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Pyrazinamide induced hyperuricemia in patients taking anti-tuberculous therapy
Abstract
To record the effect of pyrazinamide on uric acid in patients of tuberculosis.
Descriptive and observational study.
Chandka Medical College Hospital, Larkana from February 2000 to January 2003.
All patients receiving anti-tuberculosis drugs with pyrazinamide were included. Serum uric acid levels were monitored at weeks 0, 2, 8 and 12 of therapy. Serum creatinine was done at weeks 0, 8 and 12.
Results were reported on 216 patients. Mean uric acid and creatinine levels at the start of therapy, i.e., week '0' were 5.07 -/+ 0.57 mg/dl and 0.87 -/+ 0.11 mg/dl respectively. The results show significant increase in uric acid levels from week '0' to week '2', at the end of week '8', the levels remained elevated and there was no statistical significant difference from that at week '2'. The uric acid levels reduced at week '12' after pyrazinamide was stopped and the difference was significant. Despite that renal function steadily improved with the treatment of tuberculosis to the extent that comparable pre-treatment values were obtained at the end of treatment.
Anti-tuberculous therapy with pyrazinamide affects the uric acid levels early. This change is reversible after the withdrawal of the agent.
... A daily dose of 300 mg of PZA leads to an 80% reduction in renal uric acid clearance [3]. It has been documented that between 56% and 86% of patients on PZA develop hyperuricemia [20][21][22]. Consistent with previous studies, patients who were taking PZA in our study had significantly higher serum uric acid levels within the initial 2 months of treatment (mean, 9.6 mg/dL versus 5.9 mg/dL; P < 0.000) than patients not on PZA. ...
... It is worth noting that PZA-induced hyperuricemia is transient. The serum uric acid levels are known to decline after the discontinuation of PZA [22]. Our research corroborated this, as we observed that serum uric acid levels declined after PZA discontinuation among individuals who were on PZA and had hyperuricemia. ...
Background
Hyperuricemia is common during tuberculosis (TB) treatment, especially in association with pyrazinamide (PZA). This study investigated the relationship between major adverse cardiovascular events (MACEs) and hyperuricemia during TB treatment.
Methods
We conducted a single-center retrospective cohort study. From January 2010 through June 2017, we assessed all consecutive TB patients at Chonnam National University Hospital in South Korea. Hyperuricemia was defined as serum uric acid levels exceeding 7.0 mg/dL (men) and 6.0 mg/dL (women).
Results
Of the 1,143 patients included, PZA was administered to 1,081 (94.6%), and hyperuricemia was detected in 941 (82.3%). Eight patients experienced MACEs. Multivariate analysis using logistic regression indicated that prior ischemic heart disease was associated with MACE development (OR,14.087; 95% CI,3.304–60.061; P < 0.000), while hyperuricemia was not (OR, 1.505; 95% CI, 0.184–12.299; P = 0.703). For patients without drug-resistant TB, the absence of hyperuricemia was associated with higher mortality (OR, 2.609; 95% CI, 1.066–6.389; P = 0.036), whereas hyperuricemia was associated with less worse outcomes (OR,0.316; 95% CI,0.173–0.576; P < 0.000).
Conclusions
Although most patients treated with PZA developed hyperuricemia, it was not associated with MACE development. Hyperuricemia during TB treatment was associated with better outcomes, possibly due to consistent adherence to TB treatment.
... In our case, the patient had polyarthralgia with unbearable pain while walking and standing. Polyarthralgia occurred more frequently in pyrazinamide-based regimens, consistent with data from previous reports [16]. Arthralgia secondary to pyrazinamide is caused by hyperuricemia due to the competitive inhibition of xanthine oxidase by POA, a hydrolyzed product) which correlated closely with plasma pyrazinamide concentration. ...
