Oral Allopurinol Research Articles

Acute renal failure due to bilateral uric acid lithiasis in infants

Acute renal failure (ARF) is one of the complications of urolithiasis, but the role of medical treatment to relieve urinary obstruction in children with ARF is uncertain. We report on infants with acute obstructive uric acid lithiasis. We describe presentation features as well as diagnosis methods and medical treatment in five infants who were admitted to our institution with ARF due to uric acid lithiasis. The medical treatments for all patients were fluid liberalization, urine alkalinization, and oral allopurinol. Two children underwent urinary diversion. Within 8 h, urine output improved in all patients, and the stones passed spontaneously. All obstructed kidneys were relieved with medical treatment, and no renal sequel remained. So this series has showed a role of medical therapy in acute obstructive uric acid lithiasis.

Tumor Lysis Syndrome Induced by Dexamethasone

Tumor Lysis Syndrome Induced by Dexamethasone

Acute renal failure in African children with Burkitt's lymphoma: A comparison of two treatment regimens

The outcome for patients presenting with acute renal failure and Burkitt lymphoma (BLARF) without dialysis is poor. This was a retrospective non-randomized comparative study designed to determine the outcome of two different treatment protocols. One group of patients (TPA) received oral allopurinol, intravenous (IV) cyclophosphamide, vincristine, methotrexate, furosemide, 8.4% sodium bicarbonate, and intrathecal (IT) methotrexate; the other (TPB) alternate day IV infusion of low dose cyclosphosphamide (125 mg/m(2) x 4 doses), IT methotrexate (Days 1 and 5) and aggressive pre-emptive anti-tumor lysis syndrome therapy including oral allopurinol and calcium lactate, IV calcium gluconate, salbutamol, insulin and infusions of furosemide, sodium bicarbonate and glucose. Nine of 16 received TPA, 7 received TPB. Post chemotherapy anemia was more severe with TPA (P < 0.05). TPB patients received significantly more chemotherapy than those in TPA (P = 0.04). All 16 had tumor lysis syndrome (TLS). Six of nine patients with TPA died from this (three from other causes), two deaths in TPB were due to causes other than tumor lysis. Other evaluated outcome indices were similar in both groups. Slow IV infusion of low dose cyclophosphamide given on alternate days in addition to pre-emptive anti-TLS measures (TPB) were associated with better outcome in BLARF patients compared to a high dose multiple chemotherapy regimen (TPA).

Identification of Risk Factors for Tumour Lysis Syndrome in Patients with Acute Myeloid Leukaemia: Development of a Prognostic Score.

Tumour lysis syndrome (TLS) can be a life threatening complication during induction chemotherapy in patients with acute myeloid leukaemia (AML). However, its incidence, risk stratification and management strategies are based on data mainly from lymphoid malignancies. Risk-adapted prophylactic strategies for TLS are in need with the introduction agents like Rasburicase. This single-centre retrospective chart review study was conducted to identify TLS predictive factors in a large AML population undergoing first induction chemotherapy. Between January 1980 and December 2000, 614 consecutive adult patients were diagnosed of de novo AML and started therapy in our institution. Prophylaxis of TLS consisted of intravenous hydration and oral allopurinol. Laboratory TLS (LTLS) was defined as either a 25% change from baseline or level above upper laboratory normal values (ULN) (K+>5meq/l, Uric Acid >7,5mg/dl, Phosphate >5meq/l), or below lower laboratory normal values (Ca2+<8meq/l) for any two or more of this parameters; or creatinine >1,4mg/dl and level above ULN of at least one of the previously defined parameters. These criteria must be met within 3 days before and 7 days after the initiation of chemotherapy in absence of any other recognisable cause. Clinical TLS (CTLS) was defined as the presence of LTLS and at least one of the following complications: oliguric renal failure, hemodyalysis, signs of hyperkalemia in EKG, cardiac arrhythmia, tetania, or seizures. We used the variables identified in a multivariate analysis to construct a scoring system to predict TLS. Overall, 101 patients (17%) developed TLS. Of them 72 (12%) developed LTLS and 29 (5%) developed CTLS. LTLS did not impact induction death rate (21% vs 24%, p=0.51), but CTLS was associated with higher induction death rate (83% vs 24%, p<0.001). In 14 patients (2%) CTLS was considered a major cause of death. Univariate analysis showed that CTLS was significantly associated with FAB M4-M5, hepatomegaly, splenomegaly, GOT >50UI/l, Creatinine >1.4mg/dl, Uric acid >7.5mg/dl, WBC>25x109/l, and LDH >1xULN. In order to perform a multivariate analysis previous selected variables were stratified as follows: WBC>25 and ≤75x109/l, >75x109/l; Creatinine >1.4mg/dl; Uric acid >7.5mg/dl; LDH >1 and ≤4xULN, >4xULN. According to the hazard ratio of each variable a prognostic score system for CTLS was stated, giving 3 points for: Creatinine >1,4mg/dl, Uric acid >7,5mg/dl, WBC>75x109/l, or LDH >4xULN; and 1 point for: WBC>25 and ≤75x109/l or LDH >1 and ≤4xULN. CTLS incidence was 1%, 9% and 25% in patients from 0–3, 4–5, and ≥6 points respectively. 80% of patients were correctly classified, with a sensitivity of 83%, when an individual score of 4 was used as cutpoint. The observed area under the ROC curve was 87%. When our predictive model was introduced in a multivariate analysis, it remained as the solely independent prognostic factor. In conclusion, this study shows that TLS is a frequent alteration found in AML during induction therapy. Nevertheless only one third of patients who met laboratory criteria developed CTLS dramatically increasing death rate in induction. Using four routinary available laboratory data, we have developed a predictive model able to identify different CTLS risk patients subsets. This model could be useful to establish risk-adapted strategies for prophylaxis against TLS.

Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis

Pancreatitis is the most common major complication of ERCP. Efforts have been made to identify pharmacologic agents capable of reducing its incidence and severity. The aim of this trial was to determine whether prophylactic allopurinol, an inhibitor of oxygen-derived free radical production, would reduce the frequency and severity of post-ERCP pancreatitis. Methods A total of 701 patients were randomized to receive either allopurinol or placebo 4 hours and 1 hour before ERCP. A database was prospectively collected by a defined protocol on patients who underwent ERCP. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis. The groups were similar with regard to patient demographics and to patient and procedure risk factors for pancreatitis. The overall incidence of pancreatitis was 12.55%. It occurred in 46 of 355 patients in the allopurinol group (12.96%) and in 42 of 346 patients in the control group (12.14%; p = 0.52). The pancreatitis was graded mild in 7.89%, moderate in 4.51%, and severe in 0.56% of the allopurinol group, and mild in 6.94%, moderate in 4.62%, and severe in 0.58% of the control group. There was no significant difference between the groups in the frequency or the severity of pancreatitis. Prophylactic oral allopurinol did not reduce the frequency or the severity of post-ERCP pancreatitis.

Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy

Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Nontransgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2-4 mo of age. Myocardial xanthine oxidase activity was threefold higher in untreated transgenic mice compared with nontransgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for 2 mo suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved shortening fraction in the transgenic animals. In addition, cardiac muscle twitch tension was preserved to 70% of nontransgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. These findings indicate that chronic inhibition of xanthine oxidase can alter the progression of heart failure in dilated cardiomyopathy.

High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial

Pancreatitis is the most common major complication of diagnostic and therapeutic ERCP. Allopurinol, a xanthine oxidase inhibitor that blocks generation of oxygen-derived free radicals, potentially may prevent post-ERCP pancreatitis. This study assessed the efficacy of high-dose oral allopurinol for prevention of post-ERCP pancreatitis. A prospective, double-blind, placebo-controlled trial was conducted in 250 patients undergoing ERCP. Patients were randomized to receive allopurinol (600 mg) or placebo orally at 15 and 3 hours before the procedure. Patients were clinically evaluated, and serum amylase levels were determined before ERCP and at 6 and 24 hours thereafter. Standardized criteria were used to diagnose and to grade the severity of post-ERCP pancreatitis. A total of 243 patients were included in the analysis. The two groups were similar with regard to age; gender; underlying disease; indication for treatment; ERCP findings; and type of treatment, except for biliary sphincterotomy. Only 43 patients in the allopurinol group underwent biliary sphincterotomy vs. 87 in the placebo group ( p < 0.001). The frequency of acute pancreatitis was significantly lower in the allopurinol vs. the placebo group in the final multinomial regression analysis: allopurinol group, 4/125 (3.2%), with all 4 cases graded as mild, vs. placebo group, 21/118 (17.8%), of which 8/118 (6.8%) were graded as mild, 11/118 (9.3%) as moderate, and 2/118 (1.6%) as severe with fatal outcome ( p < 0.001). The protective effect of allopurinol was also apparent in the diagnostic ERCP and the biliary sphincterotomy subgroups when the frequency of post-ERCP pancreatitis was analyzed after stratification by procedure. The mean duration of hospitalization for pancreatitis was significantly shorter in the allopurinol compared with the placebo group (2.5 vs. 5.67 days; p < 0.001). Pretreatment with high-dose, orally administered allopurinol decreases the frequency of post-ERCP pancreatitis. Despite the promising results of this prospective, randomized trial, further studies are needed to verify these observations before allopurinol can be recommended for routine clinical use.

