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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All Drug Records" href="/books/n/livertox/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-livertox-lrg.png" alt="Cover of LiverTox" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK547856_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK547856_dtls__"><div>Bethesda (MD): <a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>; 2012-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/livertox/">Drug Records</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/livertox/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/livertox/Pyrantel/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/livertox/PyrimidineAnalogues/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK547856_"><span class="title" itemprop="name">Pyrazinamide</span></h1><p class="small">Last Update: <span itemprop="dateModified">December 20, 2020</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="Pyrazinamide.OVERVIEW"><h2 id="_Pyrazinamide_OVERVIEW_">OVERVIEW</h2><div id="Pyrazinamide.Introduction"><h3>Introduction</h3><p>Pyrazinamide is a first line antituberculosis medication, but is used only in combination with other antituberculosis medications such as isoniazid or rifampin. Pyrazinamide is associated with transient and asymptomatic elevations in serum aminotransferase levels and is a well known cause of clinically apparent, acute liver injury that can be severe and even fatal.</p></div><div id="Pyrazinamide.Background"><h3>Background</h3><p>Pyrazinamide (pir" a zin' a mide) is a synthetic pyrazine analogue of nicotinamide that has potent activity against mycobacterium tuberculosis. Its mechanism of action is unknown, but it appears to be both bactericidal and bacteriostatic. Pyrazinamide is considered an adjunctive therapy of tuberculosis and is always used in combination with another antimycobacterial agent such as isoniazid or rifampin. Pyrazinamide was developed and introduced into clinical use in 1956 and continues to be commonly used in therapy of active tuberculosis, but not for latent tuberculosis. It is available as tablets of 500 mg in several generic forms. A fixed combination of pyrazinamide (300 mg) with isoniazid (50 mg) and rifampin (120 mg) is also available under the brand name of Rifater. The recommended dosage of pyrazinamide is 15 to 30 mg/kg daily in one or more doses, but not in excess of 2 grams daily. Pyrazinamide can also be given in a twice weekly regimen of 50 to 70 mg/kg per dose allowing for observed administration and better compliance. Typically, pyrazinamide and ethambutol are given only for the first two months of 3- or 4-drug combination therapy of active tuberculosis, with continuation of isoniazid and rifampin for at least six months. Common side effects of pyrazinamide are fatigue, anorexia, gastrointestinal upset, arthralgias, rash and photosensitivity.</p><p>The management of tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy and management of its side effects. Optimal regimens of therapy for tuberculosis are complex and change frequently. Regularly updated recommendations on use of drugs for tuberculosis, including indications, contraindications, warnings, dosages and monitoring recommendations are available at the Centers for Disease Control and Prevention website: <a href="https://www.cdc.gov/tb/publications/guidelines/Treatment.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cdc.gov/tb/publications/guidelines/Treatment.htm</a>.</p></div><div id="Pyrazinamide.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>Combination therapy for tuberculosis using pyrazinamide is commonly associated with transient and asymptomatic elevations in the serum aminotransferase levels. These elevations are usually less than five times the upper limit of the normal range. Because pyrazinamide is used only in combination with other antituberculosis medications, its contributions to serum enzyme elevations is not completely clear, but it is frequently incriminated in transient serum enzyme elevations. Clinically apparent liver disease with symptoms and jaundice also occur with pyrazinamide therapy and it is often considered the culprit in causing liver injury in the face of double or triple antituberculosis therapy (Case 1). Indeed, the use of a short, 2 month course of combination therapy with rifampin and pyrazinamide for latent tuberculosis was abandoned because of the frequency of severe liver injury with this regimen that was occasionally fatal (Case 2). The onset of injury due to pyrazinamide is generally after 4 to 8 weeks and occasionally becomes apparent only after the pyrazinamide is stopped. The pattern of liver enzyme elevations is typically hepatocellular and the clinical syndrome resembles acute viral hepatitis, much like isoniazid hepatotoxicity. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon as are autoantibody formation. Liver biopsy demonstrates changes typical of acute hepatitis with portal and lobular inflammation, hepatocellular necrosis and variable degrees of cholestasis.