Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyperuricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrazinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazinamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.
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PMID:Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia. 110 19

Pyrazinamide is an antituberculosis drug synthesized in the 1950s and formerly used only as salvage therapy. Recent developments have elevated it to a central role in tuberculosis chemotherapy as the essential addition to isoniazid and rifampin which makes it possible to successfully complete treatment in six months. This is accomplished with no increase in hepatotoxicity. The only substantial side effect of this drug given at the dosage and for the duration used in these six-month regimens is a polyarthralgia which is only bothersome and not sufficient to warrant interruption of therapy. More rarely, acute gout is produced. The early history and pharmacology of this now first line antituberculosis drug are reviewed herein.
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PMID:The role of pyrazinamide in tuberculosis chemotherapy. 304 29

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levels. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean +/- SD) 3,707 +/- 443 micrograms/min/1.73 m2 in controls and 2,215 +/- 738 micrograms/min/1.73 m2 in patients with gout (P less than 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 +/- 202 micrograms/min/1.73 m2) than in controls (922 +/- 136 micrograms/min/1.73 m2; P less than 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal handling of uric acid in gout: impaired tubular transport of urate not dependent on serum urate levels. 378 14

A 35-year-old patient with severe gout and mild renal insufficiency presented very low urinary urate excretion. Volume expansion induced by fludrocortisone combined or not with a uricosuric drug (Benzbromarone) was unable to significantly increase his urate excretion. A combined Probenecid (PB) and Pyrazinamide (PZA) test was performed. These drugs being considered to affect renal tubular reabsorption or secretion. No significant modification of uric acid fractional excretion (FE.uric acid) was observed after PB and PZA. When the same test was performed after the administration of Triglycyl-lysine vasopressine (TGLV), a potent V1 receptor stimulator, we observed a three fold increase in FE.uric acid after PB intake (from 6 to 18%) followed by a decrease after PZA (from 18 to 5.6%). When TGLV was administered alone their was no significant modification of uric acid fractional excretion. We propose that TGLV decrease proximal tubular urate reabsorption that could only be detected when postsecretory reabsorption is blocked by an uricosuric drug.
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PMID:Restoration of the uricosuric effect of probenecid after triglycylvasopressine administration in a gouty patient. 979 74

Pyrazinamide is one of the first line drugs used for the treatment of tuberculosis. Hepatotoxicity and hyperuricaemia are important and common untoward effects seen after administration of pyrazinamide. The drug inhibits elimination of urates resulting in hyperuricaemia, the presenting features of which are arthralgia, arthritis or even gout. A-case of bilateral leg cramps due to hyperuricaemia following pyrazinamide therapy is reported here.
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PMID:Pyrazinamide induced hyperuricaemia presenting as severe bilateral leg cramps. 1823 82

Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit longstanding paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug.
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PMID:Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives. 2608 40