Role of i.v. allopurinol and rasburicase in tumor lysis syndrome

The role of i.v. allopurinol and rasburicase in tumor lysis syndrome (TLS) is described. The current standard management for TLS consists of oral allopurinol in conjunction with i.v. hydration with or without alkalinization. Despite this standard prophylactic regimen, some high-risk patients may still develop urate nephropathy from TLS. Recently, i.v. allopurinol and rasburicase became available for the management of TLS. Available data on i.v. allopurinol indicate that the administration schedule and the adverse-effect profile will be similar to the oral formulation. The primary advantage of i.v. allopurinol is the flexibility of administration for patients who cannot take anything by mouth, since there are no data indicating the superiority of the i.v. to the oral product. Rasburicase is the first agent that will oxidize uric acid to allantoin, a metabolite with 5-10-fold greater solubility than uric acid, and reduces serum uric acid (SUA) levels within four hours of administration. Rasburicase is considerably more expensive than standard management strategies and should be reserved for patients with either renal dysfunction, significant elevations in SUA values, or large tumor burdens. Preliminary evidence indicates that rasburicase offers cost savings in the treatment of TLS and is cost-effective as a strategy for preventing TLS for many cancer patients. Both i.v. allopurinol and rasburicase offer additional flexibility in the management of TLS and may allow for further avoidance of the consequences of inadequate management of this syndrome.

Anuria Secondary to Hot Weather-Induced Hyperuricaemia: Diagnosis and Management

There is little information on the management of anuria secondary to severe volume depletion or as a rare manifestation of heat stroke in areas of the world with very hot summers. We present our experience with hot weather-induced hyperuricaemia in Kuwait. Patients presenting to our urology unit as an emergency during the hot summer months of April to October (average temperature 40-55 oC) were suspected of having hot weather-induced anuria secondary to hyperuricemia if they had a history of working in the sun for 6 to 8 hours per day and a progressive decrease in urine output to complete anuria. The diagnosis was confirmed by demonstration of elevated serum creatinine and uric acid, ultrasound findings of normal kidneys, ureters, and bladder (KUB) or mild to moderate hydronephrosis, but no features of chronic renal disease and little or no urine in the bladder. Management consisted of emergency cystoscopy, retrograde pyelogram, ureterorenoscopy (URS), and J stents followed by rehydration, oral allopurinol and urinary alkalinization. Twenty-nine patients (27 males and 2 females, mean age, 44.52A +/- 8.3 years) satisfied the diagnostic criteria for anuria secondary to hot weather-induced hyperuricaemia. Twentyeight (97%) patients worked outdoors on construction sites. Six patients had small radiopaque calculi on plain KUB X-ray. During cytoscopy and URS, uric acid crystals were encountered in all patients in the ureters and bladder. Recovery of renal function was complete in 23/29 (79.3%) patients, while 4/29 (13.8%) had partial recovery and 2/29 (6.9%) had no renal recovery. Hot weather-induced anuria secondary to hyperuricaemia is a complication of severe dehydration. Effective treatment will result in successful resolution of this rare but reversible cause of acute renal failure in about 80% of cases. Ancillary treatment methods like haemodialysis or the use of PCN can be safely avoided in the majority of the patients. However, rehydration alone may be insufficient treatment in these patients.

Rasburicase.

Rasburicase (recombinant urate oxidase) is a uricolytic agent which has been developed for the prevention and treatment of chemotherapy-induced hyperuricaemia at a dosage of 0.15 or 0.2 mg/kg/day in patients with haematological malignancies. Significant reductions from baseline in plasma uric acid levels were seen in 3 noncomparative and 1 randomised comparative trial of rasburicase in patients with, or at high risk of, hyperuricaemia. A multicentre, nonblind, randomised trial found that patients who received intravenous rasburicase 0.2 mg/kg/day experienced an average 2.6-fold less exposure to uric acid than those who received oral allopurinol 10 mg/kg/day. There was no evidence of renal insufficiency in 3 noncomparative trials which monitored creatinine levels to assess renal function during chemotherapy and rasburicase treatment. Rasburicase was generally well tolerated in clinical trials, with skin rashes reported in approximately equals 2% of patients. Bronchospasm, nausea and vomiting, and haemolysis occurred less frequently. In all cases the patients had also received chemotherapy prior to the adverse event.

