Oral Administration Of Allopurinol Research Articles

The possible antianginal effect of allopurinol in vasopressin-induced ischemic model in rats

The anti-anginal effects of allopurinol were assessed in experimental model rats of angina and their effects were evaluated with amlodipine. In the vasopressin-induced angina model, oral administration of allopurinol in dose of 10mg/kg revealed remarkably analogous effects in comparison with amlodipine such as dose-dependent suppression of vasopressin-triggered time, duration and severity of ST depression. In addition, allopurinol produced dose dependent suppression of plasma Malondialdehyde (MDA) level, systolic blood pressure, cardiac contractility and cardiac oxygen consumption; while in contrast, amlodipine minimally suppressed the elevation of plasma MDA level. Endothelial NO synthase (eNOS) expression, serum nitrate were strikingly increased, however lipid profile was significantly reduced. Seemingly, allopurinol was found to be more potent than amlodipine – a calcium channel antagonist. To conclude, it was explicitly observed and verified that on the ischemic electrocardiography (ECG) changes in angina pectoris model in rats, allopurinol exerts a significant protective effects, reminiscent of enhancement of vascular oxidative stress, function of endothelial cells, improved coronary blood flow in addition to the potential enhancement in myocardial stress. Moreover, our findings were in conformity with several human studies.

Urinary Excretion and Renal Clearance of Allopurinol in Female Gout Patients

Drugs are excreted from the human body either unchanged or as metabolite. Gout is treated with allopurinol drug which lowers uric acid level in humans. Xanthine oxidase activity is inhibited with allopurinol which converts hypo-Xanthine and xanthine into uric acid. In case of kidney impairment monitoring of allopurinol drug metabolism was important option for optimization of allopurinol. Allopurinol level was measured in human serum and urine of gout patients after oral intake of allopurinol by using HPLC (high performance liquid chromatography). In female gout patients (n=10) allopurinol was measured in blood and urine samples at 254 nm after taking 300 mg drug. Serum uric acid level, renal function test (RFTs) and urine complete examination was checked before and after oral administration of allopurinol. Statistically results were analyzed and explained.

Comparative study of renal protective effects of allopurinol and N-acetyl-cysteine on contrast induced nephropathy in patients undergoing cardiac catheterization.

Objectives : To evaluate the difference in the renal protective effects of allopurinol and n-acetyl cysteine along with saline hydration in patients of contrast induced nephropathy (CIN) post cardiac interventions. CIN remains a common complication of cardiac procedures. Radio contrast agents can cause a reduction in renal function that may be related to oxidative stress underlining various patho- physiologies. Conflicting evidence suggests that administration of allopurinol, a xanthine oxidase inhibitor can prevent CIN. This is a study of 500 patients undergoing angiography and coronary revascularisation in patients showing significant coronary block. The angiography positive patients (275) were prospectively randomised to different treatment protocol to study for their reno-protective effect. The patients received either of the three drugs saline hydration (SH, 1ml/kg/hr), n-acetylcysteine (SH+NAC, 600 mg bd) or Allopurinol (SH+ALLP, 300 mg/day) 12 hours before and after administration of radio contrast agent. Levels of serum creatinine and blood urea of the 275 patients recorded at 24 hour interval were noted post angioplasty over a course of 5 days in patients receiving either omnipaque (125) or visipaque (150) contrast media. All the 500 patients were also assessed for development of any kind of adverse drug effects/reactions with the two contrast media. CIN occurred in 56 of 500 the patients (10.6%) who underwent angiography and 49 of 275 patients (17.8%) who underwent angioplasty. In the omnipaque group CIN occurred in 16/40, 8/40, nil/45 in patients receiving SH, NAC plus SH and SH plus ALLP respectively. In the visipaque group CIN occurred in 15/50, 10/50, nil/50 in the three treatments groups respectively. Allopurinol maintained a consistent fall in the serum creatinine & blood urea levels from the baseline values from the end of the 1(st) day (p < .01 & .001) in both the category. Visipaque proved to be better dye than omnipaque with less adverse drug effects/ reactions. Prophylactic oral administration of allopurinol (300 mg/day) along with hydration is better than n-acetylcysteine and saline hydration alone for protection against CIN in patients undergoing coronary procedures.