</p><p><a class="def" href="/books/n/livertox/glossary/def-item/glossary.likelihood-score/">Likelihood score</a>: A (well known cause of clinically apparent liver injury).</p></div><div id="Pyrazinamide.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The mechanism of hepatic injury by pyrazinamide is not known, but the drug is extensively metabolized by the liver and injury may be caused by a metabolic intermediate. <a class="def" href="/books/n/livertox/glossary/def-item/glossary.hepatotoxicity/">Hepatotoxicity</a> from pyrazinamide appears to be more frequent with higher doses, suggesting a direct toxic effect, at least in part.</p></div><div id="Pyrazinamide.Outcome_and_Management"><h3>Outcome and Management</h3><p>The appearance of liver injury with symptoms and serum aminotransferase levels above 3 times the ULN or any elevation in aminotransferase levels above 5 times the ULN should prompt withdrawal of pyrazinamide. Many cases of pyrazinamide hepatotoxicity are severe and prolonged, and fatal instances have occurred. Pyrazinamide has not been linked to chronic hepatitis or vanishing bile duct syndrome. There is no cross reactivity of the hepatic injury with other currently available antituberculosis agents.</p><p>After drug induced liver injury from combination antituberculosis therapy, reinitiation of therapy, if necessary, can be achieved best by sequential and incremental introduction of the agents (generally isoniazid and rifampicin), but that restarting several drugs at the standard dosage should be avoided particularly starting with pyrazinamide in full doses.</p><p>[First line medications used in the therapy of tuberculosis in the United States include isoniazid, pyrazinamide, ethambutol and the rifamycins including rifampin, rifabutin and rifapentine. Second line medications include streptomycin, capreomycin, cycloserine, ethionamide, bedaquiline, pretomanid, fluoroquinolones such as levofloxacin, and moxifloxacin, aminoglycosides such as amikacin, and para-aminosalicylic acid (PAS).]</p><p>Drug Class: <a href="/books/n/livertox/AntituberculosisAgen/">Antituberculosis Agents</a></p><p>Other Drugs in the Class: <a href="/books/n/livertox/Bedaquiline/">Bedaquiline</a>, <a href="/books/n/livertox/Capreomycin/">Capreomycin</a>, <a href="/books/n/livertox/Cycloserine/">Cycloserine</a>, <a href="/books/n/livertox/Ethambutol/">Ethambutol</a>, <a href="/books/n/livertox/Ethionamide/">Ethionamide</a>, <a href="/books/n/livertox/Isoniazid/">Isoniazid</a>, <a href="/books/n/livertox/Pretomanid/">Pretomanid</a>, <a href="/books/n/livertox/Rifabutin/">Rifabutin</a>, <a href="/books/n/livertox/Rifampin/">Rifampin</a>, <a href="/books/n/livertox/Rifapentine/">Rifapentine</a>, <a href="/books/n/livertox/Streptomycin/">Streptomycin</a></p></div></div><div id="Pyrazinamide.CASE_REPORTS"><h2 id="_Pyrazinamide_CASE_REPORTS_">CASE REPORTS</h2><div id="Pyrazinamide.Case_1_Acute_liver_failure"><h3>Case 1. Acute liver failure due to combination antituberculosis therapy.(<a class="bk_pop" href="#Pyrazinamide.REF.1">1</a>)</h3><p>A 60 year old woman with pulmonary tuberculosis was treated with isoniazid (300 mg daily), rifampin (600 mg daily) and pyrazinamide (1.5 gram daily) and improved rapidly, but was found to have jaundice with bilirubin 3.5 mg/dL, <a class="def" href="/books/n/livertox/glossary/def-item/glossary.aspartate-aminotransferase-ast-/">AST</a> 538 U/L and alkaline phosphatase 148 U/L six weeks after starting therapy (Table). Her liver tests were reported to be normal before treatment. She had no history of liver disease, alcohol abuse, or risk factors for viral hepatitis. Isoniazid and rifampin were stopped but pyrazinamide continued. One week later, she was admitted to a local hospital for worsening hepatic function. She was mildly encephalopathic and the prothrombin time was prolonged. She was transferred to a liver transplant center. She was in stage 3 hepatic coma and required artificial ventilation. Pyrazinamide was stopped and ofloxacin, ethambutol and streptomycin started. Blood tests for hepatitis A, B and C were negative. She underwent successful liver transplantation 5 days after transfer and 3 weeks after onset of symptoms. She recovered uneventfully and was discharged 16 days after transplant on cyclosporine and prednisone. She was maintained on ethambutol, streptomycin and ofloxacin for tuberculosis, and sputum cultures remained negative.</p><div id="Pyrazinamide.Key_Points"><h4>Key Points</h4><div id="Pyrazinamide.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547856/table/Pyrazinamide.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Pyrazinamide.Tc_lrgtbl__"><table><tbody><tr><th id="hd_b_Pyrazinamide.