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Critical Care Medicine Sep 2018To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.
DESIGN
Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).
SETTING
Thirty-six-bed PICU in a university-affiliated children's hospital.
PATIENTS AND SUBJECTS
Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.
INTERVENTION
Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.
MEASUREMENTS AND MAIN RESULTS
The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.
CONCLUSIONS
This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.
Topics: Acetylcysteine; Adjuvants, Pharmaceutic; Adolescent; Brain Injuries, Traumatic; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Humans; Injury Severity Score; Metabolomics; Probenecid
PubMed: 29742587
DOI: 10.1097/CCM.0000000000003203 -
European Journal of Medical Research Jan 2023Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the initial marked decrease in serum urate level. Our study evaluated the effect of early urate-lowering therapy in patients with acute GA flares.
METHODS
This study included 40 patients with acute GA; of them, 20 received colchicine 0.5 mg colchicine twice daily, while 20 received probenecid 500 mg and colchicine 0.5 mg twice daily. We evaluated GA severity and laboratory data for 2 weeks after the initial therapy. Medians and interquartile ranges (IQRs) were calculated to evaluate clinical presentations between these two groups.
RESULTS
Rapidly decreasing median serum uric acid levels was found in the patients treated with probenecid and colchicine compared with the patients treated with colchicine alone on day 8 (- 1.9 [IQR, - 3.7 to 0] vs 0.8 [IQR, - 0.1-2.2]; P < 0.001). However, the median decrease in visual analog scale score did not differ significantly between the two groups (- 5.5 [IQR, - 8.0 to - 3.0] vs - 3.5 [IQR, - 5.9 to - 2.0]; P = 0.080).
CONCLUSION
No significant increase was noted in acute gout flare severity or duration among GA patients treated with early aggressive control of hyperuricemia using probenecid plus colchicine.
Topics: Humans; Arthritis, Gouty; Gout; Gout Suppressants; Uric Acid; Probenecid; Symptom Flare Up; Colchicine; Chronic Disease
PubMed: 36609359
DOI: 10.1186/s40001-022-00982-8 -
Xenobiotica; the Fate of Foreign... Apr 20171. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses...
1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.
Topics: Acetylcysteine; Animals; Biological Transport; Brain; Drug Interactions; Organic Anion Transporters; Plasma; Probenecid; Rats; Rats, Sprague-Dawley
PubMed: 27278858
DOI: 10.1080/00498254.2016.1187777 -
Journal of the American College of... Mar 2018Patients with gout are at an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke, and heart failure (HF). (Comparative Study)
Comparative Study Observational Study
BACKGROUND
Patients with gout are at an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke, and heart failure (HF).
OBJECTIVES
The authors conducted a cohort study to examine comparative CV safety of the 2 gout treatments-probenecid and allopurinol-in patients with gout.
METHODS
Among gout patients ≥65 years of age and enrolled in Medicare (2008 to 2013), those who initiated probenecid or allopurinol were identified. The primary outcome was a composite CV endpoint of hospitalization for MI or stroke. MI, stroke, coronary revascularization, HF, and mortality were assessed separately as secondary outcomes. The authors estimated the incidence rate and hazard ratio of the primary and secondary outcomes in the 1:3 propensity score-matched cohort of probenecid and allopurinol initiators.
RESULTS
A total of 9,722 probenecid initiators propensity score-matched to 29,166 allopurinol initiators with mean age of 76 ± 7 years, and 54% males were included. The incidence rate of the primary composite endpoint of MI or stroke per 100 person-years was 2.36 in probenecid and 2.83 in allopurinol initiators with a hazard ratio of 0.80 (95% confidence interval: 0.69 to 0.93). In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke, HF exacerbation, and mortality versus allopurinol. These results were consistent in the subgroup analyses of patients without baseline CV disease or those without baseline chronic kidney disease.
CONCLUSIONS
In this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke, and HF exacerbation compared with allopurinol.
Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Cardiovascular Diseases; Cohort Studies; Female; Gout; Gout Suppressants; Humans; Male; Medicare; Probenecid; Risk Factors; United States; Uricosuric Agents
PubMed: 29496000
DOI: 10.1016/j.jacc.2017.12.052 -
Evidence-based Complementary and... 2021is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a...
is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a metabolic disorder characterized by a high uric acid level in serum due to an imbalance between uric acid production and excretion and causes gout. Recently, the prevalence of hyperuricemia worldwide has been continuously increasing. Xanthine oxidase (XOD) inhibitors (allopurinol (ALP) and febuxostat) and uricosuric agents (benzbromarone and probenecid) are used to treat hyperuricemia clinically. However, because these drugs are poorly tolerated and cause side effects, such as kidney diseases, hepatotoxicity, gastrointestinal symptoms, and hypersensitivity syndrome, only a limited number of drugs are available. We investigated the antihyperuricemic effects of leaf ethanol extract (DMLE) and its underlying mechanisms of action through and studies. We evaluated uric acid levels in serum and urine, and xanthine oxidase (XOD) inhibition activity in the serum and liver tissue of a hyperuricemic rat model of potassium oxonate (PO)-induced hyperuricemic rats. In vitro study, XOD-inhibitory activity was the lowest among the test substances at the IC50 of ALP. However, the IC50 of DMLE-70 was significantly low compared with that of other DMLEs ( < 0.05). In PO-induced hyperuricemic rats, uric acid (UA) levels in serum and urine were significantly reduced in all DMLE-70 and allopurinol-treated (ALT) groups than in the PC group ( < 0.05). UA levels in urine were lower than those in serum in all DME groups. In PO-induced hyperuricemic rats, DMEE-200 reduced UA concentration in serum and increased UA excretion in the urine. These findings suggest that DMLE exerts antihyperuricemic and uricosuric effects on promoting UA excretion by enhanced secretion and inhibition of UA reabsorption in the kidneys. Thus, DMLE may be a potential treatment for hyperuricemia and gout.
PubMed: 34335806
DOI: 10.1155/2021/3732317 -
Metabolism: Clinical and Experimental Mar 2022Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular effects. ABCB1 (expressed in brain) exports cortisol not corticosterone while ABCC1 (expressed in adipose and skeletal muscle) exports corticosterone not cortisol. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans.
METHODS
A randomised double-blind crossover study was conducted in 14 healthy men comparing placebo and ABCC1 inhibitor probenecid. Blood sampling, including from veins draining adipose and muscle, was undertaken before and after administration of mineralocorticoid receptor antagonist potassium canrenoate and glucocorticoid receptor antagonist mifepristone (RU486).
RESULTS
During placebo, systemic plasma cortisol and corticosterone concentrations increased promptly after canrenoate. Cortisol uptake was detected from adipose but not muscle following canrenoate + RU486. Probenecid significantly increased systemic cortisol concentrations, and tended to increase corticosterone and ACTH concentrations, after combined receptor antagonism but had no effects on net glucocorticoid balance in either adipose or muscle. Using quantitative PCR in brain bank tissue, ABCC1 expression was 5-fold higher in human pituitary than hypothalamus and hippocampus. ABCB1 was more highly expressed in hypothalamus compared to pituitary.
CONCLUSIONS
Although displacement of corticosterone and/or cortisol from receptors in adipose and skeletal muscle could not be measured with sufficient precision to detect effects of probenecid, ABCC1 inhibition induced a greater incremental activation of the hypothalamic-pituitary-adrenal axis after combined receptor blockade, consistent with ABCC1 exporting corticosterone from the pituitary and adding to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adipose Tissue; Adrenocorticotropic Hormone; Adult; Cross-Over Studies; Double-Blind Method; Humans; Hypothalamo-Hypophyseal System; Male; Multidrug Resistance-Associated Proteins; Muscle, Skeletal; Pituitary-Adrenal System
PubMed: 34990712
DOI: 10.1016/j.metabol.2021.155118 -
Neurobiology of Disease Aug 2023Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However,...
Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.
Topics: Mice; Animals; Serine; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Dopamine; Corpus Striatum; Mesencephalon; Amino Acids; Putamen; Homeostasis
PubMed: 37451474
DOI: 10.1016/j.nbd.2023.106226 -
Toxicology Nov 2020Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic, and immunotoxic properties....
Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic, and immunotoxic properties. Specifically, a major concern is severe nephrotoxicity, which is characterized by degeneration of epithelial cells of the proximal tubules and interstitial fibrosis. However, the mechanism of OTA toxicity, as well as the genetic risk factors contributing to its toxicity in humans has been elusive due to the lack of adequate models that fully recapitulate human kidney function in vitro. The present study attempts to evaluate dose-response relationships, identify the contribution of active transport proteins that govern the renal disposition of OTA, and determine the role of metabolism in the bioactivation and detoxification of OTA using a 3D human kidney proximal tubule microphysiological system (kidney MPS). We demonstrated that LC values of OTA in kidney MPS culture (0.375-1.21 μM) were in agreement with clinically relevant toxic concentrations of OTA in urine. Surprisingly, no enhancement of kidney injury biomarkers was evident in the effluent of the kidney MPS after OTA exposure despite significant toxicity observed by LIVE/DEAD staining. Instead, these biomarkers decreased in an OTA concentration-dependent manner. Furthermore, the effect of 1-aminobenzotriazole (ABT) and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), pan-inhibitors of P450 and glutathione S-transferase (GST) enzymes, respectively, on OTA-induced toxicity in kidney MPS was examined. These studies revealed significant enhancement of OTA-induced toxicity by NBDHEX (3 μM) treatment, whereas ABT (1 mM) treatment decreased OTA-induced toxicity, suggesting roles for GSTs and P450 enzymes in the detoxification and bioactivation of OTA, respectively. Analysis of transcriptional changes using RNA-sequencing of kidney MPS treated with different concentrations of OTA revealed downregulation of several nuclear factor (erythroid derived-2)-like 2 (NRF2)-regulated genes by OTA treatment, including GSTs. The transcriptional repression of GSTs is likely playing a key role in OTA toxicity via attenuation of glutathione conjugation/detoxification. The sequential molecular events may explain the mechanism of toxicity associated with OTA. Additionally, OTA transport studies using kidney MPS in the presence and absence of probenecid (1 mM) suggested a role for organic anionic membrane transporter(s) in the kidney specific disposition of OTA. Our findings provide a clearer understanding of the mechanism of OTA-induced kidney injury, which may support changes in risk assessment, regulatory agency policies on allowable exposure levels, and determination of the role of genetic factors in populations at risk for OTA nephrotoxicity.
Topics: Dose-Response Relationship, Drug; Epithelial Cells; Humans; Kidney Diseases; Kidney Tubules, Proximal; Models, Biological; Ochratoxins
PubMed: 32905824
DOI: 10.1016/j.tox.2020.152582 -
British Journal of Clinical Pharmacology Dec 2021Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets.... (Observational Study)
Observational Study
UNLABELLED
Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination.
METHODS
We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration).
RESULTS
Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid.
CONCLUSION
The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.
Topics: Adult; Anti-Bacterial Agents; Cross-Over Studies; Floxacillin; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Probenecid
PubMed: 33963595
DOI: 10.1111/bcp.14887 -
The Cochrane Database of Systematic... Oct 2014Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout.
OBJECTIVES
To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases.
SELECTION CRITERIA
All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout.
DATA COLLECTION AND ANALYSIS
We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach.
MAIN RESULTS
We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants) comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone, pooled RR 0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.All other comparisons were supported by small, single studies only, limiting conclusions.
AUTHORS' CONCLUSIONS
Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful.
Topics: Allopurinol; Benzbromarone; Chronic Disease; Colchicine; Febuxostat; Gout; Gout Suppressants; Humans; Probenecid; Randomized Controlled Trials as Topic; Thiazoles; Uric Acid
PubMed: 25314636
DOI: 10.1002/14651858.CD006077.pub3