别嘌醇致严重肝损害

1例83岁女性，因发现血尿酸升高服用别嘌醇100mg／d治疗。2周后出现恶心，乏力，黄疸。实验室检查示：AIJT945U／L，AST1521U／L，TBil259．3μmol／L，DBil137．8μmol／L。甲、乙、丙、戊型肝炎血清学检测为阴性，考虑肝损害与别嘌醇有关，停用别嘌醇，并给予复方甘草酸苷等治疗，1个月后症状逐渐改善，肝功能恢复正常。     

Effect of allopurinol on neutrophil superoxide production, chemotaxis, or degranulation

Recent studies examining the effect of allopurinol on bacterial killing by leukocytes [Tubaro et al., Biochem. Pharmac. 29, 3018 (1980); Tritsch and Neiswander, Life Sci. 32, 1359 (1983)] have been interpreted by those authors as proof that xanthine oxidase is the major superoxide producing enzyme in activated leukocytes. To test the assertion that xanthine oxidase is involved in the production of superoxide by activated human neutrophils, the xanthine oxidase content of neutrophils was measured, and the effect of allopurinol on neutrophil functions, including superoxide production, was studied. Neutrophils were found to contain a level of xanthine oxidase insufficient to account for the flux of superoxide associated with neutrophil activation. Allopurinol did not inhibit superoxide production induced by opsonized zymosan, phorbol myristic acetate, or formylmethionylleucylphenylalanine. Furthermore, neither chemotaxis nor degranulation was affected by allopurinol. Allopurinol was also found ineffective in blocking superoxide-mediated carrageenan-induced foot edema in the rat. These studies are interpreted as evidence that xanthine oxidase is not a major superoxide-generating system in activated neutrophils as has been suggested by others.     

Clinical pharmacokinetics of allopurinol. 3. Allopurinol/oxipurinol pharmacokinetics following administration of a controlled release allopurinol preparation

Studies of the Clinical Pharmacokinetics of Allopurinol/3rd Communication: Allopurinol/oxipurinol bioavailability and pharmacokinetics following the administration of a controlled release allopurinol formulation. Regarding the results of our studies on the localization of the absorption of allopurinol and the kinetic behavior of allopurinol/oxipurinol following multiple administration the bioavailability and kinetic properties of the drug delivered from controlled release tablets were studied in healthy volunteers. Allopurinol controlled release tablets (Sigapurol CR), containing 200 mg of the drug characterized by rapid absorption and 100 mg characterized by pH-dependent delivery, were identified as a formulation with advantages pharmacokinetic properties.     

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

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.     

Metabolic studies of purine metabolism in the pig during the oral administration of guanine and allopurinol

(1) Allopurinol and guanine, both separately and together, were fed over varying periods to diiferent groups of large white/landrace cross pigs. Although allantoin and not uric acid represented the end point of purine metabolism in this species, total urinary purine excretion approximated that of a man of equivalent weight on a purine-free diet. No abnormality in the handling of guanine was found, up to 50 per cent of an exogenous load being absorbed, metabolized and rapidly excreted in the urine as allantoin.(2) Allopurinol alone, in increasing dosage, was capable of total saturation of the enzyme xanthine oxidase at high dosage levels, but produced only slight reduction in total purine excretion at any dosage. Allopurinol riboside was the principal urinary metabolite, increasing with increasing allopurinol dosage, even at dosages above enzyme saturation levels, when oxipurinol excretion had levelled off. Xanthine replaced allantoin as the principal urinary purine metabolite during allopurinol therapy but, despite saturation of the xanthine oxidase, allantoin excretion did not fall to zero and hypoxanthine excretion was not increased. Allopurinol also had an effect on pyrimidine excretion in the pig as indicated by increased urinary orotic acid and orotidine levels, an effect not eliminated when guanine was given together with allopurinol.(3) Combined therapy with allopurinol and guanine produced three additional effects to those when allopurinol was given alone, (a) Allopurinol reduced substantially the considerable increase in total purine excretion resulting from guanine alone, a finding difficult to explain on the basis of feedback inhibition of de novo purine synthesis. (b) Urinary hypoxanthine excretion increased and at the same time allopurinol riboside excretion decreased substantially, suggesting competitive inhibition of allopurinol riboside formation as mediated by the enzyme purine nucleoside phosphorylase. (c) Xanthine was again the principal urinary metabolite, but at levels in excess of its solubility, so that coprecipitation with oxipurinol occurred in the renal tubules causing a considerable degree of renal dysfunction. Crystals were not found in any other tissue, including muscle, so that no evidence of guanine gout was noted, nor any other abnormality of purine metabolism which could be related to leg weakness in pigs.     

The effect of allopurinol on the steady-state pharmacokinetics of indomethacin.