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Medication:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isoniazid, rifampin, pyrazinamide</td></tr><tr><th id="hd_b_Pyrazinamide.Tc_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pattern:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hepatocellular (R=10.1)</td></tr><tr><th id="hd_b_Pyrazinamide.Tc_1_1_3_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Severity:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5+ (acute liver failure requiring liver transplantation)</td></tr><tr><th id="hd_b_Pyrazinamide.Tc_1_1_4_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.latency/">Latency</a>:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 weeks</td></tr><tr><th id="hd_b_Pyrazinamide.Tc_1_1_5_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recovery:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No</td></tr><tr><th id="hd_b_Pyrazinamide.Tc_1_1_6_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other medications:</th><td headers="hd_b_Pyrazinamide.Tc_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None mentioned</td></tr></tbody></table></div></div></div><div id="Pyrazinamide.Laboratory_Values"><h4>Laboratory Values</h4><div id="Pyrazinamide.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547856/table/Pyrazinamide.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Pyrazinamide.Td_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_Pyrazinamide.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Time After<br />Starting</th><th id="hd_h_Pyrazinamide.Td_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Time After<br />Stopping</th><th id="hd_h_Pyrazinamide.Td_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.aspartate-aminotransferase-ast-/">AST</a>*<br />(U/L)</th><th id="hd_h_Pyrazinamide.Td_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Protime*<br />(Seconds)</th><th id="hd_h_Pyrazinamide.Td_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.bilirubin/">Bilirubin</a>*<br />(mg/dL)</th><th id="hd_h_Pyrazinamide.Td_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</th></tr></thead><tbody><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pre</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Normal</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Normal</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Normal</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1 hd_h_Pyrazinamide.Td_1_1_1_2 hd_h_Pyrazinamide.Td_1_1_1_3 hd_h_Pyrazinamide.Td_1_1_1_4 hd_h_Pyrazinamide.Td_1_1_1_5 hd_h_Pyrazinamide.Td_1_1_1_6" colspan="6" scope="col" rowspan="1" style="text-align:center;vertical-align:top;">Isoniazid, rifampin and pyrazinamide started for active tuberculosis</td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 weeks</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-7 days</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">548</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.5</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7 weeks</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1640</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.4</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.4</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Admission</td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 days</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1100</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">32.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transfer</td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8 weeks</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7 days</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">350</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">41.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3 hd_h_Pyrazinamide.Td_1_1_1_4 hd_h_Pyrazinamide.Td_1_1_1_5 hd_h_Pyrazinamide.Td_1_1_1_6" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">Emergency liver transplantation</td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 months</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 month</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.0</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Discharge</td></tr><tr><td headers="hd_h_Pyrazinamide.Td_1_1_1_1 hd_h_Pyrazinamide.Td_1_1_1_2" colspan="2" scope="row" rowspan="1" style="text-align:center;vertical-align:top;">
|
||
<b>Normal Values</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><40</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><14</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><1.2</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Td_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>* </dt><dd><div id="Pyrazinamide.TF.d.1"><p class="no_margin">Some values estimated from Figure 2.</p></div></dd></dl></div></div></div></div><div id="Pyrazinamide.Comment"><h4>Comment</h4><p>This case demonstrates an acute viral hepatitis-like presentation of drug induced liver injury. While the case represents “definite” drug induced liver disease, it is impossible to be definitive about which agent was responsible. Isoniazid is a likely culprit, but pyrazinamide and (to a lesser degree) rifampin are also capable of causing acute severe liver injury, and continuing pyrazinamide in the face of an acute hepatitis-like syndrome was not advisable. Despite stopping isoniazid and rifampin therapy promptly, the patient progressed to hepatic failure and required liver transplantation within 3 weeks of initial presentation. Risk factors for antituberculosis therapy associated hepatitis included age and combination therapy. Risk factors for severe outcome were age and sex.