Xanthine inhibitors

Bld-HrTH administration to B. discoidalis in vivo or to isolated fat body fails to stimulate either fat body cAMP levels or adenylate cyclase activity and supports the previous findings (25). Nevertheless, for B. discoidalis, fat body phosphorylase activity is elevated and trehalose levels increase both in vivo and in vitro, and calcium is essential in vitro in addition to Bld-HrTH. No stimulation of trehalose synthesis is noted with agents that elevate adenylate cyclase, such as forskolin, or by inhibitors of phosphodiesterase such as theophylline or isobutylmethylxanthine (IBMX). Additions of cAMP, dibutyryl cAMP or 8-bromo-cAMP are not stimulatory to trehalose synthesis either in vivo or in vitro. This same result was observed for P. americana in that neither cAMP nor dbcAMP stimulated trehalose production by fat body in vitro, and xanthine inhibitors of phosphodiesterase that should cause accumulation of intracellular cAMP were inhibitory, except for isobutylmethylxanthine (IBMX) which was stimulatory for unknown reasons (26). We have not observed a stimulatory effect by IBMX with B. discoidalis fat body in vitro. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

As an inhibitor of xanthine oxidase, allopurinol also markedly decreases oxidation of both hypoxanthine and xanthine itself to the sole source of uric acid (19) in man. This metabolic block thus removes the source of uric acid that in gout causes the painful crystalline deposits in the joints. It is of interest that allopurinol itself is oxidized to the somewhat less effective drug, oxypurinol (21), by xanthine oxidase. 

Therapeutic Function Xanthine oxidase inhibitor gout therapy Chemical Name 1 H-pyra2olo[3,4-d] pyrimidin4-ol Common Name —... 

Anti-gout Drugs. Figure 1 Xanthine oxidase-catalyzed reactions. Xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid, respectively. Hypoxanthine and xanthine are more soluble than uric acid. Xanthine oxidase also converts the uricostatic drug allopurinol to alloxanthine. Allopurinol and hypoxanthine are isomers that differ from each other in the substitution of positions 7 and 8 of the purine ring system. Although allopurinol is converted to alloxanthine by xanthine oxidase, allopurinol is also a xanthine oxidase inhibitor. Specifically, at low concentrations, allopurinol acts as a competitive inhibitor, and at high concentrations it acts as a noncompetitive inhibitor. Alloxanthine is a noncompetitive xanthine oxidase inhibitor. XOD xanthine oxidase. 

Schumacher HR Jr (2005) Febuxostat a non-purine, selective inhibitor of xanthine oxidase for the management of hyperaricaemia in patients with gout. Expert Opin Investig Drugs 14 893-903... 

Allopurinol 1 mM Xanthine oxidase inhibitor, suppresses oxygen free radical production... 

A series of annulated purines 114-6 have been synthesised as potential inhibitors of xanthine oxidase but, in general, they showed poor activity and the simple pyrimidines 117 were more effective in vitro < 96MI06 96CA(125)86586 96JMC2529 >. 

Granger, D.N., McCord, J.M., Parks, D.A. and FloUwarth, M.E. (1986). Xanthine oxidase inhibitors attenuate ischaemia-induced vascular permeability changes in the cat intestine. Gastroenterology 90, 80-84. 

Administration of synthetic antioxidants and/or chelating agents that suppress iron ion-dependent free-radical reactions. Some enzyme inhibitors may be appropriate here, for example, xanthine oxidase inhibitors. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Pharmacologic prevention strategies for tumor lysis syndrome are aimed at low- and high-risk patients (Fig. 96-7). Allopurinol is a xanthine oxidase inhibitor that is used for prevention only because it has no effect on preexisting elevated uric acid. Rasburicase is a recombinant form of urate oxidase that is useful for both prevention and treatment but is extremely expensive (Table 96-12). Although the approved dose is 0.2 mg/kg per day... 

Fig. 6. Difference spectra between xanthine oxidase inactivated with various pyra-zolo [3, 4-d] pyrimidines and the native enzyme. The spectra are believed to represent the increase in absorption occurring when Mo(VI) of native enzyme is converted to Mo(IV) complexed with the inhibitors. Spectra were obtained by treating the enzyme with inhibitors in the presence of xanthine, then admitting air, so as to re-oxidize the iron and flavin chromophores. The extinction coefficients, de, are expressed per mole of enzyme flavin. Since some inactivated enzyme was present, extinction coefficients per atom of molybdenum of active enzyme will be about 30% higher than these values. (Reproduced from Ref. 33, with the permission of Dr. V. Massey.)...

Saito et al. (134) found that the cytosolic nitroreductase activity was due to DT-diaphorase, aldehyde oxidase, xanthine oxidase plus other unidentified nitroreductases. As anticipated, the microsomal reduction of 1-nitropyrene was inhibited by 0 and stimulated by FMN which was attributed to this cofactor acting as an electron shuttle between NADPH-cytochrome P-450 reductase and cytochrome P-450. Carbon monoxide and type II cytochrome P-450 inhibitors decreased the rate of nitroreduction which was consistent with the involvement of cytochrome P-450. Induction of cytochromes P-450 increased rates of 1-aminopyrene formation and nitroreduction was demonstrated in a reconstituted cytochrome P-450 system, with isozyme P-448-IId catalyzing the reduction most efficiently. 

Two forms of xanthine oxidoreductase namely XO and XDH are present in many human and animal cells and plasma, XDH and XO are the predominant species in cytoplasma and serum, respectively [39]. Damaging effects of XO-catalyzed superoxide production in post-ischemic tissues were demonstrated by many authors. For example, Chambers et al. [40] and Hearse et al. [41] have shown that the suppression of superoxide production by the administration of XO inhibitor allopurinol or SOD resulted in the reduction of infarct size in the dog and of the incidence of reperfusion-induced arrhythmia in the rat. Similarly, Charlat et al. [42] has also shown that allopurinol improved the recovery of the contractile function of reperfused myocardium in the dog. However, the use of allopurinol as the XO inhibitor has been questioned because this compound may affect oxygen radical formation not only as a XO inhibitor but as well as free radical scavenger [43]. Smith et al. [44] also showed that gastric mucosal injury depends on the oxygen radical production catalyzed by XO and iron. 

The answer is c. (Hardman, pp 649—650.) Acute hyperuricemia, which often occurs in patients who are treated with cytotoxic drugs for neoplasic disorders, can lead to the deposition of urate crystals in the kidneys and their collecting ducts. This can produce partial or complete obstruction of the collecting ducts, renal pelvis, or ureter. Allopurinol and its primary metabolite, alloxanthine, are inhibitors of xanthine oxidase, an enzyme that catalyzes the oxidation of hypo xanthine and xanthine to uric acid. The use of allopurinol in patients at risk can markedly reduce the likelihood that they will develop acute uric acid nephropathy. 

The 4-hydrazino-pyrazolo[3,4-rf]pyrimidine derivative 80 yields pyrazolo[4,3-e]-[l,2,4]triazolo[4,3-c]pyrimidinones 82 through hydrazone derivatives 81 <00JCS(P1)33>, these compounds being a new class of potential xanthine oxidase inhibitors. 

Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol also lowers the intracellular concentration of PRPP. Because of the long half-life of its metabolite, allopurinol can be given once daily orally. It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. Serum levels can be checked about 1 week after starting therapy or modifying the dose. Although typical doses are 100 to 300 mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose should be reduced in patients with renal insufficiency (200 mg/day for CLcr 60 mL/min or less, and 100 mg/day for CLcr 30 mL/min or less). 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. 

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