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At least 19 recordsLinked to original sources
PubMed1989

The activity of AA-193, a new uricosuric agent, in animals.

A new uricosuric agent, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (AA-193), was compared with other uricosurics in the rat, mouse and cebus monkey. In rats, probenecid and tienilic acid increased the urate excretion, but benzbromarone did not have the uricosuric activity. Thus, the presecretory reabsorption of urate is probably dominant in rats. We found that in rats AA-193 was the most potent uricosuric tested. In mice, probenecid not only had so-called paradoxical actions but stimulated urinary urate wasting after administration of pyrazinamide. These data suggest that the renal transport system of urate in the mouse is similar to that in man. AA-193 as well as benzbromarone enhanced the urate excretion dose-dependently, but the effects were different in pyrazinamide suppression tests in mice. In cebus monkeys, the uricosuric and hypouricemic effects of AA-193 were more potent than those of probenecid and similar to those of tienilic acid, but less than those of benzbromarone. Benzbromarone had a considerable role in postsecretory reabsorption in the monkey. These results suggest that AA-193 is a new class of uricosuric agent that controls the renal reabsorption of filtered urate particularly.

Animals↗
PubMed1976

Pharmacokinetic and clinical studies of a new uricosuric agent - benzbromarone.

Benzbromarone, a potent uricosuric agent, is a benzofuran derivative with a bromine on the 3rd and 5th positions of the benzene ring. Readily absorbed after oral administration, it is promptly dehalogenated in the liver and excreted via the biliary system. Peak drug concentration usually precedes maximal uricosuria following a single dose of 40 mg of benzbromarone, since benzarone, one of the two metabolites, likewise has a uricosuric action. Longterm studies in 24 gouty patients indicate that the drug is well tolerated. It has not produced any skin rash or renal colic. Renal hemodynamics, blood picture, and liver enzymes were unchanged. Since it is eliminated by the biliary tract, it may cause diarrhoea in some patients. Being a very potent uricosuric agent, it is not advocated in patients with a history of uric acid lithiasis. The uricosuric effect is not liable to be counteracted when used in conjunction with hyperuricemic diuretics. The drug is particularly useful in patients with chronic gouty arthritis and tophi, either refractory or allergic to probenecid, sulfinpyrazone, or allopurinol.

Adult↗
PubMed2005

The dual actions of morin (3,5,7,2',4'-pentahydroxyflavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity.

Hyperuricemia is associated with a number of pathological conditions such as gout. Lowering of elevated uric acid level in the blood could be achieved by xanthine oxidase inhibitors and inhibitors of renal urate reabsorption. Some natural compounds isolated from herbs used in traditional Chinese medicine have been previously demonstrated to possess xanthine oxidase inhibitory activities. In the present investigation, morin (3,5,7,2',4'-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature to treat conditions akin to gout, was demonstrated to exert potent inhibitory action on urate uptake in rat renal brush-border membrane vesicles, indicating that this compound acts on the kidney to inhibit urate reabsorption. Lineweaver-Burk transformation of the inhibition kinetics data demonstrated that the inhibition of urate uptake was of a competitive type, with a K(i) value of 17.4 microM. In addition, morin was also demonstrated to be an inhibitor of xanthine oxidase. Lineweaver-Burk analysis of the enzyme kinetics indicated that the mode of inhibition was of a mixed type, with K(i) and K(ies) values being 7.9 and 35.1 microM, respectively. Using an oxonate-induced hyperuricemic rat model, morin was indeed shown to exhibit an in vivo uricosuric action, which could explain, in part at least, the observed hypouricemic effect of morin in these rats. The potential application of this compound in the treatment of conditions associated with hyperuricemia was discussed.

Alkaline Phosphatase↗
PubMed2002

A simple method of selecting gout patients for treatment with uricosuric agents, using spot urine and blood samples.