Uric acid excretion in healthy subjects: a nomogram to assess the mechanisms underlying purine metabolic disorders

The reference range for urinary uric acid excretion has not been precisely defined. Different urinary variables have been proposed to determine the renal contribution to increased or decreased serum urate concentrations. We examined which urinary variable best indicates uric acid excretion over a wide range of serum urate concentrations. Purine metabolism was studied in 10 healthy male subjects (aged 26-58 years) both at their endogenous normal serum urate levels (normouricemic state) and after the oral administration of allopurinol (300 mg/24 h for 5 days) and ribonucleic acid (4 g/8 h for 4 days) to decrease (hypouricemic state) and increase (hyperuricemic state) serum urate concentrations, respectively. The results from patients with several conditions known to affect uric acid synthesis and/or the renal excretion of uric acid were used to validate a constructed nomogram. Over a wide range of mean serum urate levels (from 2.7 to 9.5 mg/dL) and mean 24-hour urinary uric acid excretion (171 to 1368 mg/[24 h 1.73 m2]), the highest correlation coefficient between serum urate and uric acid excretion was obtained for the 24-hour uric acid determination (r = 0.928; P < .001). The constructed nomogram allowed the definition of the mechanism underlying hyperuricemia and hypouricemia in patients with a myriad of diseases known to affect purine metabolism. The urinary variable that best correlates with a wide range of serum urate concentrations is 24-hour urinary uric acid excretion. The constructed nomogram allows the identification of the kidney contribution to a given purine metabolic abnormality.

Novel HGPRT 293 A&gt;G point mutation presenting as neonatal acute renal failure

We report on a rare case of hypoxanthine guanine phosphoribosyl transferase (HGPRT) deficiency that presented in the newborn period with acute renal failure (ARF). The clinical diagnosis was made on the basis of non-oliguric ARF and evidence of crystal nephropathy on renal biopsy. HGPRT deficiency was eventually confirmed by enzymatic and genetic testing, showing a novel point mutation, 293 A>G. Immediate treatment consisted of peritoneal dialysis with, initially, lactate- then bicarbonate-buffered 1.36% glucose solution together with oral administration of allopurinol. Follow-up after more than 4 years continued to show hyper-echogenic kidneys with almost normal renal glomerular function. There continues to be no neurobehavioural abnormalities.

Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen

Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.p.) to analyze allopurinol and ebselen alone and in combination for their ability to reduce cisplatin associated hearing loss and nephrotoxicity. The results from our studies indicate that a combined formulation of ebselen and allopurinol affords significant protection to the cochlea and kidney from cisplatin toxicity. In the cochlea, protection is dependent on the preservation of outer hair cell number, while in the kidney, protection is associated with the preservation of proximal tubular epithelia. Further evaluation of the chemoprotective effects of ebselen and allopurinol on cisplatin side effects in the presence of tumor appears warranted.

Bioavailability and pharmacokinetics of intravenously and orally administered allopurinol in healthy Beagles

Abstract Objectives To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. Animals 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. Procedure In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined. Results Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Conclusions Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food. Clinical Relevance A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of &gt; 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding. (Am J Vet Res 1997;58:504–510)

Allopurinol: Discrimination of antioxidant from enzyme inhibitory activities

This study was designed to quantitatively discriminate the specific xanthine oxidase (XO) inhibitory from the relatively nonspecific antioxidant activities of allopurinol, both in vitro and in vivo in the rat. XO activity, determined by the spectrophotometric assay for urate generation over time, was completely inhibited in vitro by allopurinol at concentrations ≥ 200 μM. Allopurinol's antioxidant activity was determined in vitro using a linolenic acid peroxidation (LAP) assay. Although the known antioxidant butylated hydroxytoluene effectively inhibited LAP (80% inhibition of malondialdehyde generation at 10 1 μM), allopurinol (10 1–10 3 μM) did not inhibit this LAP ( p < .01). Rat serum obtained after oral administration of allopurinol (100 mg/kg × 2 doses) did not suppress LAP in vitro more than did control rat serum. Following oral administration of allopurinol (2–50 mg/kg × 2 doses), dose-dependent inhibition of XO activity was observed in the homogenates of the liver (to 5% of control level; p < .001) and the intestine (to 12% of control level; p < .001). We conclude that while 2–50 mg/kg of oral allopurinol effectively suppresses XO activity in the rat liver and intestine, antioxidant activity is not seen even in doses up to 100 mg/kg. The selective enzymatic inhibitory effect of allopurinol at these doses therefore should provide a useful tool to allow the discrimination of the effects of xanthine oxidase in particular from the effects of reactive oxygen metabolites in general.

