Allopurinol
The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits.

Akdemir H, Asik Z, Pasaoglu H, Karakucuk I, Oktem IS, Koc RK.

Department of Neurosurgery, Erciyes University, School of Medicine, Kayseri, Turkey. akdemirh hotmail.com

In this experimental study, the neuroprotective effect of the xanthine oxidase inhibitor allopurinol on focal cerebral ischaemia created by permanent middle cerebral artery occlusion (MCAO) was investigated. Using high performance liquid chromatography (HPLC), we measured hypoxanthine, xanthine, and uric acid (UA) levels in rabbit brains following focal cerebral ischaemia. Rabbits were randomly and blindly assigned into four groups of eight animals each. The control groups received 2% carboxymethylcellulose solution, while 10% allopurinol 150 mg/kg was given to the treatment group 1 h before ischaemia. Each group was subdivided into two groups which were sacrificed 4 h or 24 h after ischaemia, respectively. UA and xanthine values of the rabbits in the control groups were quite high at both times and highest after 24 h, particularly in the centre of the ischaemia. A significant decrease in UA and xanthine values was observed in rabbits that were given allopurinol (P<0.05). According to our results, it was concluded that allopurinol pretreatment protects neural tissue in the early period after arterial occlusion and prevents cerebral injury in the late period, especially in the perifocal area, possibly by preventing the formation of free radicals with xanthine oxidase inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11485235&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol attenuates endolymphatic hydrops in the guinea pig cochlea.

Shinomori Y, Kimura RS.

Department of Otolaryngology, Ehime University School of Medicine, Onen-gun, Ehime, Japan.

Based on the hypothesis that Ca(2+) overload in the scala media may produce endolymphatic hydrops and generate free oxygen radicals (FOR), allopurinol, a xanthine oxidase inhibitor and free radical scavenger, was administered to guinea pigs after the surgical obliteration of the endolymphatic duct. Allopurinol was given intraperitoneally (50 mg/kg/day) for 15 days starting 1 day prior to the surgical blockage procedure. Measurements from histological serial sections of these temporal bones showed that the total volume of the scala media was significantly reduced (p = 0.007) compared with control hydropic ears. There was an indication of reduced incidence of atrophy in sensorineural structures and stria vascularis. These findings suggest that allopurinol may attenuate the development of endolymphatic hydrops and cell damage by preventing the formation of FOR or scavenging FOR. This study may lead to a new aspect of treatment for Meniere's disease. Copyright 2001 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11528268&dopt=Abstract allopurinol Zyloprim



Allopurinol
A novel parasite-derived suicide gene for cancer gene therapy with specificity for lung cancer cells.

Trudeau C, Yuan S, Galipeau J, Benlimame N, Alaoui-Jamali MA, Batist G.

Department of Pharmacology, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada.

The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) expressed by the parasite Trypanosoma brucei (Tb) can convert allopurinol, a purine analogue, to corresponding nucleotides with greater efficiency than its human homologue. We have developed a retroviral system that expresses the parasitic enzyme and tested its capacity to activate the prodrug allopurinol to a cytotoxic metabolite. Cytotoxicity assays demonstrated that five non-small cell lung carcinoma cell lines transduced with the construct were sensitized to the prodrug by 2.1- to 7.6-fold compared with control values. This selectivity was not observed in seven other cell lines also expressing the construct, such as breast carcinoma. Assays indicated that enhanced cytotoxicity to allopurinol correlated with induction of apoptosis in lung cancer cells. The selectivity of this suicide gene was not explained either by the TbHGPRT expression or by the allopurinol accumulation. Our study shows that this novel system may represent a therapeutic tool for gene prodrug targeting of lung cancer, considering the fact that allopurinol is well tolerated in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11535170&dopt=Abstract allopurinol Zyloprim



Allopurinol
Relation between adverse events associated with allopurinol and renal function in patients with gout.

Vazquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R.