</p></div></div><div id="Pyrazinamide.Case_2_Acute_liver_failure"><h3>Case 2. Acute liver failure complicating two month course of rifampin and pyrazinamide.(<a class="bk_pop" href="#Pyrazinamide.REF.2">2</a>)</h3><p>A 68 year old man with a history of a positive tuberculin test requested antituberculosis therapy so as to obviate the need for annual chest X-rays required by his employer. He had a history of alcoholic liver disease, but had stopped drinking 5 years previously. He also had gout, hypertension and type 2 diabetes for which he took aspirin, colchicine, ibuprofen, lisinopril and metformin on a chronic basis. He was started on rifampin (600 mg daily) and pyrazinamide (2 grams daily) and monitored monthly. He tolerated therapy without symptoms and liver tests were normal at baseline and at one month (Table). Immediately after stopping therapy, however, he began to feel ill and presented to the emergency room with jaundice, lethargy and confusion. On examination, he was icteric and had asterixis. Laboratory tests showed marked elevations in serum aminotransferase levels and bilirubin of 16.7 mg/dL. The prothrombin time was prolonged [INR 6.0]; and there were elevations in serum creatinine (5.4 mg/dL), ammonia (181 μmol/L: normal <35) and lactate (13.2 mmol/L, normal <2.2). Abdominal ultrasound showed ascites, but no evidence of biliary obstruction. He was given supportive care but developed worsening coma, respiratory and renal failure and died 3 days after admission.</p><div id="Pyrazinamide.Key_Points_1"><h4>Key Points</h4><div id="Pyrazinamide.Te" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547856/table/Pyrazinamide.Te/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Pyrazinamide.Te_lrgtbl__"><table><tbody><tr><th id="hd_b_Pyrazinamide.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Medication:</th><td headers="hd_b_Pyrazinamide.Te_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pyrazinamide, rifampin</td></tr><tr><th id="hd_b_Pyrazinamide.Te_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pattern:</th><td headers="hd_b_Pyrazinamide.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hepatocellular (R=10)</td></tr><tr><th id="hd_b_Pyrazinamide.Te_1_1_3_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Severity:</th><td headers="hd_b_Pyrazinamide.Te_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5+ (death)</td></tr><tr><th id="hd_b_Pyrazinamide.Te_1_1_4_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.latency/">Latency</a>:</th><td headers="hd_b_Pyrazinamide.Te_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 months</td></tr><tr><th id="hd_b_Pyrazinamide.Te_1_1_5_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recovery:</th><td headers="hd_b_Pyrazinamide.Te_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><th id="hd_b_Pyrazinamide.Te_1_1_6_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other medications:</th><td headers="hd_b_Pyrazinamide.Te_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Aspirin, colchicine, ibuprofen, lisinopril, metformin</td></tr></tbody></table></div></div></div><div id="Pyrazinamide.Laboratory_Values_1"><h4>Laboratory Values</h4><div id="Pyrazinamide.Tf" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547856/table/Pyrazinamide.Tf/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Pyrazinamide.Tf_lrgtbl__"><table><thead><tr><th id="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Time After<br />Starting</th><th id="hd_h_Pyrazinamide.Tf_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Time After<br />Stopping</th><th id="hd_h_Pyrazinamide.Tf_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.alanine-aminotransferase-alt-/">ALT</a><br />(U/L)</th><th id="hd_h_Pyrazinamide.Tf_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Alk P<br />(U/L)</th><th id="hd_h_Pyrazinamide.Tf_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.bilirubin/">Bilirubin</a><br />(mg/dL)</th><th id="hd_h_Pyrazinamide.Tf_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Other</th></tr></thead><tbody><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pre</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">66</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.5</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">INR=1.0</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3 hd_h_Pyrazinamide.Tf_1_1_1_4 hd_h_Pyrazinamide.Tf_1_1_1_5 hd_h_Pyrazinamide.Tf_1_1_1_6" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">Pyrazinamide and rifampin started</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 weeks</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">63</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.5</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8 weeks</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3 