Allopurinol test

Diagnosis is based upon hyperammonaemia, which is detectable either spontaneously or after the oral intake of proteins - or, most obviously, following intravenous infusion of amino acids. The respective amino acids are increased in the serum prior to the disturbed metabolic reaction. Argininosuccinate is only detectable in the urine. A striking feature in these patients is their thin, brittle hair. With defective ornithine transcarbamylase, there is an increase in orotic acid, uridine and uric acid in the urine, while the respective citrulline concentration is decreased. The determination of OTC activity in liver tissue verifies the diagnosis and facilitates a genomic analysis. (172) The allopurinol test can be applied for the identification of heterozygosity (or the mild form of OTC deficiency). The liver shows steatosis, portal inflammation and portal fibrosis. 

Protein load A protein load is done when a diagnosis is unclear or for heterozygote detection in OTC deficiencies. After one has determined a daily profile for pre- and postprandial ammonia and the amino acids in a self chosen diet, the protein content should be estimated per meal. The patient should not be in a catabolic but steady state for at least 4 days. For women, the test should be avoided around the period of menstruation. The protein load is, in contrast to the allopurinol test, also useful for assessing protein tolerance. False negatives have been described in conjunction with OTC heterozygote testing skewed toward a predominance of wild-type OTC. 

Hepatotoxicity A few cases of reversible clinical hepatotoxicity have occurred in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase levels have been observed. If anorexia, weight loss or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. Perform periodic liver function tests during early stages of therapy. 

Fasted Cebus monkeys (Cebus albifrons) of either sex weighing 3.0 to 5.0 kg are used. On the morning of the experiment, the animals receive 20 ml/kg drinking water by gavage, followed by oral administration of the test compound. Allopurinol and probenecid are used as control compounds. Control animals receive water only. The animals are placed in individual metabolism cages and the spontaneously voided urine is collected after 2, 6, and 24 h. After 2 and 6 h, an additional 4 ml/kg water is given by gavage. From a cubital vein blood is withdrawn prior to the experiment and 2, 6 and 24 h after application. 

The urinary caffeine test is not based on assays of specific substrates and products of NAT2 ( including other metabolism pathways involving at least xanthine-oxidases), and is affected by diet habits, xanthine-oxidase inhibitors such as allopurinol (Fuchs 1999), or other drugs (Klebovitch 1995). NAT activities are affected by anti-inflammatory drugs. Of note, acetominophen is an inhibitor of NAT2 in vivo (Rothen 1998). 

A 66-year-old man had taken trovafloxacin 100 mg/day for 4 weeks for refractory chronic sinusitis (10). For several years he had also taken allopurinol, doxepin, hydrochlorothiazide, losartan, metoprolol, and nabumetone. He developed nausea, vomiting, malaise, and abdominal distension. His white cell count was 8000 x 10 /1 with 16% eosinophils his serum aspartate transaminase was 537 IU/1, alanine transaminase 841 IU/1, direct bilirubin 17 pmol/l total bilirubin 27 pmol/l, alkaline phosphatase 111 IU/1 blood urea nitrogen 5 pmol/l and creatinine 190 pmol/l. Tests for hepatitis A, B, and C were negative. A biopsy of the liver showed centrilobular and focal periportal necrosis and eosinophilic infiltration the sinusoids were dilated and contained lymphocytes and eosinophils many hepatocytes were undergoing mitosis. After withdrawal of trovafloxacin and treatment with prednisone, his hepatic and renal function returned to normal, and the eosinophilia gradually resolved. 

The sensitivity of this test is increased by increasing the flux in the pyrimidine biosynthetic pathway. The enhanced flux is accomplished by allopurinol, which by way of oxypurinol ribonucleotide inhibits the formation of final product uridine 5 -phosphate (UMP) in the pyrimidine biosynthesis (Chapter 27). 

When allopurinol is used for prophylaxis, start with a low dose (1 00 mg/day) after the acute attack has settled, and adjust the dose every 4 weeks until the goal is reached (serum urate of <6 mg/dL). Give colchicine (0.5 mg twice daily) during the first 3 months of therapy, and stop allopurinol if rash develops or liver function tests become abnormal. 

Long chain hydrocarbons and fatty acids are best known as constitutents of waxes and lipophilic compounds. Some representatives of this natural product group show high antiprotozoal activity but mostly combined with a high levels of toxicity to mammalian cells. One example is traws-aconitic acid (2) that was used in combination with sodium stibogluconate, allopurinol, or pentamidine for experimental visceral leishmaniasis to determine synergistic effects [34]. When these three drugs (50, 15, 8 mM/kg/day, respectively) were used with trans-aconitic acid (5 mM/kg/day) the parasite load in BALB/c mice was inhibited by 100, 88, and 100%, respectively. At tested concentration trans-aconitic acid itself showed an inhibition of 59.2 %. 