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).     

Clinical pharmacokinetics of allopurinol

Allopurinol is a widely used drug in the management of hyperuricaemia. It is rapidly and extensively absorbed following oral administration. The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. Up to 80% of allopurinol is recovered in the urine within 24 hours, mainly in the form of oxypurinol. Allopurinol is negligibly absorbed after rectal administration. In animals, allopurinol is found in highest concentrations in vascular tissue, blood, liver, intestine and heart. It is negligibly bound to plasma proteins. Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. Allopurinol inhibits the metabolism of 6-mercaptopurine and azathioprine, which require dosage modifications. The interaction of allopurinol with oral anticoagulants and phenytoin has not been clearly established in clinical practice.     

A simple method for quantification of allopurinol and oxipurinol in human serum by high-performance liquid chromatography with UV-detection

OBJECTIVES: Allopurinol is a uric acid lowering drug used in the treatment of gout and the prevention of tumor lysis syndrome. Allopurinol and its active metabolite oxipurinol inhibit xanthine oxidase, which forms uric acid from xanthine and hypoxanthine. Therapeutic drug monitoring is an important option for evaluation and optimization of allopurinol treatment in case of renal impairment, interaction with uricosuric drugs or to verify patient adherence. In this study we developed and validated a simple quantitative assay using reverse phased high-performance liquid chromatography (HPLC) with UV-detection as a method for quantification of allopurinol and oxipurinol in human serum in the presence of different frequently used drugs. METHODS: The HPLC-UV method uses a mobile phase consisting of sodium acetate (0.02 M; pH 4.5), at a flow rate of 1.0 mL/min. Allopurinol and oxipurinol are detected by UV-absorption at 254 nm with a retention time of 9.9 min for oxipurinol and 12.3 min for allopurinol. Aciclovir is used as internal standard. RESULTS: Validation showed for allopurinol lower and upper limits of quantification of 0.5 and 10mg/L and for oxipurinol 1 and 40 mg/L, respectively. The assay was linear over the concentration range of 0.5-10mg/L (allopurinol) and 1-40 mg/L (oxipurinol). Intra- and inter-day precision showed coefficients of variation <15% over the complete concentration range; accuracy was within 5% for allopurinol and oxipurinol. Endogenous purine-like compounds were separated from allopurinol, oxipurinol and aciclovir with a resolution factor >1.5. Exogenous purine-like compounds and co-medication frequently used by gout patients did not hinder the analysis due to the dichloromethane washing step or to low UV-absorpion at 253 nm. Serum levels of 66 patients prescribed allopurinol 300 mg/day were determined using this HPLC-UV method. Measured serum allopurinol and oxipurinol concentrations in clinical practice showed large variability with a range of <0.5-4.3 mg/L for allopurinol and <1.0-39.2 mg/L for oxipurinol, respectively. CONCLUSION: We developed an easy-to-operate and validated HPLC-UV method for the quantification of allopurinol and oxipurinol in human serum. This method was proven to be valid for samples of gout patients frequently using concomitant medications.     

Stimulation of healing by free radical scavengers of ischemia-induced acute gastric mucosal injury in the rat.

Allopurinol and dimethyl sulfoxide (DMSO; 1 mL of 1, 2, or 5% by gavage daily) were used to examine the influence of scavenging oxygen-derived free radicals on the healing of reserpine- (5 mg/kg, intraperitoneal) and 5-hydroxytryptamine- (50 mg/kg, intraperitoneal) induced acute ischemic injury of the rat gastric mucosa. Allopurinol and DMSO demonstrated a time- but not dose-dependent power to stimulate healing of this injury. The magnitude of injury produced by reserpine or 5-hydroxytryptamine (serotonin) followed by gavage with allopurinol or DMSO was significantly (p < 0.01) less after day 4 than that after day 3 of this gavage, and the magnitude after day 3 was itself significantly (reserpine, p < 0.001; 5-hydroxytryptamine, p < 0.01) less than that after day 2 of the same gavage. The actions of allopurinol and DMSO were not associated with any significant influence on H+ output. These results suggest that oxygen-derived free radicals are detrimental to the integrity of the rat gastric mucosa and that scavenging them stimulates healing of the ischemia-induced injury of the mentioned mucosa.     

Allopurinol induced erythroderma

Allopurinol, a widely prescribed urate lowering agent is responsible for various adverse drug reactions, including erythroderma. A 45-year-old male patient was admitted with the complaints of fever, redness and scaling all over the body after 3-4 weeks of allopurinol treatment for asymptomatic hyperuricemia. Elevated liver enzymes were detected in his blood analysis. Skin biopsy was consistent with drug induced erythroderma. Allopurinol was stopped and steroids were started. Patient improved over a period of 2 weeks.KEY WORDS: Allopurinol, erythroderma, hyperuricemia     

The effect of allopurinol on the liver ultrastructure,reduced glutathione and lipid peroxide levels during liver ischemia in guinea pigs

1. The preventive effect of allopurinol on reduced glutathione and lipid peroxide levels of the liver and the accompanying ultrastructural changes during liver ischemia was investigated in guinea pigs.2. Liver glutathione levels decreased significantly while lipid peroxide levels increased slightly in the ischemic group.3. Allopurinol administered before ischemia resulted in a reverse significant increase in liver glutathione levels and a significant decrease in lipid peroxide levels indicating a protective effect upon cell membrane during ischemia.4. On the other hand, electron microscopic changes in the liver associated with ischemia could not be altered by allopurinol.     

Role of xanthine oxidase in dexamethasone-induced hypertension in rats

1. Glucocorticoid-induced hypertension (GC-HT) in the rat is associated with nitric oxide-redox imbalance. 2. We studied the role of xanthine oxidase (XO), which is implicated in the production of reactive oxygen species, in dexamethasone-induced hypertension (dex-HT). 3. Thirty male Sprague-Dawley rats were divided randomly into four treatment groups: saline, dexamethasone (dex), allopurinol plus saline, and allopurinol plus dex. 4. Systolic blood pressures (SBP) and bodyweights were recorded each alternate day. Thymus weight was used as a marker of glucocorticoid activity, and serum urate to assess XO inhibition. 5. Dex increased SBP (110 +/- 2-126 +/- 3 mmHg; P < 0.001) and decreased thymus (P < 0.001) and bodyweights (P" < 0.01). Allopurinol decreased serum urate from 76 +/- 5 to 30 +/- 3 micromol/L (P < 0.001) in saline and from 84 +/- 13 to 28 +/- 2 micromol/L in dex-treated (P < 0.01) groups. 6. Allopurinol did not prevent dex-HT. This, together with our previous findings that allopurinol failed to prevent adrenocorticotrophic hormone induced hypertension, suggests that XO activity is not a major determinant of GC-HT in the rat.     

Allopurinol influences aminophenazone elimination

The authors observed an interaction between allopurinol and both theophylline and warfarin in 2 patients. To determine the possible effect of allopurinol on hepatic oxidative metabolism a [14C]-aminophenazone (aminopyrine) breath test was performed before and during treatment with allopurinol 100mg daily in 5 patients with hyperuricaemia. Allopurinol prolonged the [14CO2]-aminophenazone half-life from 72 +/- 13 to 104 +/- 16 minutes (mean +/- SEM, p less than 0.05). It is possible that allopurinol may produce clinically significant drug interactions through an inhibitory effect not only on xanthine oxidase metabolism but also on oxidative metabolism.     

Observations and effects of educational consults on allopurinol prescribing

Allopurinol has been used in the management of hyperuricemic states for several years. Despite its efficacy for these indications, recent concerns have been raised regarding the unnecessary morbidity and mortality occasionally associated with its inappropriate use. In an effort to assess the utilization of allopurinol, a concurrent drug utilization review was undertaken. Fifty patients who were prescribed allopurinol were entered into the study and underwent health record review and patient interview, to determine appropriateness of therapy and the need for educational intervention. A number of inconsistencies with regard to established guidelines were identified. As well, 11 of 50 patients (22%) required intervention because of either lack of indication or excessive dose. Fifty-five percent of the educational interventions, performed by the pharmacist, were accepted as written. The current utilization of allopurinol at our facility differs substantially from guidelines developed for optimal utilization of allopurinol. Further, a pharmacy based intervention program can improve prescribing practices of allopurinol.     

Allopurinol for the treatment of aggressive behaviour in patients with dementia

Aggressive behaviour is commonly observed in patients with dementia, and current pharmacological treatments are still deficient in terms of efficacy and tolerability. Allopurinol is an inhibitor of the enzyme xanthine oxidase, with previously suggested anti-aggressive effects. After successful treatment of aggression in two patients, we performed a case-series study with allopurinol 300 mg a day orally for 6 weeks (increasing 300 mg every 2 weeks if the response was less than 50%) in six patients with dementia associated with prominent aggressive behaviour who failed to respond to two previous treatment strategies. Five patients were considerably responsive to allopurinol (four with 300 mg within 2 weeks and one with 600 mg), apparently without side-effects, which is in accordance with its well-established safety and tolerability profile. The observed therapeutic effect of allopurinol might be due to the inhibition of the enzyme xanthine oxidase, possibly decreasing production of oxygen-free radicals or promoting the accumulation of purines. Controlled studies are warranted to confirm these preliminary observations.     