Influence of dose and age on the response of the allopurinol test for ornithine carbamoyltransferase deficiency in control infants.

Measurement of urinary orotidine and orotic acid after an oral allopurinol challenge is an important diagnostic test for ornithine carbamoyltransferase deficiency that is sometimes used in infants (< 1 year of age), although there is little information on normal test results in this age group. We found higher orotidine excretion in normal infants than in older children given the test, whereas orotate excretion was similar in both groups. The increased orotidine excretion appears to be due to the use in the infants of higher allopurinol doses per kilogram of body weight than in the children. The normalized-dose dependency of the orotidine response extends even to adult age. Thus, dose-normalized responses should be used in the test and there is no need for careful age-matching of the controls.

Allopurinol: intravenous use for prevention and treatment of hyperuricemia.

To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.

The Role of Allopurinol and Deferoxamine in Preventing Pressure Ulcers in Pigs

Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the antifree radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for antifree radical agents in the reduction of pressure-induced injury. (Plast. Reconstr. Surg. 105: 1408, 2000.)

The role of allopurinol and deferoxamine in preventing pressure ulcers in pigs.

Ischemia and reperfusion may be important in the pathogenesis of pressure ulcers. On the basis of this hypothesis, the effects of intermittent pressure and the anti-free radical agents allopurinol and deferoxamine were studied in a pig model in which a pressure of 150 mmHg was applied intermittently to the scapulae. Cutaneous blood flow, transcutaneous oxygen tension, skin and muscle damage, and muscle levels of adenosine triphosphate were quantified. A control group of pigs (n = 6) was untreated, the allopurinol group (n = 6) received oral allopurinol beginning 2 days before the experiment, and the deferoxamine group (n = 6) received an intramuscular injection of deferoxamine 2 hours before the experiment. Pressure (150 mmHg) was applied to the scapulae for 210 minutes, and it was relieved for 30 minutes. This 4-hour cycle was repeated continuously for 48 hours, and it resulted in pressure injuries in all animals. Allopurinol and deferoxamine improved cutaneous blood flow and tissue oxygenation, but only deferoxamine could significantly reduce cutaneous and skeletal muscle necrosis (p < 0.001). This study suggests a future role for anti-free radical agents in the reduction of pressure-induced injury.

Pretreatment with allopurinol diminishes pancreatography-induced pancreatitis in a canine model

Background: The role of oxygen-derived free radicals in the pathogenesis of pancreatitis has been supported by data from previous studies using animal models. This study was conducted to determine whether prophylaxis with the xanthine oxidase inhibitor allopurinol would decrease the incidence and severity of pancreatography-induced pancreatitis in a canine model. Methods: Thirty-two dogs were randomized to receive either placebo or oral allopurinol 1 hour before the procedure. A laparotomy and duodenotomy were performed and a pancreatogram was obtained. Postoperatively, pancreatic enzymes were drawn for 5 days. The animals were then euthanized, and the pancreas was weighed and evaluated histologically. Results: The histologic incidence of pancreatitis was significantly reduced in the allopurinol pretreatment group (6.7%) as compared with the placebo group (41.2%, p < 0.01). A significant decrease in postoperative serum amylase levels among dogs pretreated with allopurinol was also noted. A similar trend was observed in lipase levels. The pancreas weight index was decreased in the allopurinol pretreatment group as well (control = 0.00246 vs. allopurinol = 0.00195, p < 0.02). Conclusions: Pretreatment with oral allopurinol decreases the incidence of pancreatography-induced pancreatitis. These results support the role of xanthine oxidase inhibitors in the prevention of endoscopic retrograde cholangiopancreatography–induced pancreatitis. (Gastrointest Endosc 1998;48:180-3.)