In 21 healthy subjects, allopurinol 300 mg daily for 8 days altered the levels of urinary caffeine metabolites of a single 200-mg dose of caffeine. In particular, the metabolic ratio used to determine whether people are fast or slow acetylators was substantially changed. Thus, allopurinol may invalidate the results of phenotyping with the urinary caffeine test. In addition, the caffeine metabolite ratio used to express the activity of the cytochrome P450 isoenzyme CYP1A2 was not stable when allopurinol was used. This interaction is of relevance to research rather than clinical practice. 

Evidence appears to be limited to a single case report and the studies in healthy subjects. The interaction only appears to be of moderate importance. Nevertheless, it would seem prudent to check for any signs of theophylline adverse effects (headache, nausea, tremor) during concurrent use, particularly in situations where the metabolism of the theophylline may already be reduced (other drugs or diseases), or where high doses of allopurinol are used. For mention that allopurinol may invalidate the results of phenotyping tests using caffeine, see Caffeine + Allopurinol ,... 

The investigation was conducted with the voluntary cooperation of 10 normal males (mean age, 33 years) who were placed on an essentially purine-free diet during the study. Renal handling of uric acid was examined by means of the pyrazinamide (PZA) and probenecid (PB) tests, performed in three uricemia states normouricemia 3.6 to 6.4 mg/dl), allopurinol-induced hypouricemia (under 3.5 mg/dl), and hyperuricemia after oral administration of RNA monosodium salt (over 6.5 mg/dl). 

Since allopurinol is converted rapidly in man to oxipurinol (60 per cent of the total pyrazolopyrimidines) and allopurinol-1-ribonucleoside (10 per cent), we tested these compounds for their antileishmanial effects. Oxipurinol was relatively ineffective but HPPR was very active against all three Leishmania sp. The promasti-gotes of braziliensis and donovani are about 100-fold more sensitive to HPPR than to HPP. For mexicana, the toxicity of HPPR and HPP are approximately the same. 

Fig. 1 shows the urinary excretion of allopurinol and its metabolites in subject 1(oxipurinol-7-riboside not determined). The administration of hypoxanthine as well as the other purines tested(table 2) caused a marked decrease of the excretion of allopurinol-1-riboside. This is most likely due to the increased formation of hypoxanthine (table 1) which can competitively inhibit the conversion of allopurinol by PNP or HGPRT, allopurinol-1-riboside... 

Pig. 1 demonstrates the effects of all these tested substances on pyrimidine biosynthesis in cultures frcm Neurospora crassa. Allopurinol and oxipurinol have marked inhibitory effects. Allopurinol-1-ribonuclecside inhibits pyrimidine biosynthesis in the order of 55 to 6o percent in concentrations from 10 5 to 10 during our incubation period of 45 minutes. Allopurinol-1-ribonucleotide shows influences comparable to those of allopurinol. The inhibitory effect of oxipirinol-7-ribonucleoside is in straight parallelity to the effect of oxipurinol, whereas oxipurinol-7-ribonucleotide begins with its marked effect (8o - 90 percent inhibition) at concentrations between 10 to 10 M. 

Arranz JA, Riudor E, Rodes M, et al. Optimization of allopurinol challenge sample purification, protein intake control, and the use of orotidine response as a discriminative variable improve performance of the test for diagnosing ornithine carbamoyl-transferase deficiency. Clinical Chemistry 1999 45(7) 995-1001... 

Elevated concentrations of orotic acid and uracil may be found in the urine of heterozygote carriers for urea cycle disorders, most commonly ornithine carbamoyltransferase (OCT) deficiency. This is due to the increased flux through the pyrimidine pathway which occurs, especially where the relevant enzymes are expressed only in liver tissue, as is the case when urea cycle enzymes are defective. A protein load was used previously to stress this route and the elevation in orotic acid excretion used as a diagnostic marker. However, the test frequently failed to detect known carriers. The al-lopurinol loading test (measurement of the increment in urinary orotic acid and orotidine in three separate 8 hour urine collections over the 24 hours following a 300 mg allopurinol tablet) is the most reliable test so far for carrier detection for such disorders [17]. 

Fairbanks LD, Sebesta I, Simmonds HA, Leonard JV. The allopurinol loading test for evaluation of carriers for ornithine carbamoyltransferase deficiency. Clin Chim Acta 1994 224 45-54... 

In a retrospective study of inflammatory bowel disease patients treated with co-prescription of thiopurines and allopurinol, 20 of 25 patients with hepatotoxicity tolerated combination treatment and their liver function tests were normalised [75 ]. 

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