The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.

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Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

http://www.lqtc.fcien.edu.uy/cursos/Fq2/2010/Proyectos2010/Proyecto9/Paper1.pdf

Structure and function of xanthine oxidoreductase: where are we now?

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.

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Is there new hope for therapeutic matrix metalloproteinase inhibition

Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications.

Superoxide radical (O2-) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O2- in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (n=6) compared with Wistar-Kyoto rats (WKY; n=6) (145+/-4 versus 118+/-4 mmHg, P<0.05, and 24+/-3 versus 17+/-1 mmHg x mL(-1) x min(-1), respectively; P<0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (tempol; 72 micromol/kg i.v.) normalized MAP (103+/-9 versus 96+/-6 mm Hg for SHR and WKY, respectively) and RVR (17+/-2 versus 15+/-1 mm Hg x mL(-1) x min(-1)) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 micromol x kg(-1) x h(-1) i.v.) than that of WKY. To determine whether O2- increases MAP by inactivation of NO, its synthesis was blocked in SHR with NW-nitro-L-arginine methyl ester (L-NAME, 11 micromol x kg(-1) x min(-1) i.v., n=6). Whereas tempol alone significantly reduced MAP by 32% (184+/-12 to 121 +/- 18 mm Hg, P<0.05, n=6), L-NAME infusion abolished the MAP response to tempol (187+/-8 to 186+/-4 mm Hg, n=5). In contrast, tempol did reduce MAP of SHR (188+/-7 to 161+/-7 mm Hg, P<0.05) where MAP was elevated by norepinephrine (31 nmol x kg(-1) x min(-1) i.v., n=6). Finally, to determine the longer-term effect of O2-, tempol (1.5 mmol x kg(-1) x d(-1) i.p.) was given for 7 days. Tempol had no effect on MAP in WKY (96+/-1 to 97+/-1 mmHg, n=7) but significantly decreased MAP in SHR (133+/-2 to 120+/-3 mm Hg, P<0.05, n=7). These data implicate O2- in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O2- inactivates NO and thus diminishes its vasodilatory actions.

Normalization of Blood Pressure and Renal Vascular Resistance in SHR With a Membrane-Permeable Superoxide Dismutase Mimetic: Role of Nitric Oxide

Activation of human matrix metalloproteinases by various bacterial proteinases

Nitric oxide (NO), now almost synonymous with endothelium-derived relax- ing factor (EDRF), reacts with superoxide anion radical (O,-) and forms a potentially toxic molecular species, peroxynitrite (ONOO-). Because xanthine oxidase (XO) seems to be a major 0,--producing enzyme in the vascular system, it is important to clarify the mechanism of XO regulation of NO/EDRF. We first characterized the inhi- bition of XO in vitro by three types of pyrazolopyrimidine derivatives. Kinetic studies indicated that 4-amino-6-hydroxypyrazolo(3,4-d)pyrimidine (AHPP) and allopurinol competitively inhibited the conversion of xanthine to uric acid catalyzed by XO, with apparent K, values of 0.17 f 0.02 and 0.50 f 0.03 pM, respectively; alloxanthine inhibited this conversion in a noncompetitive manner with an apparent K, value of 3.54 2 1.12 pM. 0,- generation in the xanthine/XO system assayed by lucigenin- dependent chemiluminescence was suppressed most strongly by AHPP in a dose- dependent fashion; allopurinol itself appears to reduce the enzyme by transfer of an electron to 02, thus generating 0,-. AHPP significantly augmented EDRF-mediated relaxation of aortic rings from both rabbits and spontaneously hypertensive rats (SHR) in a dose-dependent manner, whereas allopurinol did not affect the relaxation and only marginal potentiation of the vasorelaxation was observed with alloxanthine. Finally, iv injection of AHPP (50.4 mglkg; 100 pmo1/300 g rat) reduced the blood pressure of SHR rats to 70% of the initial pressure; this pressure is al- most the blood pressure of normal rats. Allopurinol (100 pmo1/300 g rat; iv) showed transient decrease in blood pressure and moderate reduction of hypertension of SHR (10%) was observed with iv injection of alloxanthine (100 pmo1/300 g rat). On the basis of these results, it seems that XO regulates EDRFINO via production of 0,-. (P.S.E.B.M. 1996, Vol 21 11

Hidechika Horie

Papers

Activation of human matrix metalloproteinases by various bacterial proteinases

Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors