Effect-of benzbromarone

Pyrazinamide commonly causes hyperuricaemia and may therefore reduce the uricosuric effect of benzbromarone and probenecid. Allopurinol is unlikely to be effective against pyrazinamide-induced hyperuricaemia, and may exacerbate the situation, whereas benzbromarone may have modest efficacy in reducing hyperuricaemia caused by pyrazinamide. 

Sinclair DS, FoxIH. The pharmacology of hypouricemic effect of benzbromarone. 

Muller FO, Scl ll Groenewoud G, Hundt HKL, van der Merwe JC, van Dyk M The effect of benzbromarone on allopurinol/oj urinol kinetics in patients witii gout EurJ Clin Phar-maco/(1993) 44,69-72. 

The daily dose of benzbromarone is 50-200 mg. In combination with allopurinol, the benzbromarone dose is reduced to 20 mg. Benzbromarone is well tolerated. Rare side effects are headaches, gastrointestinal problems, and exanthems. 

As benzbromarone is a coumarin derivative, it can potentiate the effects of anticoagulants, which act as vitamin K antagonists. 

Locuson CW, 2nd, Suzuki H, Rettie AE, Jones JP. Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors. J Med Chem 2004 47 6768-76. 

Takahashi, H. Sato, T. Shimoyama, Y. Shioda, N. Shimizu, T. Kubo, S. Tamura, N. Tainaka, H. Yasumori, T. Echizen, H. Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin. Pharmacol. Ther. 1999, 66, 569-581. 

The anticoagulant effects of warfarin are increased by benzbromarone and bleeding has been seen. Simiiariy, the anticoaguiant effects of acenocoumarol, ethyl biscoumacetate, diphenadione and warfarin are increased by benziodarone. 

Early information about benzbromarone noted that no increase in the anticoagulant effects of the coumarins acenocoumarol and ethyl biscoumacetate or the indanedione phenindione had been seen in a few patients also given benzbromarone. ... 

Twenty-five kidney transplant patients taking eielosporin were given benzbromarone 100 mg daily to treat hyperurieaemia. The plasma uric acid levels decreased from 579 to 313 micromol/L and the 24-hour urinary uric acid secretion rose from 2082 to 3233 micromol after 4 weeks of treatment. The plasma uric acid levels normalised in 21 of the patients who had creatinine clearances of over 25 mL/minute. No significant adverse effects developed and the ciclosporin serum levels remained unchanged. The authors of the report emphasise the advantages of benzbromarone over allop-urinol because of its efficacy, lack of significant adverse effects and because, unlike allopurinol, it does not interact with azathioprine, which often accompanies ciclosporin treatment. ... 

Patients with healthy kidneys receiving longterm treatment with benzbromarone are not expected to display bromide accumulation. 50 mg of benzbromarone contains 18.85 mg bromide. Even if the entire amount is reabsorbed and set free from its organic ties, this would result in a bromide pool of 336.5 mg in the steady state. Proceeding from a volume distribution where the plasma volume alone is approximately 2 500 ml, one would reckon with a maximal bromide concentration of between 13 and 14 mg/100 ml serum. Side effects normally only appear with serum concentrations of at least 150 to 200 mg/... 

Without wanting to discuss the working mechanism of Benzbromaron more closely, which, according to Zollner, is only based upon the uricosuric effect, it should be mentioned that from the urological point of view a longer lasting application of Benzbromaron can lead to urate obstruction and uric acid stone formation in the descending renal tract, if there is no satisfactory diuresis and alkalization of the urine. 

The activity of benzbromarone is as powerful as benziodarone and so more effective than other classical uricosuric drugs. 

It is generally admitted that renal excretion of urate may involve a three component system glomerular filtration and tubular reabsorption and/or secretion (1). Tubular microinjection experiments in the rat kidney showed that urate was essentially reabsorbed along the proximal tubule presumably by a carrier-mediated mechanism. Under these experimental conditions a secretory process for urate could not be shown nor excluded (2). In an attempt to further unravel some of the uncertainties related to these transport mechanisms we have investigated the effects of benzofu-ranne derivatives on urate transport along the rat nephron. Rats were pretreated with benzbromarone or benziodarone which are two potent uricosuric drugs in man (3,4). 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

In the proximal tubule probenecid, sulfinpyrazone and benzbromarone enhance the excretion of uric acid Although they compete with uric acid for active secretion by the proximal tubules, resorption of uric acid in the proximal tubules is also inhibited with as a net effect the promotion of uric acid excretion. Indications for the use of uricosurics are repeated attacks of gout, the presence of renal impairment associated with hyperuricaemia and the presence of chronic gouty arthropathy or tophi. 

The uricosurics are most effective when used during the first few weeks after an acute attack of gout. It is to be expected that in this period high serum levels of uric acid exist with insufficient excretion of urate in the urine. Oral doses of both probenecid and sulfinpyrazone are completely absorbed. Benzbromarone has an oral bioavailability... 

This potent uricosuric agent is used in Europe. It is a potent and reversible inhibitor of the urate-anion exchcmger in the proximal tubule. As the micronized powder, it is effective in a single daily dose of 40-80 mg. It is effective in patients with renal insufficiency and may be useful clinically in patients who are either allergic or refractory to other drugs used for the treatment of gout. Preparations that combine allopurinol and benzbromarone lower serum uric acid levels more effectively than either drug alone, despite the fact that benzbromarone lowers plasma levels of oxypurinol, the active metabolite of allopurinol. 

Benzbromarone selectively inhibits the metabolism of S-warfarin by the cytochrome P450 isoenzyme CYP2C9 so that its effects are increased. The metabolism of the 7 -warfarin remains unchanged. Acenocoumarol and phenprocoumon are also known to be metabolised by CYP2C9, and would therefore be expected to interact similarly. Benziodarone is another ben-zofuran derivative with a similar structure to benzbromarone, and therefore probably interacts via a similar mechanism. 

When benzbromarone is combined with citrate there are two resulting guaranteed effects -normalization of the serum uric acid and improvement of their solubility in urine. 

We have used benzbromarone at a daily dose of one hundred mg, sometimes fifty, even twenty five mg have been effective. 

These results show that benzbromarone Is a strong uricosuric drug and has no Inhibitory effect on purine synthesis more over on xanthine oxidase activity, as proved by unchanged levels of plasma and urine xanthine plus hypoxanthlne. 

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