hd_h_Pyrazinamide.Tf_1_1_1_4 hd_h_Pyrazinamide.Tf_1_1_1_5 hd_h_Pyrazinamide.Tf_1_1_1_6" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">Pyrazinamide and rifampin stopped: asymptomatic</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 days</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">620</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">175</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">16.7</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">INR=6.0</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9 weeks</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 days</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1930</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">207</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19.2</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">INR=10.1</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8 days</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3 hd_h_Pyrazinamide.Tf_1_1_1_4 hd_h_Pyrazinamide.Tf_1_1_1_5 hd_h_Pyrazinamide.Tf_1_1_1_6" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">Death from multiorgan failure</td></tr><tr><td headers="hd_h_Pyrazinamide.Tf_1_1_1_1 hd_h_Pyrazinamide.Tf_1_1_1_2" colspan="2" scope="row" rowspan="1" style="text-align:center;vertical-align:top;">
|
||
<b>Normal Values</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><45</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><130</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><1.2</b>
|
||
</td><td headers="hd_h_Pyrazinamide.Tf_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></div><div id="Pyrazinamide.Comment_1"><h4>Comment</h4><p>The patient developed an abrupt onset of acute liver failure a few days after stopping an 8 week course of rifampin and pyrazinamide for latent tuberculosis. This combination is highly effective for latent tuberculosis, but has been associated with an unacceptably high rate of liver injury and cases of acute liver failure, for which reasons it is no longer recommended. Whether the injury was due to pyrazinamide or rifampin was unclear; there is likely an interaction that promotes the risk of injury. The risk of liver injury increases with age not just with isoniazid, but also with other antituberculosis medications and combinations. History of alcohol abuse and alcoholic liver injury are believed to also be risk factors for antituberculosis medication hepatotoxicity, but it has not been clearly defined. Because pyrazinamide inhibits the renal excretion of urates, it should be used with caution in patients with gout. This report does not mention testing for viral hepatitis or autopsy results; but the clinical history and course are entirely compatible with drug induced liver injury from antituberculosis medications.</p></div></div></div><div id="Pyrazinamide.PRODUCT_INFORMATION"><h2 id="_Pyrazinamide_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
|
||
<b>REPRESENTATIVE TRADE NAMES</b>
|
||
</p><p>Pyrazinamide – Generic, Tebrazid®</p><p>
|
||
<b>DRUG CLASS</b>
|
||
</p><p>Antituberculosis Agents</p><p>
|
||
<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=pyrazinamide" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
|
||
</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="Pyrazinamide.CHEMICAL_FORMULA_AND_STRUCT"><h2 id="_Pyrazinamide_CHEMICAL_FORMULA_AND_STRUCT_">CHEMICAL FORMULA AND STRUCTURE</h2><div id="Pyrazinamide.Tg" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547856/table/Pyrazinamide.Tg/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Pyrazinamide.Tg_lrgtbl__"><table><thead><tr><th id="hd_h_Pyrazinamide.Tg_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Pyrazinamide.Tg_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_Pyrazinamide.Tg_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Pyrazinamide.Tg_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Pyrazinamide.Tg_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pyrazinamide</td><td headers="hd_h_Pyrazinamide.Tg_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134971473" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">98-96-4</a>
|
||
</td><td headers="hd_h_Pyrazinamide.Tg_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C5-H5-N3-O</td><td headers="hd_h_Pyrazinamide.Tg_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134971473" title="View this structure in PubChem" class="img_link" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem"><img src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&sid=134971473" alt="image 134971473 in the ncbi pubchem database" /></a>
|
||
