The Development of Allopurinol

Rundles, R. Wayne

doi:10.1001/archinte.1985.00360080174026

Cited by 53 publications

(19 citation statements)

References 103 publications

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“…1) is best known for its use in the treatment of gout with hyperuricemia, even though it was discovered in an effort to develop anticancer drugs. In the 1950s, Hitchings noticed that purine antimetabolites had antitumor activity in cultures of transplanted tumors, but their effect was limited because the tumors were refractory to treatment [15]. Developed in 1963 [16], allopurinol was used in conjunction with the antitumor drug 6-mercaptopurine (6-MP) because it was both a substrate and an inhibitor of the enzyme that metabolized 6-MP [15].…”

Section: Introductionmentioning

confidence: 99%

“…In the 1950s, Hitchings noticed that purine antimetabolites had antitumor activity in cultures of transplanted tumors, but their effect was limited because the tumors were refractory to treatment [15]. Developed in 1963 [16], allopurinol was used in conjunction with the antitumor drug 6-mercaptopurine (6-MP) because it was both a substrate and an inhibitor of the enzyme that metabolized 6-MP [15]. Allopurinol was successful in slowing the degradation of 6-MP in human trials and is used today in secondary gout induced by tumors, radiation, or chemotherapy [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Allopurinol was successful in slowing the degradation of 6-MP in human trials and is used today in secondary gout induced by tumors, radiation, or chemotherapy [17][18][19]. It was incidentally noted that there was a decrease in the uric acid in serum and the urate in urine accompanied by a concomitant increase in xanthine and hypoxanthine in urine of these same original patients [15].…”

Section: Introductionmentioning

confidence: 99%

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Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion

Peglow

Toledo

Anaya-Prado³

et al. 2010

J Hepato Biliary Pancreat

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Introduction Allopurinol was first introduced, in 1963, as a xanthine oxidase inhibitor when it was investigated for concomitant use with cancer chemotherapy drugs. Today it is used in gout and hyperuricemia. Due to its additive benefit in preventing oxidative damage, attention has shifted towards the use of allopurinol in organ ischemia and reperfusion. Current status Currently, the mechanism by which allopurinol exerts a protective benefit in ischemia reperfusion related events is not fully understood. There are various theories: it may act by inhibiting the irreversible breakdown of purine substrates, and/or by inhibiting the formation of reactive oxygen species, and/or by protecting against damage to the mitochondrial membrane. Aim This work focuses on liver ischemia and reperfusion injury in an effort to better understand the mechanisms associated with allopurinol and with this pathological entity. Review of literature The current research, mainly in animal models, points to allopurinol having a protective benefit, particularly if used pre‐ischemically in liver ischemia reperfusion injury. Furthermore, after reviewing allopurinol dosing and administration, it was found that 50 mg/kg is statistically the most effective dose in attenuating liver ischemia reperfusion injury. Owing to the limited number of samples, the time of administration did not show statistical difference, but allopurinol was often beneficial when given around 1 h before ischemia. Conclusion In conclusion, allopurinol, through its known xanthine oxidase inhibitory effect, as only one of the potential mechanisms, has demonstrated its potential application in protecting the liver during ischemia and reperfusion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion

Peglow

Toledo

Anaya-Prado³

et al. 2010

J Hepato Biliary Pancreat

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“…A significant proportion of any genome codes for proteins that recognize purine-containing ligands (e.g., kinases, DNA and RNA polymerases, ATPases, GTPases, purine receptors). Unsurprisingly, structural analogues of purines have proved attractive templates for drug discovery programs, leading to a number of significant synthetic drugs (e.g., 6-thiopurine for leukaemia [5], acyclovir as an antiviral [6] and allopurinol for treatment of gout [7]). Recently, the purine core has been exploited in the synthesis of protein kinase inhibitors [8,9,10,11] inhibitors of carbohydrate [12] and estrogen [13] sulfotransferases, as well as in compounds displaying osteogenesis-inducing activity in stem cells [14].…”

Section: Introductionmentioning

confidence: 99%

Facile One‐Pot Synthesis and Antimycobacterial Evaluation of Pyrazolo[3,4‐d]pyrimidines

Trivedi

Dodiya

Surani

et al. 2008

Archiv der Pharmazie

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The present article describes a facile one-pot synthesis of a series of eight pyrazolo[3,4-d]pyrimidines 4a-h which were evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar-Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compounds 4b, 4c, 4d, and 4g exhibited the best results (1.2 microg/mL) when compared with first-line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore, this class of compounds could be a good starting point to develop new lead compounds in the treatment of multidrug-resistant tuberculosis.

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“…Allopurinol itself is a substrate of xanthine oxidase and its major metabolite, oxypurinol, is also a potent inhibitor of xanthine oxidase (Elion et al, 1966;Rundles, 1985). The inhibitory effect of allopurinol on xanthine oxidase can be largely attributed to oxypurinol, which has a longer plasma half-life than allopurinol (Elion et al, 1968;Hande et al, 1972;Appelbaum et al, 1982;Yamamoto et al, 1991).…”

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confidence: 99%

Involvement of Uric Acid Transporter in Increased Renal Clearance of the Xanthine Oxidase Inhibitor Oxypurinol Induced by a Uricosuric Agent, Benzbromarone

Iwanaga

Kobayashi²,

Hirayama³

et al. 2005

Drug Metabolism and Disposition

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ABSTRACT:Benzbromarone has been reported to increase the renal clearance of oxypurinol, an active metabolite of allopurinol. We examined the renal transport of oxypurinol to determine whether such a change in renal clearance could be explained by altered transporter-mediated reabsorption. Since the first step of reabsorption takes place at the renal epithelial apical membrane, we focused on membrane transporters. Benzbromarone is an inhibitor of reabsorption of uric acid mediated by the uric acid transporter (URAT) URAT1 (SLC22A12), which is expressed at the apical membrane of proximal tubular cells in humans. Uptake of oxypurinol by Xenopus oocytes injected with complementary RNA of URAT1 was significantly higher than that by water-injected oocytes, and the uptake was saturable, with a K m of about 800 M. Moreover, benzbromarone inhibited the oxypurinol uptake by URAT1 at concentrations as low as 0.01 M. The uptake of oxypurinol by another organic anion transporter (OAT), OAT4 (SLC22A11), which is also expressed at the apical membrane of proximal tubular epithelial cells, was negligible, whereas the uptake of [ 3 H]estrone-3-sulfate by OAT4 was significantly inhibited by oxypurinol. Furthermore, neither the transport activity of organic cation/carnitine transporter (OCTN) 1 nor OCTN2 was affected by oxypurinol or benzbromarone. These results indicate that URAT1 is involved in renal reabsorption of oxypurinol, and the increment of renal clearance of oxypurinol upon concomitant administration of benzbromarone could be due to drug interaction at URAT1.

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The Development of Allopurinol

Cited by 53 publications

References 103 publications

Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion

Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion

Facile One‐Pot Synthesis and Antimycobacterial Evaluation of Pyrazolo[3,4‐d]pyrimidines

Involvement of Uric Acid Transporter in Increased Renal Clearance of the Xanthine Oxidase Inhibitor Oxypurinol Induced by a Uricosuric Agent, Benzbromarone

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