Rheumatology Unit, Hospital General de Mexico, Mexico DF. jvazquezmellado yahoo.com

BACKGROUND: Because serious adverse reactions to allopurinol have been related to a reduce creatinine clearance rate and prolonged half life of oxypurinol, it has been recommended that the dose should be adjusted according to the rate of creatinine clearance. However, in some patients with gout the dose is not sufficient to reduce serum levels of uric acid (< or =390 micromol/l) and to halt disease progression. OBJECTIVE: To determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate. METHODS: Data on 120 patients with gout receiving allopurinol, in whom the starting dose was adjusted according to creatinine clearance rate and later increased in some patients to control the disease, were retrospectively reviewed. Two groups were compared: group A, 52 patients receiving creatinine clearance adjusted maintenance doses of allopurinol and group B, 68 patients receiving non-adjusted higher maintenance doses of allopurinol. RESULTS: During follow up 57% required higher allopurinol doses than those recommended according to their creatinine clearance rate. Only five (4%) of 120 consecutive patients developed allopurinol related adverse reactions: four minor skin reactions and one allopurinol hypersensitivity syndrome (AHS). Three of these (including the case of AHS) occurred in group A and two in group B (p=NS). The duration of allopurinol treatment was the same in both groups (group A: 2.3 (3.3) years; group B: 3.7 (4.8) years). No patient in group A, but 44% in group B had a creatinine clearance rate of <50 ml/min. None of the patients received concomitant diuretics, ampicillin, or azathioprine. CONCLUSIONS: No increase was seen in the prevalence of adverse reactions to allopurinol in patients who received higher allopurinol maintenance doses than those recommended according to creatinine clearance rate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11557658&dopt=Abstract allopurinol Zyloprim



Allopurinol
Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells.

Peeters C, Hoelen D, Groenendaal F, van Bel F, Bar D.

Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Reactive oxygen species-induced reperfusion injury of the brain is an important cause of neonatal morbidity and mortality following perinatal hypoxia-ischemia. Deferoxamine, allopurinol and oxypurinol have previously been shown to be neuroprotective in vivo during or directly after hypoxia-ischemia. To further characterize and more precisely elucidate whether the neuroprotective properties of these agents are mediated via neuronal and glial cells, or whether endothelial cells contribute to this effect, we tested their ability to protect CA1 neurons in organotypic hippocampal slices. Hippocampal slices obtained from 8-day-old rats were cultured for 7 days and exposed to oxygen/glucose deprivation for 50 min, or used as control slices. Cell damage was assessed at 48 h after oxygen/glucose deprivation using propidium iodide staining. At different time points following oxygen/glucose deprivation we administered dizocilpine, 6-cyano-7-nitroquinoxaline-2,3-dione, and alpha-phenyl-N-tert-butyl nitrone for validation purposes. Deferoxamine, allopurinol or oxypurinol were used as test substances. As expected, 89% and 98% protection was demonstrated with dizocilpine present during or during/after oxygen/glucose deprivation resp. alpha-Phenyl-N-tert-butyl nitrone administered during/after oxygen/glucose deprivation provided 44% protection. However, iron chelation with deferoxamine and inhibition of xanthine oxidase by allopurinol or oxypurinol did not confer neuroprotection. The neuroprotective effect of deferoxamine, allopurinol or oxypurinol, as seen in vivo, may be obtained via inhibition of the production of damaging factors by blood born substances or endothelial cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12560112&dopt=Abstract allopurinol Zyloprim



Allopurinol
Differences in the composition of inflammatory cell infiltrate in lens-induced uveitis under therapy with allopurinol or steroids.

Sekundo W, Augustin AJ.

Department of Ophthalmology, University of Marburg, Germany. sekundo mailer.uni-marburg.de

PURPOSE: The aim of this study was to compare the qualitative changes in the composition of inflammatory cell infiltrate in lens-induced uveitis (LIU) under treatment with allopurinol (Allo), methylprednisolone (Pred) or the two drugs combined (Allo/Pred). METHODS: Twenty male Wistar rats were sensitized with lens proteins for eight weeks. Intravenous (IV) therapy was started after anterior capsule disruption in one eye of each animal. Five rats were randomly assigned to each of the four groups: controls, Allo (50 mg/kg bw), Pred (7.5 mg/kg bw) and Allo/Pred (50 mg/7.5 mg per kg bw). Eyes were enucleated 24 hours later and fixed in paraformaldehyde/glutaraldehyde. Sections at three levels were stained with Giemsa and examined using a 0 to 4+ score for each type of inflammatory cell. Granulocytes were seen as neutrophils and eosinophils. Neutrophils were divided into polymorphs and "others", and graded with lymphocytes. RESULTS: In all therapy groups there was a significant reduction of polymorphs (p<0.05) in comparison to the control group. There was also a significant reduction in lymphocytes (p<0.05) in the Pred and Allo/Pred groups as compared to the control group and the Allo group. CONCLUSIONS: Single-dose IV allopurinol significantly reduced the overall number of polymorphonuclear leucocytes in LIU. Unlike methylprednisolone, allopurinol did not have any significant impact on lymphocytes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11681506&dopt=Abstract allopurinol Zyloprim