ciprofloxacin
PubMed: 36068705
DOI: 10.1093/cid/ciac704