Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol
http://www.100md.com
Pál Pacher, Alex Nivorozhkin and Csaba S
| 第1页 |
| 第11页 |
| 第1页 |
| 第12页 |
| 第9页 |
| 第22页 |
参见附件(200KB，22页)。
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (P.P.)
Center for Integration of Medicine and Innovative Technology, Cambridge, Massachusetts (A.N.)
Department of Surgery, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey (C.S.)
Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Hungary (C.S.)
Abstract
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.
I. Introduction, Historical Background
Allopurinol, or 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, was one of the crown jewels of the venerable drug discovery program at Burroughs Wellcome that started in 1940s and culminated by the awarding of a 1988 Nobel Prize in Physiology and Medicine to Gertrude B. Elion and George H. Hitchings, shared with British scientist James W. Black, for "discoveries of important principles for drug treatment." An excellent overview of this effort, which yielded, in addition to the xanthine oxidase (XO)1 inhibitor allopurinol, blockbuster drugs such as acyclovir, trimethoprim, and the early antineoplastic compounds thioguanidine and 6-mercaptopurine (6-MP), can be found in the Nobel lectures by Elion and Hitchings and elsewhere [Hitchings and Elion, 1963; Elion, 1988 (http://nobelprize.org/medicine/laureates/1988/elion-lecture.pdf), 1993]. As they recount, the program grew up out of a very general notion that synthetic analogs of the purine and pyrimidine bases can interfere with nucleic acid biosynthesis. They soon found antibacterial activity for multiple compounds, some of which were tested at Sloan-Kettering Institute for their anticancer properties. 6-MP emerged as having very high activity against leukemia. These compounds rapidly progressed into clinical trials and culminated in regulatory approval in 1953, propelled by a desperate need for new treatments, especially for acute leukemia in children, which were limited at the time to methotrexate and steroids ......
您现在查看是摘要介绍页，详见PDF附件(200KB，22页)。