OBJECTIVE: To develop a simple means of selecting gout patients for treatment with uricosuric agents. METHODS: In 124 gout patients, spot urine and blood were sampled before breakfast and after overnight fast (except water) on the day of 24 h urine collection. Spot urine uric acid/creatinine ratio (Ua/Cr mmol/mmol) and serum creatinine x Ua/Cr (Scr*Ua/Cr micromol/l) were calculated together with 24 h urinary uric acid excretion/body surface (24 Ua/S). The patients were then classified either below or above 2.84 mmol/m2/day for 24 Ua/S. RESULTS: Classifications based on spot urine Ua/Cr (cut off value set at 0.34), spot urine Scr*Ua/Cr (cut off value set at 28.1), and a combination of spot urine Ua/Cr and Scr*Ua/Cr were found to be not significantly different in diagnostic accuracy for the detection of patients with 24 Ua/S below 2.84 mmol/m2 (77%, 81%, and 81%, respectively) and sensitivity (80%, 83%, and 76%, respectively). However, specificity by a combination of spot urine Ua/Cr, and spot urine Scr*Ua/Cr was higher than by spot urine Ua/Cr alone (91% vs 74%, P < 0.05), although the specificity was not significantly different between a combination and spot urine Scr*Ua/Cr alone (91% vs 78%) or between spot urine Ua/Cr and spot urine Scr*Ua/Cr (74% vs 78%). CONCLUSION: A combination of spot urine Ua/Cr and spot urine Scr*Ua/Cr may be clinically useful in selecting gout patients with 24 Ua/S below 2.84 mmol/m2 for treatment with uricosuric agents without adverse effects.

Adult↗
PubMed1999

Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone.

OBJECTIVE: To clarify the mechanism(s) for the interaction between warfarin and benzbromarone, a uricosuric agent, and to predict changes in the in vivo pharmacokinetics of (S)-warfarin from in vitro data. METHODS: Warfarin enantiomers and benzbromarone in serum, 7-hydroxywarfarin in urine, and serum unbound fractions of warfarin enantiomers were measured in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d). In vitro inhibition constants (K(i)) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes. The magnitude of changes in the formation clearance for 7-hydroxylation (CLf), the unbound oral clearance (CL(oral,u)), and the oral clearance (CL(oral)) for (S)-warfarin were predicted by equations incorporating the in vitro Ki, the theoretical maximum unbound hepatic benzbromarone concentration, and the fractions of warfarin eliminated through metabolism and of CYP2C9-mediated metabolic reaction susceptible to inhibition by benzbromarone. RESULTS: The patients given warfarin with benzbromarone required a 36% less (P < .01) warfarin dose than those given warfarin alone (2.5 versus 3.9 mg/d) to attain similar international normalized ratios (2.1 and 2.2, respectively), and the former had 65%, 53%, and 54% lower (P < .05 or P < .01) CLf, CL(oral),u, and CL(oral) for (S)-warfarin than the latter, respectively. In contrast, no significant differences were observed for (R)-warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inhibitor (Ki < 0.01 micromol/L) for (S)-warfarin 7-hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CL(oral),u, and CL(oral)values for (S)-warfarin induced by benzbromarone were largely predictable by the proposed equations. CONCLUSION: Benzbromarone would intensify anticoagulant response of warfarin through an enantioselective inhibition of CYP2C9-mediated metabolism of pharmacologically more potent (S)-warfarin. The magnitude of changes in the in vivo warfarin kinetics may be predicted by in vitro data.

Aged↗
PubMed1978

GLC determination of the polyvalent saluretic uricosuric agent (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid in biological fluids.

A specific and quantitative GLC method was developed for the determination of (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy) acetic acid, a novel saluretic uricosuric agent, in biological fluids. The procedure involves the addition of an internal standard to the biological specimens followed by extraction of the acids into benzene at pH 1. The extracted acids, following back-extraction into base and reextraction into methylene chloride at an acidic pH, are converted to the respective methyl esters by reaction with ethereal diazomethane. The sensitivity of the method is such that 2 microgram of material can be detected per aliquot of plasma or urine. In the 2.5-50-microgram/ml range, recoveries were 98.1 +/- 9.6% (plasma, n = 157) and 99.3 +/- 6.4% (urine, n = 181). GLC-mass spectrometric techniques established analysis specificity.

Animals↗
PubMed1999

Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: application of In vitro approaches to predicting In vivo reduction of (S)-warfarin clearance.

