Allopurinol
Anticonvulsant effect of allopurinol on hippocampal-kindled seizures.

Wada Y, Hasegawa H, Nakamura M, Yamaguchi N.

Department of Neuropsychiatry, Kanazawa University School of Medicine, Japan.

This study assessed the anticonvulsant effect of allopurinol (5 and 50 mg/kg, IP) on seizures kindled from the feline hippocampus. Allopurinol at a higher dose significantly reduced the behavioral seizures stage, but not afterdischarge duration, without producing any behavioral toxicity. The present results lend experimental support to the contention that allopurinol possesses anticonvulsant efficacy in the treatment of human epilepsy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1513873&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of allopurinol on the survival of experimental pig flaps.

Picard-Ami LA Jr, MacKay A, Kerrigan CL.

Microsurgical Research Laboratory, Royal Victoria Hospital, Montreal, P.Q., Canada.

Allopurinol has been reported to improve cell survival in a variety of conditions, including the ischemia-reperfusion injury occurring in skin flaps. It has been suggested that the beneficial effect of allopurinol on rat skin flaps is through blockage of xanthine oxidase-generated oxygen-derived free radicals. We have previously reported on the lack of xanthine oxidase activity in the skin of humans and pigs as compared with that of rats. This current study attempts to improve skin and myocutaneous flap survival in pigs in two separate experiments using allopurinol. In the first experiment, a suspension of 50 mg/kg (N = 12) allopurinol resulted in no significant difference in the survival of control and treated flaps. Because of the negative results in the first experiment, a second experiment was designed making several changes. The length of the global ischemic insult was reduced from 8 to 6 hours, and allopurinol was administered as a solution of 300 mg/kg (N = 14). This higher dose is expected to produce complete inhibition of xanthine oxidase in this animal model. These changes resulted in three operative deaths, no improvement in skin-flap survival, and a decrease in myocutaneous flap survival. Allopurinol's therapeutic effectiveness and its mechanism of action in an ischemia-reperfusion injury model lacking xanthine oxidase activity are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1584870&dopt=Abstract allopurinol Zyloprim



Allopurinol
Breakdown of hepatic tight junctions during reoxygenation injury.

Konno H, Lowe PJ, Hardison WG, Miyai K, Nakamura S, Baba S.

Second Department of Surgery, Hamamatsu University School of Medicine, Japan.

We investigated whether reoxygenation following anoxia increased biliary permeability and whether or not allopurinol had a protective effect. Isolated rat livers were perfused for 30 min in a one-pass system with buffer equilibrated with 100% nitrogen after stabilization, and then for 60 min with the oxygenated buffer. Hepatic tight junction permeability was assessed by quantifying the early appearance in the bile of horseradish peroxidase (HRP) injected with the perfusate. This early peak represents paracellular passage of HRP, whereas a later second peak results from transcellular passage. In the control livers, 7% of the total HRP passage (93 +/- 50 pg/g liver) was paracellular and 93% was transcellular. After 30 min of reoxygenation following anoxia, however, 516 +/- 20 pg/g liver of HRP passed paracellularly. Addition of allopurinol (5 micrograms/ml) to the perfusate from the start of perfusion reduced paracellular passage of HRP to 219 +/- 49 pg/g liver after anoxia and reperfusion (P less than 0.01). Allopurinol also reduced the cumulative lactate dehydrogenase (LDH) release during the first 30 min of reoxygenation from 2.1 +/- 0.3 x 10(4) to 1.4 +/- 0.4 x 10(4) units/g liver (P less than 0.01). Reduction of the anoxic period from 30 min to 25 min significantly reduced the change in tight junction permeability and the extent of cellular injury: Paracellular passage of HRP was 336 +/- 20 pg/g and LDH release was 0.7 +/- 0.1 x 10(4) units/g liver, both significantly lower than those at 30 min (P less than 0.01). No significant difference in hepatic ATP levels after 60 min of reoxygenation was noted among the experimental groups, but all had lower levels than the control group. The protective effect of allopurinol suggests that the mechanism of biliary reoxygenation injury involves free radical generation. Susceptibility of tight junctions suggests a pattern of injury similar to that involved in anoxic damage of the vascular endothelium.

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Allopurinol
Allopurinol fails to protect against gentamicin-induced renal damage in normotensive and spontaneously hypertensive rats.

Smyth BJ, Davis WG.

Department of Pathology, Medical University of South Carolina, Charleston 29425-2645.