</td></tr></tbody></table></div></div></div><div id="Pyrazinamide.CITED_REFERENCES"><h2 id="_Pyrazinamide_CITED_REFERENCES_">CITED REFERENCES</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="Pyrazinamide.REF.1">Farrell FJ, Keeffe EB, Man KM, Imperial JC, Esquivel CO. Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. <span><span class="ref-journal">Dig Dis Sci. </span>1994;<span class="ref-vol">39</span>:2255–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7924752" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7924752</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="Pyrazinamide.REF.2">Medinger A. Death associated with rifampin and pyrazinamide 2-month treatment of latent Mycobacterium tuberculosis. <span><span class="ref-journal">Chest. </span>2002;<span class="ref-vol">121</span>:1710–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12006469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12006469</span></a>]</div></dd></dl></div><div id="Pyrazinamide.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Pyrazinamide_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 20 December 2020</p><p>Abbreviations: DRESS, drug rash with eosinophilia and systemic symptoms; HIV, human immunodeficiency virus; MAC, Mycobacterium avium complex; PAS, para-aminosalicylic acid.</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Pyrazinamide.REF.zimmerman.1999">Zimmerman HJ. Antituberculosis agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 611-21.<div><i>(Extensive review of hepatotoxicity of antituberculosis medications including pyrazinamide published in 1999).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.verma.2013">Verma S, Kaplowitz N. Hepatotoxicity of antituberculosis drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 483-504.<div><i>(Review of hepatotoxicity of antituberculosis drugs).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.gumbo.2018">Gumbo T. Chemotherapy of tuberculosis, mycobacterium avium complex disease and leprosy. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1067-86.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.aquinas.1964.181">Aquinas SM. Reactions to antituberculosis drugs among Chinese in Hong Kong. <span><span class="ref-journal">Tubercle. </span>1964;<span class="ref-vol">45</span>:181–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14227802" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14227802</span></a>]<div>
|
||
<i>(Among 389 patients treated with pyrazinamide and ethionamide for tuberculosis, side effects requiring discontinuation of therapy occurred in 4 [1%], including 3 with jaundice [all attributed to pyrazinamide], one of whom died).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ramakrishnan.1968.775">Ramakrishnan CV, Janardhanam B, Krishnamurthy DV, Stott H, Subbammal S, Tripathy SP. Toxicity of pyrazinamide, administered once weekly in high dosage, in tuberculous patients. <span><span class="ref-journal">Bull World Health Organ. </span>1968;<span class="ref-vol">39</span>:775–9.</span> [<a href="/pmc/articles/PMC2554433/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2554433</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/5306313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5306313</span></a>]<div>
|
||
<i>(Pilot study of once weekly pyrazinamide [70 mg/kg] with isoniazid and streptomycin for 12 months in 19 patients with tuberculosis, found minor elevations in ALT and AST during therapy usually in first two weeks [peak ALT 63 U/L], but no patient developed clinically apparent hepatitis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.simpson.1970.138">Simpson AJ, Mirza AM, Martin JF, O'Brien TF Jr. Hepatitis secondary to pyrazinamide toxicity: accompaniments of transient hypolipoproteinemia, acanthocytosis, and changes in stomach and small bowel. <span><span class="ref-journal">South Med J. </span>1970;<span class="ref-vol">63</span>:138–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5411920" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5411920</span></a>]<div>
|
||
<i>(34 year old developed jaundice 6 months after starting pyrazinamide and streptomycin for tuberculosis [bilirubin 26.4 mg/dL, AST 318 U/L, Alk P normal, protime 22.9 sec, cholesterol 68 mg/dL and acanthocytosis], resolving slowly over next 3 months).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.rossouw.1975.1">Rossouw JE, Saunders SJ. Hepatic complications of antituberculous therapy. <span><span class="ref-journal">Q J Med. </span>1975;<span class="ref-vol">44</span>:1–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/50605" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 50605</span></a>]<div>
|
||
<i>(Retrospective review identified 38 cases of hepatitis [~0.32%] due to antituberculosis therapy [Cape Town, SA], 16 due to PAS, 12 to PAS with isoniazid, 3 isoniazid alone, 1 each of others including ethambutol; rash and fever typical of PAS reactions, most within 90 days; 33 with jaundice).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.hong_kong_tuberculosis_treatment_servicesbritish_medical_research_council.1976.81">Hong Kong Tuberculosis Treatment services/British Medical Research Council. Adverse reactions to short-course regimens containing streptomycin, isoniazid, pyrazinamide and rifampicin in Hong Kong. <span><span class="ref-journal">Tubercle. </span>1976;<span class="ref-vol">57</span>:81–95.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/134476" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 134476</span></a>]<div>