A uricosuric agent, bucolome, has been shown to intensify the anticoagulant effect of warfarin. The aims of the present study were to clarify its mechanism(s) and to apply in vitro approaches for predicting this potentially life-threatening in vivo interaction. An in vivo study revealed that Japanese patients given warfarin with bucolome (300 mg/day, n = 21) showed a 1.5-fold greater international normalized ratio than those given warfarin alone (n = 34) despite that the former received a 58% smaller warfarin dose than the latter. Enantioselective assays revealed that bucolome increased plasma unbound fractions of (S)- and (R)-warfarin by 2-fold (p <.01), reduced unbound oral clearances of (S)- and (R)-warfarin by 84 (p <.01) and 26% (p <.05), respectively, and inhibited the unbound formation clearance for (S)-warfarin 7-hydroxylation by 89% (p <.01). In contrast, bucolome elicited no appreciable changes in the plasma unbound (S)-warfarin concentration versus the international normalized ratio relationship. In vitro studies with recombinant human cytochrome P-450 2C9 and liver microsomes showed that bucolome was a potent mixed-type inhibitor for (S)-warfarin 7-hydroxylation, with K(i) of 8.2 and 20.2 microM, respectively. An in vitro model incorporating maximum unbound bucolome concentration in the liver estimated as a sum of hepatic artery and portal vein concentrations and in vitro K(i) made an acceptable prediction for bucolome-induced reductions in in vivo total (bound + unbound) oral clearance, unbound oral clearance, and unbound formation clearance for (S)-warfarin. In conclusion, the augmented anticoagulant effect of warfarin by bucolome due to the metabolic inhibition for pharmacologically more potent (S)-warfarin may be predictable from in vitro data.

Adult↗
PubMed1980

Renal handling of urate in healthy man in hyperuricaemia and renal insufficiency: circadian fluctuation, effect of water diuresis and of uricosuric agents.

To differentiate between extrarenal and renal causes of hyperuricaemia and gout, clearances of urate and creatinine were monitored for 3 1/2 days in fifty-two individuals (seven with a history of gout) with no gross impairment of renal function (creatinine clearance 52-137 ml/min). Dietary purine intake was kept constant. Monophasic circadian fluctuations of fractional urate excretion (= urate clearance over creatinine clearance) were observed with peak values in the afternoon, about 50% higher than during the night. Circadian fluctuations of urinary flow rate were almost identical. However, enhancement of urinary flow rate due to water diuresis had no effect on urate clearance. Despite wide variation of plasma urate concentrations among different individuals (+/- 30% SD), daily urate excretion varied little (+/- 4% SD) and did not correlate with plasma urate (r = 0.03). Thus extrarenal factors appear not to account for the occurrence of hyperuricaemia in these patients. In contrast, a clearcut negative correlation was apparent between plasma urate concentration and fractional urate clearance (r = 0.72), which could fully account for the variations of plasma urate concentration. To elucidate further the mechanism responsible for antiuricosuria in hyperuricaemic patients, the effects of the uricosuric agents benzbromarone and probenecid were tested. A clearcut correlation was apparent between control fractional urate excretion and uricosuric effect of both benzbromarone and probenecid (r = 0.83 and 0.88, respectively), suggesting that anti-uricosuria was due to defective secretion. In an additional series, the uricosuric effect of probenecid was tested in ten patients with renal insufficiency. In these patients the uricosuric effect was clearly blunted, indicating that urate reabsorption is reduced in renal insufficiency.

Adult↗
PubMedDate not supplied

Halofenate. Its selection and trial as a primary uricosuric agent.

In vitro binding studies on antiinflammatory and uricosuric acidic anions performed under "physiologic" conditions have demonstrated that these substances displace urate from its protein bond. The property of urate displacement appears to be a useful marker for potential uricosuric activity in vivo, and thereby a means to detect novel uricosuric drugs. One such drug, halofenate, was indeed a safe and effective uricosuric (comparable to probenecid) when used to treat hyperuricemia/gout over the long term; it did result in a modest and variable fall in serum lipid concentrations. However, used as a single fixed dose, halofenate did not produce a marked and consistent effect on the elevated serum triglyceride concentrations so commonly present in gouty patients.

Adult↗