Oxygen free radicals and contrast nephropathy

Ionic, high-osmolality contrast medium causes nephrotoxicity associated with increased intrarenal adenosine production. To test the hypothesis that oxygen free radicals (produced during intrarenal adenosine catabolism to xanthine) should be implicated in the pathogenesis of ionic, high-osmolality contrast medium nephrotoxicity in humans and to determine whether magnesium protects the kidney from oxygen free radical injury following contrast, 39 patients with mild renal dysfunction were divided into low (LoMg++) and normal (NlMg++) magnesium states and randomized to precoronary angiography oral allopurinol (a xanthine oxidase inhibitor) or placebo. Creatinine clearance and urinary xanthine excretion were measured before and after angiography. Forty-eight hours after contrast medium exposure, placebo- treated LoMg++ and NlMg++ patients had 61%+/-5% and 67%+/-6% increases in urinary xanthine excretion, respectively; however, placebo-treated LoMg++ patients had a greater (79%+/-9% v 35%+/-6%; P < 0.01) decrease in creatinine clearance than placebo-treated NlMg++ patients. Allopurinol-treated LoMg++ and NlMg++ patients had no significant change in urinary xanthine excretion, but did have 40%+/-7% and 33%+/- 5% decreases, respectively, in creatinine clearance 48 hours after contrast medium exposure. There was no difference in renal dysfunctional response among placebo-treated NlMg++ patients or allopurinol-treated LoMg++ or NlMg++ patients. These data suggest (1) that oxygen free radicals contribute to ionic, high-osmolality contrast medium nephrotoxicity in hypomagnesemic patients with mild renal disease and (2) that magnesium attenuates the nephrotoxicity mediated by oxygen free radicals. (Am J Kidney Dis 1998 Jul;32(1):64-71)

Use of allopurinol for maintenance of remission in dogs with leishmaniasis.

Current treatments for infected dogs with leishmaniasis do not always provide long-term control of the disease and clinical relapses are common. In this study, the usefulness of long-term allopurinol administration in the maintenance of clinical remission in canine leishmaniasis was evaluated. Fifteen dogs with natural leishmania infection were subjected to an initial treatment based on the simultaneous administration of meglumine antimoniate (100 mg/kg/day) and allopurinol (30 mg/kg/day). Once clinical remission was achieved, a maintenance treatment with allopurinol (20 mg/kg/day) administered for one week a month was instituted. Results were compared with those of a retrospective control group comprising 15 infected dogs which only followed the induction treatment. Relapses occurred in 86 per cent of control dogs within 14 months of discontinuing treatment. In contrast, those dogs on intermittent oral allopurinol administration were successfully maintained in clinical remission for a follow-up period of 10 to 44 months. In this latter group, specific antibody titres decreased or were unchanged, no side effects directly attributable to allopurinol were seen and treatment was well accepted by the owners. It is concluded that long-term intermittent administration of allopurinol is an effective way of maintaining clinical remission in dogs with leishmaniasis.

Oxygen Free Radicals Contribute to Postburn Cardiac Cell Membrane Dysfunction

This study evaluated the contribution of O2free radicals to changes in cardiac function after burn injury. Full-thickness scald burns comprising 42% of the total body surface area were produced in rats. Mean arterial pressure, heart rate, pH, cardiac transmembrane potential (Ling Gerard electrode, Em), myocardial ATP, creatine phosphate (CP), glucose 6-phosphate, and lactate were measured enzymatically 24 hr postburn in four groups: Group 1, sham burn controls,N= 12; Group 2, untreated burn injury,N= 14; Group 3,N= 10, burn injury resuscitated with Ringer's lactate (Parkland formula); Group 4, burns pretreated with oral allopurinol (10 mg/kg) for 5 days before burn injury,N= 11.In vitrocardiac contractile function was assessed 24 hr after burn injury in additional animals (N= 8) from each of the four experimental groups. Untreated burn injury caused hypotension, bradycardia, depolarization of the cardiac cell membrane (Em fell from 78.5 ± 0.4 to 66.8 ± 0.4,P< 0.05), and left ventricular contractile depression despite no significant fall in cardiac ATP content. In contrast, cardiac tissue CP fell and myocardial tissue lactate rose. Allopurinol pretreatment oblated burn-induced hypotension, bradycardia, and cardiac cell membrane depolarization and improved cardiac contractile function despite no fluid resuscitation from burn injury. In contrast, aggressive fluid resuscitation from burn injury (Group 3) repolarized cardiac cell membrane but did not reverse burn-induced cardiac contractile deficits. These data suggest that xanthine oxidase-mediated free radical production contributes, in part, to postburn alterations in cardiac function.

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.

1007 New trends in the treatment of liver metastases—regional cytostatic and cytokinotherapy

The concept of regional infusion or perfusion therapy of liver malignancies has been known for many years but has never gained wide acceptance—mainly due to lack of prospective randomized trials. Recently one randomized study has identified a significantly prolonged survival for patients subjected to temporary hepatic artery occlusion followed by intraportal 5-fluorouracil and oral allopurinol compared to a no treatment group. One “phase I” study has shown that isolated regional perfusion of the liver with hyperthermia and cytostatic drugs is feasible. An ongoing phase I study with a similar design plus TNF-α is under way. Preliminary results show an effect on sarcomas and melanomas. More prospective studies evaluating regional therapy are warranted.