Pyrazinamide Induced polyarthralgia is common but myalgia is an uncommon adverse drug reaction. Understanding a case with estimated peak plasma concentration correlation is very rarely performed. We describe a case of a 45-year-old female patient with pulmonary tuberculosis who developed polyarthralgia and myalgia with the standard dose of pyrazinamide in a fixed-dose antitubercular regimen. She had an estimated peak plasma concentration of 48.2 μg/ml which was in the upper limit of the normal range of the proposed therapeutic range for pyrazinamide. She had increased levels of serum uric acid and creatine kinase. Resolution of polyarthralgia was observed within 14 days of pyrazinamide dechallenge. However, the resolution of myalgia was delayed.
... Pyrazinamide (pyrazine-2-carboxamide) is a well-known antituberculosis drug, and it was previously reported that pyrazinamide induces hyperuricemia as a side effect in clinical use. 17,18 URAT1 mediates the exchange of urate for several organic anions, inorganic anions, and monocarboxylic acids such as 2-pyrazinoic acid. 4 After taking pyrazinamide, it is presumed that pyrazinamide is converted into pyrazinoic acid, and 5-hydroxypyrazinoic acid in the body. ...
The purpose of this study was to create novel urate under-excretion animal models using pyrazinamide and to evaluate whether dihydropyridine calcium channel blockers (CCBs) have uricosuric effects in vivo.
Adult male ICR mice were treated with pyrazinamide, vehicle (DMSO), or tap water. Thirty minutes later, pyrazinamide-treated mice were given benzbromarone, losartan, nilvadipine, nitrendipine, nifedipine or azelnidipine. Six hours after the second administration, urine (by urinary bladder puncture) and plasma were collected to measure uric acid and creatinine levels, and fractional excretion of uric acid (FEUA) and creatinine clearance (Ccr) were calculated and evaluated. There was no significant difference in the levels of plasma uric acid, plasma creatinine, Ccr, urinary N-acetyl-β-d-glucosaminidase (NAG) and urinary NAG-creatinine ratio between water, DMSO, and pyrazinamide-treated mice. But the FEUA of pyrazinamide-treated mice was significantly lower than water mice. The FEUA was significantly higher in mice taking the dihydropyridine CCBs (nilvadipine, nitrendipine, nifedipine, and high-dose azelnidipine) than in pyrazinamide-treated mice. There was no significant difference in Ccr.
Thus, a novel animal model created with PZA administration was useful as a urate under-excretion animal model that was probably URAT1-mediated, and the uricosuric effect of dihydropyridine CCBs was confirmed in vivo.
Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.
Hyperuricemia is common during tuberculosis (TB) treatment, mainly pyrazinamide (PZA). This study investigated the relationship between major adverse cardiovascular events (MACEs) and hyperuricemia during TB treatment.
From January 2010–June 2017, this study retrospectively evaluated TB patients treated in a South Korean tertiary hospital. Hyperuricemia was defined as elevated serum uric acid >7.0 mg/dL (men) and >6.0 mg/dL (women).
A total of 1,143 patients were enrolled in this study, and PZA was used in 1081 (94.6%), while hyperuricemia was detected in 941 (84.4%). Eight patients developed MACEs. Multivariate analysis using logistic regression revealed that previous ischemic heart disease was associated with MACE development (OR, 19.071; 95% CI, 4.648–78.249; P < 0.000), while hyperuricemia was not (OR, 1.505; 95% CI, 0.184–12.299; P = 0.703). Among patients without drug-resistant TB, no hyperuricemia was associated with increased deaths (OR, 2.923; 95% CI, 1.119–7.638; P = 0.029), while hyperuricemia was associated with increased favorable outcomes (OR, 3.366; 95% CI, 1.787–6.340; P < 0.001).
In conclusions, most patients who received PZA had hyperuricemia; however, it was not associated with MACE development. Hyperuricemia during TB treatment was associated with better outcomes, possibly due to good compliance with TB treatment.
Objectives: To assess the effect of glibenclamide and metformin on serum uric acid level in patients with type 2 diabetes.
Study design: Case control study.