Recent research suggests the involvement of hydroxyl and superoxide free radicals in the development of gentamicin-induced acute renal tubular necrosis. Xanthine oxidase has been implicated as an important source of superoxide free radicals. Spontaneously hypertensive (Wistar-Kyoto) rats (SHR) have excessive oxidant stress which may render them more sensitive to the proported oxygen free radical producing effects of gentamicin. This study was undertaken to determine if the xanthine oxidase inhibitor allopurinol will ameliorate the effects of gentamicin. Normotensive Wistar-Kyoto (WKY) rats and SHR were administered allopurinol (40 mg/kg twice daily) orally 4 days before and throughout a 12-day gentamicin treatment period. The allopurinol only treatment group demonstrated no noticeable histological or functional changes considered to be indicative of nephrotoxicity. Gentamicin-injected WKY rats and SHR equally demonstrated extensive proximal tubular and glomerular damage characteristic of aminoglycoside-induced kidney damage. Allopurinol failed to protect either rat strain against the histological damage caused by gentamicin. Equivalent alterations in serum creatinine, serum gentamicin, urinary N-acetyl-beta-D-glucosaminidase excretion, body weight, urinary output, and blood pressure occurred in the gentamicin with allopurinol and gentamicin only treatment groups. Our results demonstrate allopurinol does not ameliorate the pathogenesis of gentamicin. SHR do not appear to be more sensitive to the effects of gentamicin induced kidney damage with or without allopurinol as compared with WKY rats.

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Allopurinol
Lack of a pharmacokinetic interaction between oral famciclovir and allopurinol in healthy volunteers.

Fowles SE, Pratt SK, Laroche J, Prince WT.

Drug Metabolism and Pharmacokinetics Department, SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, UK.

Famciclovir has been shown to have potent and selective activity against herpesviruses. The possibility of a pharmacokinetic interaction between the anti-viral agent, famciclovir and allopurinol has been investigated in twelve healthy male volunteers following a single oral dose of famciclovir (500 mg) in the presence and absence of steady-state levels of allopurinol (300 mg). Similarly, the pharmacokinetic profiles of allopurinol and oxypurinol prior to and following a single dose of famciclovir were compared. Mean values of Cmax, AUC and terminal-phase half-life for penciclovir following administration of famciclovir alone at 3.3 micrograms.ml-1, 8.8 micrograms.h.ml-1 and 2.1 h, respectively were unchanged by co-administration of allopurinol. Similarly, mean urinary recovery and renal clearance values of penciclovir following famciclovir alone were 56.8% and 27 l.h-1, and when given with allopurinol 59.7% and 27.5 l.h-1, respectively. No evidence of accumulation of the inactive precursor to penciclovir, BRL 42359, was noted as a result of co-administration of the two drugs. Mean steady-state Cmax, AUC and terminal-phase half-life values for allopurinol after co-administration of allopurinol with famciclovir also appeared unchanged from values obtained after dosing of allopurinol alone, at 2.12 micrograms.ml-1, 5.73 micrograms.h.ml-1 and 1.38 h, respectively. Mean Cmax and AUC values of the active metabolite of allopurinol, oxypurinol were 11.2 micrograms.ml-1 and 96.0 micrograms.h.ml-1, respectively, and these were also unaltered by co-administration of famciclovir with allopurinol, with values of 10.6 micrograms/ml and 89.8 micrograms.h/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Allopurinol
Effect of allopurinol on the concentration of endogenous glutathione in hepatocytes after an hour of normothermic liver ischemia.

Karwinski W, Ulvik R, Farstad M, Svardal A, Berge R, Soreide O.

Department of Surgery, Haukeland Hospital, University of Bergen, Norway.

OBJECTIVE: To find out whether oxygen free radical liberated by activation of xanthine oxidase change the tissue concentration of glutathione. DESIGN: Controlled study. MATERIAL: 42 male Wistar rats. INTERVENTION: Laparotomy, induction of ischemia, and reperfusion. 27 rats were treated with allopurinol (to inhibit xanthine oxidase) and the remaining 15 acted as controls. MAIN OUTCOME MEASURES: Concentrations of reduced glutathione, oxidized glutathione, and total glutathione in hepatocytes, blood, and bile. RESULTS: Concentration of reduced and total glutathione in hepatocytes decreased significantly during reperfusion and oxidized glutathione was unchanged in all groups. Total glutathione in peripheral venous blood was reduced by half during the period of ischemia and increased gradually during reperfusion whereas the concentration of total glutathione in bile decreased appreciable during reperfusion. Production of bile improved significantly during reperfusion in the group treated with allopurinol compared with the control group. CONCLUSION: Xanthine oxidase may not be the main source of production of oxygen free radicals as allopurinol did not affect the hepatic concentration of glutathione during reperfusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8104497&dopt=Abstract allopurinol Zyloprim