Allopurinol-induced palisaded neutrophilic and granulomatous dermatitis

We describe a 64-year-old man with past chronic myeloid leukemia. Palisading neutrophilic granulomatous dermatitis of the hands was diagnosed and related to recent allopurinol intake. Allopurinol is known to rarely cause granulomatous reactions, but this appears to be the first case of palisading neutrophilic granulomatous dermatitis induction. Possible mechanisms include immune complex deposition, an immune response directed against the metabolites of allopurinol, or allopurinol hypersensitivity exclusively localized to the skin.     

Purine and pyrimidine excretion in psoriasis: A comparison with healthy controls during allopurinol therapy

1 Urinary purine excretion has been investigated in two healthy controls and two patients with psoriasis, one a hyperuricaemic, one a normouricaemic. No difference was detected between the patients and controls. Therapy with allopurinol effectively lowered blood and urinary uric acid levels and produced a deficit in total urinary oxypurine excretion in both controls and patients with psoriasis. The concomitant increase in xanthine excretion was greater than the increase in hypoxanthine excretion and xanthine/hypoxanthine ratios (average 0.70 and 1.0 prior to therapy) were increased by allopurinol to an average of 3.0 and 3.8 respectively in the two groups. Allopurinol also reduced the excretion of 8-hydroxy-7-methyl guanine but no effect on the excretion levels of other minor purine bases was noted.

2 Allopurinol was metabolized similarly by both patients and controls, 84% of the administered allopurinol being accounted for as urinary metabolites. 74% of the drug in the urine was excreted as oxipurinol, 26% as unchanged allopurinol plus allopurinol riboside, the remainder being oxipurinol riboside.

3 Pseudouridine excretion in 25 healthy controls was 86.5 ± 17.8 mg/24 hours. Pseudouridine excretion was not excessive in the patients with psoriasis and was not altered by allopurinol therapy.

4 No abnormality or difference in purine or pyrimidine excretion in either patient was detected prior to or during therapy which could be related to the epidermal lesion.

     

别嘌醇研究的新进展

别嘌醇为次黄嘌呤的异构体。临床上主要用于治疗痛风 ,随着氧自由基学说研究的不断拓展 ,发现别嘌醇能减少缺血再灌注损伤中氧自由基的生成而达到抗氧化的作用 ,故许多研究者把别嘌醇用于治疗心血管、脑、肺、胃肠和肝等部位缺血再灌注的损害 ;另外 ,它还具有扩管作用为治疗慢性心衰提供了新的药物 ;别嘌醇降低尿酸合成的作用还可用于治疗非细菌性前列腺炎和肿瘤溶解综合征     

Theobromine metabolism in man

The effects of allopurinol on the plasma clearance and metabolism of theobromine have been investigated under multiple-dosing conditions. Allopurinol had no effect on the clearance of theobromine, indicating that the elimination of this compound is dependent on enzyme systems other than xanthine oxidase, presumably the hepatic mixed-function oxidases. The excretion of 3-methylxanthine, 6-amino-5-(N-methylformylamino)-1-methyluracil, and unchanged theobromine were similarly unaffected by the allopurinol treatment. Although allopurinol abolished the formation of 7-methyluric acid (7MU) and increased the excretion of 7-methylxanthine (7MX), the metabolic clearance to (7MX + 7MU) was not significantly different with and without allopurinol. It is proposed that the secondary biotransformation of 7MX to 7MU is mediated by xanthine oxidase.     

Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction

Allopurinol, an inhibitor of xanthine oxidase, was shown to improve the regional ventricular function after coronary artery occlusion and reperfusion in animal models. The effects of oral administration of allopurinol on a transient increase in free radical generation after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction (AMI) and on their clinical outcomes were examined. Thirty-eight AMI patients undergoing primary PTCA were randomly assigned to control (group 1, n = 20) and allopurinol treatment groups (group 2, n = 18). Allopurinol (400 mg) was administered orally just after the admission (approximately 60 min before reperfusion). Free radical production was assessed by successive measurement of urinary excretion of 8-epi-prostaglandin F(2alpha) (PGF(2alpha)) after PTCA. Urinary 8-epi-PGF(2alpha) excretion was increased by twofold at 60-90 min after PTCA compared with the baseline value in group 1. This increase was completely inhibited in group 2. Plasma allopurinol concentration was 1,146 +/- 55 ng/ml in group 2 when reperfusion was achieved. Slow flow in the recanalized coronary artery after PTCA occurred less frequently in group 2 than in group 1. Cardiac index determined just after reperfusion and left ventricular ejection fraction at 6 months after PTCA were both significantly greater in group 2 than in group 1 although pulmonary capillary wedge pressure was similar in the two groups. In conclusion, allopurinol pretreatment is effective in inhibiting generation of oxygen-derived radicals during reperfusion therapy and the recovery of left ventricular function in humans.