Subjects and Methods: This study was conducted from March 2009 to January 2010. Fasting blood sugar and serum uric acid level were measured in patients suffering from type2 diabetes mellitus who were referred to Al-Wafa Diabetic Center in Mosul City. Group 1:32 patients on glibenclamide therapy, group 2:42 patients on metformin therapy and group 3:42 patients on combination therapy, group 4:32 patients on restricted diet, and 23 apparently healthy volunteers, were taken as a control group.
Results: The study showed a significant increase in the serum uric acid level of the diabetic patients as compared with the control. Glibenclamide and/or metformin showed no significant difference in the serum uric acid level in patients with type2 diabetes mellitus.
Conclusion: Glibenclamide and/or metformin had no significant effect on serum uric acid level in patients with type2 diabetes mellitus.
The review analyzes publications devoted to the frequency of renal adverse reactions during tuberculosis chemotherapy. The most significant pathophysiological mechanisms causing development of drug-induced nephrotoxicity are presented. The article describes the specific features of nephrotoxic effect of aminoglycosides, capreomycin, rifampicin, pyrazinamide, fluoroquinolones, and linezolid. The authors concluded that it was necessary to perform clinical and laboratory monitoring of kidney function for the timely detection of nephrotoxic reactions.
Aim:
This study aimed to investigate the clinical features and risk factors of gout attacks during anti-tuberculosis (TB) treatment in South Korea.
Method:
We investigated the clinical characteristics of 49 patients who suffered from gout attacks while taking anti-TB medications. Among them, 25 TB patients having newly developed gout attacks without prior history of gout were set to the gout group. Seventy-five age- and sex-matched TB patients without gout attacks during anti-TB therapy were randomly selected as the control group. The demographics, clinical features, and laboratory findings between the two groups were compared to establish risk factors of gout attack during anti-TB treatment.
Results:
The gout patients had a mean age of 67.7 ± 13.2 years and 39 patients (79.6%) were male. Approximately half of the patients experienced an attack within 2 months of treatment initiation. The attacks typically involved lower extremity joints (87.8%). The serum uric acid (SUA) levels were significantly elevated at 2 and 6 months after starting anti-TB medication compared with those at baseline. In the case-control study, the factors associated with gout attack were higher body mass index (BMI), higher pre-treatment SUA levels, dyslipidemia, and reduced renal function. In the multivariate model, higher BMI, chronic kidney disease (CKD), and pre-treatment hyperuricemia (SUA ≥ 6.8 mg/dL) were independent risk factors of gout attack while taking anti-TB medication.
Conclusions:
Patients with high BMI, CKD, and pre-treatment hyperuricemia are at a higher risk of gout attack during TB treatment.
The first anti-tuberculosis drug streptomycin was created in 1945. Before this time the therapy for TB was based on diet and fresh air. Un-controlled using of antibiotics provoked development of drug resistant strains, so the history of urogenital TB can be divided into three periods: before antibiotics (AB), AB era and novo-days – MDR period. Mtb is drug-resistance, which may be: mono – Mtb are resistant to one of any antituberculous drugs; poly – Mtb are resistant to more than one of any drugs used for the treatment of the disease, excluding isoniazid and rifampicin simultaneously; multi-drug resistance (MDR) – Mtb are resistant to at least isoniazid and rifampicin, with or without resistance to other first-line drugs. Extensively drug-resistant TB (XDR-TB) refers to resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin and kanamycin). Persistence excluded an old specific for UGTB symptom – aseptic pyuria. Mtb hurts tissue and fades in persistence – for example, because the patient takes drugs for “UTI”. Damaged tissues are rapidly colonized by E.Coli – and now co-morbidity of UGTB and non-specific UTI enriches 75 %.
WHO notes that five drugs are currently regarded as essential in the management of TB – isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol. Thioacetaxone is also widely used to supplement isoniazid in many developing countries because of its low cost. Other drugs, including para-aminosalicylic acid (PAS), kanamycin, cycloserine, capreomycin, viomycin and ethionamide, can be of value in treating patients with MDR, but, in general, are more expensive and more toxic.
