Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk.

The aim of the present study was to evaluate the effect of increased serum uric acid (UA) levels and their therapeutic reduction with allopurinol on endothelium-dependent dilation in subjects with a high cardiovascular (CV) risk but who were free from clinical CV disease. Patients with hyperuricemia had impaired flow-mediated dilation (FMD) compared with matched controls with normal UA levels and elevated CV risk. Three-month therapy with allopurinol improved FMD in hyperuricemic subjects, showing an intrinsic negative effect of elevated UA levels on the arterial wall; conversely, FMD remained unchanged in controls, thus suggesting that the reduction of UA to less than a certain value does not affect endothelial function.

A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis.

BACKGROUND AND STUDY AIMS: Acute pancreatitis is the most frequent and difficult-to-avoid complication of endoscopic retrograde cholangiopancreatography (ERCP). Corticosteroids, potent anti-inflammatory drugs, and allopurinol--a xanthine oxidase inhibitor that blocks the generation of oxygen-derived free radicals--may be potentially effective in preventing post-ERCP pancreatitis. The aim of this prospective study was to determine the effect of prophylactic oral corticosteroids and allopurinol on the incidence and severity of procedure-induced pancreatitis. PATIENTS AND METHODS: 300 patients were randomly assigned to receive oral prednisone (40 mg), allopurinol (200 mg), or placebo 15 h and 3 h prior to ERCP. The diagnosis and grading of ERCP complications were based on commonly accepted criteria. Patients receiving prednisone or allopurinol were compared with the placebo group in a search for differences in pancreatitis rates associated with endoscopic techniques. RESULTS: The overall incidence of pancreatitis was 10.7 %, with 12 % in the prednisone group, 12.1 % in the allopurinol group, and 7.9 % in the placebo group. There were no statistical differences in the incidence or distribution of severity grades between the groups, although severe pancreatitis occurred only in the prednisone and allopurinol groups. Multiple cannulations and prolonged manipulations of the papilla of Vater were identified as risk factors for ERCP-induced pancreatitis. CONCLUSIONS: Neither prednisone nor allopurinol showed a beneficial influence on the incidence and severity of post-ERCP pancreatitis.

Effects of morphine on the electrochemical signal modified by noxious stimuli in the nucleus raphe magnus of anesthetized rats.

The effects of noxious stimuli and morphine on the serotonergic system in the nucleus raphe magnus were examined by in vivo voltammetry studies, using anesthetized rats. The normal electrochemical signal of 280-300 mV was essentially due to the presence of 5-hydroxyindoles in the nucleus raphe magnus. Heating or pinching produced mean decreases of 21.9 +/- 5.2% and 18.0 +/- 6.1% of control, respectively in the 5-hydroxyindole signal. Non-noxious (brushing or warm water) stimulation did not affect the 5-hydroxyindole signal. A small dose of morphine (0.5 mg/kg, i.p.) enhanced the inhibition of the signal by noxious stimuli but large doses (2.0 or 5.0 mg/kg, i.p.) resulted in lesser reductions of the signal. The value of the 5-hydroxyindole signal was unaffected by morphine alone (0.5, 2.0 and 5.0 mg/kg). Effects of both small- and large-doses of morphine were antagonized by naloxone (1 mg/kg, i.v.). Allopurinol (20 mg/kg, i.p.), a xanthine oxidase inhibitor, decreased the steady signal (40.7 +/- 16.2%). After pretreatment with allopurinol, noxious stimuli-induced decreases, both with and without administration of morphine, were similar to those in nontreated rats. In brief, noxious stimulation was found to decrease 5-hydroxyindole signal in the nucleus raphe magnus; morphine enhanced or attenuated this decrease in the anesthesized rat.

Tissue protection by allopurinol in the myocardial calcium paradox.

The aim of the present study was to evaluate the protective properties of the xanthine oxidase inhibitor allopurinol in the myocardial calcium paradox. Two injury levels, minimal and total calcium paradox, caused by different volumes (5 ml and 45 ml) of calcium-free perfusion (5 min) prior to calcium repletion (15 min) were examined +/- allopurinol (0.15 mmol/l) in the normothermic isolated rat heart model. Allopurinol supplementation (5 min prior to, during and 5 min following Ca2+-free perfusion) had no effect upon tissue injury in the total calcium paradox, but afforded considerable protection as assessed by enzymatic, physiologic, and metabolic parameters in the minimal calcium paradox. When allopurinol was omitted during calcium repletion, tissue protection was less apparent. The presence of verapamil (2 mumol/l) in addition to allopurinol (5 min prior to, during, and 5 min following calcium depletion) afforded only a marginal further protection in the minimal calcium paradox. It is concluded from the present study that tissue protection by allopurinol in the calcium paradox is limited to minimal or less severe calcium paradox models and that the protective action of allopurinol may indicate an inhibition of the xanthine oxidase reaction and the generation of free oxygen radicals.

Antitrypanosomal effect of allopurinol: conversion in vivo to aminopyrazolopyrimidine nucleotides by Trypanosoma curzi.

The parasite Trypanosoma cruzi metabolizes allopurinol by a sequential conversion to allopurinol mononucleotide and aminopurinol mononucleotide. The latter is incorporated into RNA. This transformation of a widely used innocuous agent, allopurinol, into a toxic adenine analog appears to account for the antiprotozoan effect of allopurinol. These unique enzymatic activities appear to occur only in T. cruzi and the pathogenic lesihaminae. Allopurinol may serve as a model for the synthesis of similar antiprotozoan agents.

The mechanism of inhibition of rat liver tryptophan pyrrolase activity by 4-hydroxypyrazolo(3,4-d)pyrimidine (Allopurinol).

1. Allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine) selectively inhibits the apotryptophan pyrrolase activity in homogenates of rat liver in vitro and after intraperitoneal administration. The inhibition is abolished by an excess of haematin. The allopurinol metabolite alloxanthine has no effect on the pyrrolase activity in vitro or after administration. Allopurinol also inhibits the activation of the enzyme in vitro by ascorbate, ethanol plus NAD(+), NADH, hypoxanthine or xanthine. It is suggested that these agents cause the conversion of a latent form of the pyrrolase into the apoenzyme, and that xanthine oxidase is not involved in this process. 2. The raised total pyrrolase activity observed after the administration of cortisol, cyclic AMP, tryptophan, salicylate or ethanol is lowered by allopurinol in vitro to the corresponding holoenzyme values. A similar effect is observed when allopurinol is administered shortly before cortisol or cyclic AMP. Pretreatment of rats with allopurinol completely prevents the enhancement of the pyrrolase activities by tryptophan, salicylate or ethanol. 3. It is suggested that allopurinol inhibits rat liver tryptophan pyrrolase activity in vitro and after administration by preventing the conjugation of the apoenzyme with its haem activator. The possible usefulness of combined allopurinol-tryptophan therapy of affective disorders is discussed.