Allopurinol
The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease.

Bonham JR, Guthrie P, Downing M, Allen JC, Tanner MS, Sharrard M, Rittey C, Land JM, Fensom A, O'Neill D, Duley JA, Fairbanks LD.

Department of Chemical Pathology and Neonatal Screening, Children's Hospital NHS Trust, Sheffield, UK.

Thirty-three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary ourotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0 mumol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0 mumol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl-phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10234613&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effects of systemically applied allopurinol and prednisolone on experimental autoimmune uveitis.

Augustin AJ, Loeffler KU, Sekundo W, Grus FH, Lutz J.

Department of Ophthalmology, University of Bonn, Germany. 106020.560 compuserve.com

PURPOSE: To compare the effects of allopurinol to those of prednisolone on the oxidative tissue damage and inflammatory response in experimental autoimmune uveitis (EAU). METHODS: Experiments were performed using 27 male Lewis rats. EAU was induced by means of crude retina extract, Freund's adjuvant and pertussis toxin. One group of animals served as controls and two groups were treated systemically, one with allopurinol and one with prednisolone. At the end of the experiments lipid peroxides (LPO), myeloperoxidase activity (MPO), and histological changes were determined in the retinal tissue. LPO were measured by two different methods [thiobarbituric acid reactive substances (TBARS) and malondialdehyde-like substances]. RESULTS: Allopurinol led to a significant reduction in LPO and MPO levels. The steroid treatment also resulted in a significant reduction in MPO activity but LPO were significantly reduced only when measured as TBARS. Histological changes were significantly reduced by allopurinol only. DISCUSSION: Allopurinol is more effective than prednisolone in treating EAU. Its efficacy can be explained by the antioxidative/antiinflammatory and probably immunological action. The antiinflammatory effects of prednisolone are not sufficient to reduce the tissue damage. Allopurinol promises to be a useful alternative to steroids in the treatment of uveitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10379613&dopt=Abstract allopurinol Zyloprim



Allopurinol
[Protective effect of allopurinol in the exposure to noise pulses]

[Article in Italian]

Attanasio G, Cassandro E, Sequino L, Mafera B, Mondola P.

Istituto di Clinica Otorinolaringoiatrica, Universita di Roma La Sapienza.

Free oxygen radicals cause particularly severe tissues and organ damage. They appear to play an important role in the cochlea, mediating noise-exposure damage. In the present study 16 guinea pigs were implanted with permanent electrodes to record cochlear action potential. Eight animals were exposed to a 2-3 kHz, 125 dB SPL noise pulse, at a rate of 4 stimulations per second for 1.8 hours. Prior to noise exposure four out of eight animals were treated with a known dose of allopurinol. The remaining eight animals were used as controls. Endolymphatic malondialdehyde concentration was used as indicator of the lipid peroxidization processes exerted by the free radicals. No significant difference was found between the variations in hearing threshold and malondialdehyde concentration in the animals treated with allopurinol and then exposed to noise vs. the control group. The electophysiological and biochemical results have, therefore, demonstrated that preventative administration of allopurinol can provide valid protection vs. noise impulse damage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10418186&dopt=Abstract allopurinol Zyloprim



Allopurinol
Prevention of oxidative stress due to tourniquet application. Analysis of the effects of local hypothermia and systemic allopurinol administration.

Erdogan D, Omeroglu S, Sarban S, Atik OS.

Department of Histology and Embryology, Gazi University Faculty of Medicine, Ankara, Turkey.

In this study various methods for the prevention of oxidative stress due to tourniquet application were compared. An ischemia period of two hours followed by a reperfusion period of one hour was produced in the right posterior limb in 32 rats. In the first group no treatment was given. In the second group local cold application was performed before and after ischemia. In the third group allopurinol was given orally for 5 days before the procedure. In the fourth group both local hypothermia application and oral allopurinol treatment were given. Ultrastructural study of the gastrocnemius muscles in the various groups revealed that the least damage in the ultrastructure of the striated muscle was obtained using allopurinol alone and using a combination of allopurinol and local hypothermia. When tissue glutathione levels were measured, it was seen that a combination of allopurinol and local hypothermia was the best treatment for preventing oxidative stress.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10427797&dopt=Abstract allopurinol Zyloprim



Allopurinol
Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure.

Ekelund UE, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, Kass DA, Marban E, Hare JM.

Department of Medicine, Cardiology Division, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (n=10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt)(max) increased from 3103+/-162 to 3373+/-225 mm Hg/s (+8.3+/-3.2%; P=0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (n=5), this effect was larger; (dP/dt)(max) rose from 1602+/-190 to 1988+/-251 mm Hg/s (+24.4+/-8.7%; P=0.03), preload-recruitable stroke work increased from 55.8+/-9.1 to 84. 9+/-12.2 mm Hg (+28.1+/-5.3%; P=0.02), and ventricular elastance rose from 6.0+/-1.6 to 10.5+/-2.2 mm Hg/mm (P=0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49+/-4.6%; P=0. 002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; +122+/-42%; P=0.04). Moreover, xanthine oxidase activity was approximately 4-fold increased in failing versus control dog hearts (387+/-125 versus 78+/-72 pmol/min. mg(-1); P=0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10473673&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol increases ear swelling and mortality in a dinitrofluorobenzene-induced contact hypersensitivity mouse model.

Horiuchi H, Ota M, Kitahara S, Ohta T, Kiyoki M, Komoriya K.

Pharmacological Research Department, Pharmaceuticals Development Research Laboratories, Teijin Institute for BioMedical Research, Hino, Tokyo, Japan.

The immunomodulatory effects of allopurinol were investigated in a mouse contact hypersensitivity model. Allopurinol caused a time- and dose-dependent lethal effect in dinitrofluorobenzene (DNFB)-sensitized mice. Furthermore, allopurinol markedly increased ear swelling in the remaining mice. In contrast, TMX-67, a newly synthesized xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitor, had almost no effect on DNFB-sensitized mice. Allopurinol reduced both the spleen weight and white blood cell count in DNFB-sensitized mice without affecting the T cell subset of splenocytes. The production of interferon (IFN)-gamma, in the splenocytes of DNFB-sensitized mice was reduced by allopurinol administration. Death due to allopurinol was much lower in the non-sensitized mice than in the DNFB-sensitized mice. These findings indicate that allopurinol may interact with DNFB to enhance its toxicity and allopurinol might also modulate or enhance the inflammatory effect of DNFB. Also, DNFB may cause metabolic alterations via inflammation, leading to enhanced allopurinol toxicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10480318&dopt=Abstract allopurinol Zyloprim