Kinetics of allopurinol and its metabolite oxypurinol after oral administration of allopurinol alone or associated with benzbromarone in man. Simultaneous assay of hypoxanthine and xanthine by gas chromatography‐mass spectrometry

Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo-uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar. Analysis of the pharmacokinetic parameters of allopurinol and its metabolite after each treatment showed dose-linearity for the metabolite but not for the drug itself. The area under the concentration time curve for allopurinol was 40.3 +/- 9.3 mumol l-1 h after AL, against 8.4 +/- 3.9 mumol-1 h after AL + BZB, while for oxypurinol it was 948.0 +/- 125.4 mumol l-1 h after AL and 285.2 +/- 77.9 mumol l-1 h after AL + BZB. The difference in dosage form may partly account for this difference, but the benzbromarone also seems to be involved. Its role on the blood uric acid lowering action of the drug association is complex. Although benzbromarone appreciably favors the elimination of oxypurinol, which should result in a weakening of its hypo-uricaemic action, this is offset by enhanced elimination of hypoxanthine and xanthine. Renal clearance of xanthine was significantly increased under AL + BZB (173.1 +/- 65.6 ml/min against 112.2 +/- 32.9 ml/min after AL). Similarly, blood xanthine levels were proportionately higher in the presence of benzbromarone. The action of the two agents may thus be synergistic and not antagonistic, a pharmacological justification for the therapeutic use of this drug association.

Role of oxyradicals in cold water immersion restraint-induced gastric mucosal injury in the rat

Cold water immersion restraint of the rat results in focal gastric mucosal erosions. The lesions are associated with powerful, prolonged-duration gastric contractions. Phasic gastric contractions may attenuate gastric mucosal blood flow, resulting in ischemia followed by reperfusion. Therefore, the conditions of cold-water-immersion restraint might lead to mucosal injury by an oxyradical-mediated mechanism. To test this hypothesis, we studied the effect of oxyradical inhibition on cold water immersion restraint-induced lesions. In separate groups of rats subjected to cold water immersion restraint (6-10 animals per group), oxyradical inhibition was achieved by chronic feeding of a sodium tungstate diet, oral administration of allopurinol, or intraperitoneal administration of dimethylsulfoxide. None of these regimens significantly attenuated the number of lesions per stomach, the total lesion area, or the percent of corpus mucosa containing lesions. We conclude that oxyradicals do not play a role in the pathogenesis of cold water immersion restraint-induced lesions.

Allopurinol Absorption from Different Sites of the Rat Gastrointestinal Tract

Allopurinol exhibits good bioavailability (78–90%) after administration of oral dosage forms to humans and rabbits; however, it is not absorbed rectally from any of the dosage forms to any significant extent. Oral administration of allopurinol in a polyethylene glycol suspension, to which allopurinol may be reversibly complexed, to rabbits has been shown to produce erratic and poor absorption of allopurinol. This suggests the possibility of differential absorption of allopurinol from various sites of the Gl tract. The mechanism of allopurinol absorption was investigated in rats using the in situ Levine technique. The allopurinol absorption rate was 0.56 ± 0.10 μ/min/cm from the upper portion of the small intestine and was 0.48 ± 0.12 μ/min/cm from the midgut. The absorption from the lower portion of the small intestine was 0.33 ± 0.14 μ/min/cm and from the upper and lower large intestine segments was negligible (0.04 ± 0.06 μ/min/cm). The normalization of these absorption rates for surface area yielded flux values (normalized absorption rate as μ/min/cm2) with significant differences in permeability between small and large intestine for allopurinol. The allopurinol absorption rate increased with increases in the dose, and there was a linear relationship between dose and absorption rate. Thus, allopurinol absorption, although specific to particular sites, is not dose dependent in the dose range from 0.25 to 2.5mg/mL. Differences in the rates of absorption may be due to anatomical differences of the various parts of the Gl tract or due to physicochemical properties of the drug itself.