|
||
<i>(Summary of 3 clinical trials of antituberculosis therapy [isoniazid, rifampin and pyrazinamide] from Hong Kong; hepatotoxicity in 6-11% of subjects, jaundice in 0.7%, no deaths, pyrazinamide implicated most frequently).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.girling.1978.13">Girling DJ. The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. <span><span class="ref-journal">Tubercle. </span>1978;<span class="ref-vol">59</span>:13–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/345572" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 345572</span></a>]<div>
|
||
<i>(History and review of hepatotoxicity of first line antituberculosis medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ellard.1978.628">Ellard GA, Mitchison DA, Girling DJ, Nunn AJ, Fox W. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. <span><span class="ref-journal">Am Rev Respir Dis. </span>1978;<span class="ref-vol">118</span>:628–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/707886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 707886</span></a>]<div>
|
||
<i>(Among 145 patients with active tuberculosis treated with isoniazid, pyrazinamide and streptomycin, there was no correlation of acetylator phenotype and ALT elevations; postulate that rapid acetylators also rapidly metabolize and excrete monoacetylhydrazine the first product of acetylation and purported hepatotoxin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.singapore_tuberculosis_servicebritish_medical_research_council.1979.579">Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. <span><span class="ref-journal">Am Rev Respir Dis. </span>1979;<span class="ref-vol">119</span>:579–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/375787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 375787</span></a>]<div>
|
||
<i>(Among 397 patients with active tuberculosis treated with combination regimens, 11 [3%] developed hepatitis with jaundice, all in first 3 months, all recovered, all on rifampin, 10 on pyrazinamide and 2 on isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.addington.1979.782">Addington WW. The side effects and interactions of antituberculosis drugs. <span><span class="ref-journal">Chest. </span>1979;<span class="ref-vol">76</span>(6) Suppl:782–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/510025" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 510025</span></a>]<div>
|
||
<i>(Review of side effects of antituberculosis medications states that isoniazid, rifampin and pyrazinamide are major causes of hepatotoxicity, but ethambutol rarely causes liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.zierski.1980.41">Zierski M, Bek E. Side-effects of drug regimens used in short-course chemotherapy for pulmonary tuberculosis. A controlled clinical study. <span><span class="ref-journal">Tubercle. </span>1980;<span class="ref-vol">61</span>:41–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6989067" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6989067</span></a>]<div>
|
||
<i>(Among 530 patients treated with 5 regimens for active tuberculosis and monitored monthly, 9% developed hepatic injury but usually without symptoms, ALT >250 U/L in 6 [1.1%], bilirubin rise in 7 [1.3%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.pretet.1980.307">Pretet S, Perdrizet S. <span><span class="ref-journal">Rev Fr Mal Respir. </span>1980;<span class="ref-vol">8</span>:307–30.</span> [Toxicity of pyrazinamide in antituberculous treatments] French. [<a href="https://pubmed.ncbi.nlm.nih.gov/6454227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6454227</span></a>]<div>
|
||
<i>(Review of large trials worldwide of antituberculosis therapy for rate of adverse drug reactions; overall hepatotoxicity occurred in 2.2% of 4,025 subjects treated with pyrazinamide containing regimens vs 0.5% of 2,368 without).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.british_thoracic_association.1981.141">British Thoracic Association. A controlled trial of six month chemotherapy in pulmonary tuberculosis. First report: results during chemotherapy. <span><span class="ref-journal">Br J Dis Chest. </span>1981;<span class="ref-vol">75</span>:141–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7023526" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7023526</span></a>]<div>
|
||
<i>(Comparison of 3 regimens of therapy in 611 patients with active tuberculosis; 6 vs 9 months duration, with and without pyrazinamide; hepatitis occurred in 4% of patients with all 3 regimens and 8 patients [1.3%] had jaundice; hepatotoxicity occurred in 3% of men and 6% of women).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.danan.1981.1056">Danan G, Pessayre D, Larrey D, Benhamou JP. Pyrazinamide fulminant hepatitis: an old hepatotoxin strikes again. <span><span class="ref-journal">Lancet. </span>1981;<span class="ref-vol">2</span>:1056–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6118518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6118518</span></a>]<div>