Possibilities of chemotherapy may be limited by different side effects. Usually a patient with TB has at least one more disease, and co-morbidity demands to take into account potential drug interaction, which may lead both to increasing and decreasing therapeutic effect.
We administered pyrazinamide (PZA) and probenecid (PB) --two well-known modulators of urate transport via the proximal tubules - to evaluate their impact on urate transport through the peritoneal membrane and to clarify mechanisms affecting peritoneal transport.
A continuous ambulatory peritoneal dialysis (CAPD) unit in 2nd Hospital of IKA (Social Services Institute), Greece.
In 20 stable CAPD patients, on the study day, a 4-hour, 2-L, 1.36% glucose exchange was performed (control exchange). Pyrazinamide 3 g was given orally and another identical exchange was performed (study exchange). The same protocol was repeated with 2 g PB. KtN, peritoneal clearances of urea, creatinine, and urate for each exchange, and mass transfer area coefficients (MTAC) for the three solutes and their dialysate-to-plasma concentration (D/P) ratios were used to estimate peritoneal transport.
Administration of PZA resulted in decreased clearances and MTAC values for the three solutes. The D/P ratio decreased significantly only for urate, indicating a more intense influence of PZA on urate. After PB administration, clearances of urea, creatinine, and urate were increased. MTAC and DIP ratio increased significantly only for urate (p < 0.05), demonstrating an action similar to that exerted on renal tubules.
These findings provide evidence that unrestricted diffusion is not the only transport mechanism in the case of urate, and demonstrate the existence of an active mechanism in peritoneal urate transport with a reabsorptive and, probably, a secretive component that resembles that of renal tubule urate transport. Attention should be given in the case of CAPD patients undergoing antituberculous (PZA) treatment: it might have a negative impact on urea, creatinine, and urate peritoneal transport rates.
Some anti-tuberculosis chemotherapeutic agents have been established as causing hyperuricaemia. Hyperuricaemia in turn causes renal damage. This study therefore aims at establishing the effect of anti-tuberculosis drugs-induced hyperuricaemia on renal function of the patients. Fifty patients with newly diagnosed pulmonary tuberculosis with mean age of 36.8 years (SD 13.69) consisting of 14 females and 17 males were longitudinally studied each for 6 months to determine the effect of drug-induced hyperuricaemia on their renal function. The Biochemical indices determined included serum urate level, serum creatinine level, and creatinine clearance of newly diagnosed patient with tuberculosis, before and during treatment with anti-tuberculosis therapy. Serum urate level revealed that 16 (51.6%) and 15 (48.4%) of the patients were hyperuricaemic at the end of the first and second months of anti-tuberculosis therapy. There was no significant difference in the mean serum creatinine level of the control group 96 micromol/L when compared with both the pre-treat value 89 micromol/L (P > 0.25) as well as the value at the end of the sixth month of treatment 91 micromol/L (P > 0.40). However, there was a statistically significant difference in the mean creatinine clearance of the control group 102 ml/min/1.73 m2 when compared with the patient's mean pre-treatment value (89 ml/min/1.73 m2) P < 0.05. Also the mean creatinine clearance increased to (103 ml/min/1.73 m2) by the end of the 6th month of treatment, a value that is statistically significant when compared with the pretreatment value of (89 ml/min/1.73 m2) P < 0.05. We submit as follows: that pulmonary tuberculosis as a disease with significant impairment of renal function; despite the associated drug-induced hyperuricaemia recorded during the treatment, renal function steadily improved with the treatment of pulmonary tuberculosis to the extent that comparable values with control was obtained at the end of treatment. We conclude therefore that drug-induced hyperuricaemia associated with treatment of pulmonary tuberculosis has no detectable negative effect on renal function of the patient.
This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children.
A total of 114 children ages 6 months to 15 years (4.5 +/- 3.4 years) with diagnosed pulmonary tuberculosis from 1985 to 1995 entered the trial. A 2-month regimen of isoniazid, rifampin and pyrazinamide, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to all children. Clinical adverse effects specifically investigated were gastrointestinal disturbances, rash, signs of hepatotoxicity and arthralgias. Laboratory toxicity data (number of leukocytes, erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and serum uric acid) were collected before treatment and 1, 3 and 5 months after the beginning of chemotherapy.
Clinical adverse effects were mild in all cases. Three children (2.6%) had fever and 5 (4.4%) had gastrointestinal disturbances. Aspartate aminotransferase and alanine aminotransferase mean values showed no differences along time and no patients had clinical signs of hepatotoxicity. Only 11 children (19.6%) showed a slight increase in alanine aminotransferase (< 194 units/l). Serum uric acid increased in 92.2% of the children compared with pretreatment values. This increase remained within the normal range in all but 9.8% of patients. There was a significant increase in uric acid mean concentrations after 1 month of therapy (from 3.7 +/- 0.7 mg/dl to 5.7 +/- 1.6 mg/dl, P < 0.05), which fell again (4.0 +/- 1.1) 1 month after pyrazinamide was stopped. There were no signs of gout or arthralgias. In no case was the treatment interrupted.
The addition of pyrazinamide in chemotherapy for pulmonary tuberculosis in children was found to be safe. The slight increase in uric acid concentration during its administration had no recognized adverse consequences.
Autosomal dominant polycystic kidney disease (ADPKD) might affect urate homeostasis and clearance. Renal tubular urate transport was studied by means of probenecid (PB) and pyrazinamide (PZA) tests in individuals with ADPKD and normal renal function as well as various degrees of renal failure (49 patients). Comparisons were made between polycystic and chronic glomerulonephritic kidney (CGNK), as well as with controls (men with normal renal function). Patients with ADPKD and normal renal function showed plasma urate levels within normal range and normal renal urate handling. In contrast higher plasma urate levels comparing to controls were found in patients with CGNK and normal renal function. During the evolution of renal failure ADPKD patients showed lower urate plasma levels and higher renal clearance as well as, fractional urate excretion, comparing to CGNK patients with the same degree of renal failure. In conclusion patients with ADPKD and normal renal function have normal urate handling and plasma urate levels within normal range. With increasing severity of disease and during evolution of renal failure CGNK patients showed higher urate plasma levels and lower clearances comparing to ADPKD patients. When renal disease becomes more advanced there was no difference in renal urate handling between ADPKD and CGNK patients.
Veterans General Hospital-Taipei, Taiwan.
To assess the efficacy and safety of a fixed-dose combination (FDC) of Rifater (RFT)/Rifinah (RFN) in the treatment of newly diagnosed smear-positive pulmonary tuberculosis.
Patients were randomly assigned to two 6-month short-course chemotherapy regimens. One group of patients was treated with FDCs and another was given the four component drugs (INH, RMP, EMB and PZA) as separate formulations.
The 105 patients enrolled in the study were divided into two treatment groups. Fifty-one patients who had completed treatment without interruption, 26 in the FDC group and 25 in the separate regimen, were eligible for analysis at the end of 2 years. Among the patients with a drug susceptibility test result available, four in the FDC group had bacilli resistant to pyrazinamide. In the separate regimen group, two patients had bacilli resistant to ethambutol and six had bacilli resistant to pyrazinamide. The two regimens were of similar effectiveness with regard to sputum conversion, compliance and radiological improvement. No patient with FDC treatment developed gastointestinal symptoms, visual disturbance or peripheral neuropathy (P < 0.05). However, FDC treatment resulted in drug-induced fever in one patient. One patient (3.8%) in the FDC group relapsed 5 months after completing treatment.
This study suggests that the two regimens had similar effectiveness in the treatment of smear-positive pulmonary tuberculosis. However, the fewer adverse drug events among those patients treated with the FDC regimen suggests that it has a better safety profile.