|
||
<i>(37 year old man with active tuberculosis developed elevated ALT after 8 months of therapy; isoniazid was stopped and pyrazinamide continued, and patient developed acute liver failure [ALT 30 times ULN, Alk P twice normal] and died).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.pilheu.1981.720">Pilheu JA, De Salvo MC, Koch O. Liver alterations in antituberculosis regimens containing pyrazinamide. <span><span class="ref-journal">Chest. </span>1981;<span class="ref-vol">80</span>:720–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7307595" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7307595</span></a>]<div>
|
||
<i>(Prospective study of 59 alcoholic men with active tuberculosis treated with four drugs including isoniazid, rifampin, streptomycin and either pyrazinamide or ethambutol with monthly monitoring and liver biopsy before and after 2 months of therapy found no evidence of increased hepatotoxicity comparing pyrazinamide and ethambutol groups).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.hong_kong_chest_servicebritish_medical_research_council.1982.89">Hong Kong Chest Service/British Medical Research Council. Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. <span><span class="ref-journal">Tubercle. </span>1982;<span class="ref-vol">63</span>:89–98.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6758252" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6758252</span></a>]<div>
|
||
<i>(Among 833 patients with active tuberculosis randomized to one of 5 regimens, hepatotoxicity occurred in 2.7% and only 3 [0.4%] were jaundiced; most were able to finish therapy).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.girling.1982.56">Girling DJ. Adverse effects of antituberculosis drugs. <span><span class="ref-journal">Drugs. </span>1982;<span class="ref-vol">23</span>:56–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6459920" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6459920</span></a>]<div>
|
||
<i>(Review of side effects of drugs for tuberculosis; isoniazid alone leads to hepatitis in 0.5% of patients increasing with age from 0.3% <35, 0.8% >55 years, higher rates when it is combined with other agents; pyrazinamide found to be hepatotoxic in high doses [40 mg/kg/day], but not with lower doses – “So far there has been no report of a high incidence of hepatotoxicity with the modern pyrazinamide regimens studied”).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cohen.1983.960">Cohen CD, Sayed AR, Kirsch RE. Hepatic complications of antituberculosis therapy revisited. <span><span class="ref-journal">S Afr Med J. </span>1983;<span class="ref-vol">63</span>:960–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6857425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6857425</span></a>]<div>
|
||
<i>(Among 5565 patients treated for tuberculosis in Cape Town SA, 17 [0.3%] developed hepatitis, rate similar to that when PAS was used. Among 28 cases seen, 13 attributed to isoniazid, 16 pyrazinamide and 8 rifampin, mostly in combination; 2 deaths).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.fiala.1983.1956">Fiala W, Häcki MA, Brändli O. <span><span class="ref-journal">Schweiz Med Wochenschr. </span>1983;<span class="ref-vol">113</span>:1956–9.</span> [Pyrazinamide versus ethambutol in short-term therapy of lung tuberculosis. A randomized study] German. [<a href="https://pubmed.ncbi.nlm.nih.gov/6658432" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6658432</span></a>]<div>
|
||
<i>(Controlled trial comparing pyrazinamide [n=52: <2 g/day] vs ethambutol [n=61] for first 2-3 months with isoniazid and rifampin for 9 months to treat active tuberculosis; hepatitis occurred in 5 on pyrazinamide and 2 on ethambutol, all in first month, 3 symptomatic, no deaths, most were >70 years of age).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cataldi_amatriain.1984.174">Cataldi Amatriain RM, Rossi Case E. <span><span class="ref-journal">Rev Esp Enferm Apar Dig. </span>1984;<span class="ref-vol">66</span>:174–7.</span> [The hepatotoxicity of pyrazinamide] Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/6494560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6494560</span></a>]<div>
|
||
<i>(Pyrazinamide is similar in structure to isoniazid, initially found to be hepatotoxic, but then lower doses appeared to be safe and combination therapy allowed for shorter courses; among 34 patients treated, Alk P was 2-3 times ULN in 5 and ALT 2-3 times ULN in 4, all arising during first 30 days, all asymptomatic and resolving once pyrazinamide stopped).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cataldi_amatriain.1984.174_1">Cataldi Amatriain RM, Rossi Case E. <span><span class="ref-journal">Rev Esp Enferm Apar Dig. </span>1984;<span class="ref-vol">66</span>:174–7.</span> [The hepatotoxicity of pyrazinamide] Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/6494560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6494560</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.parthasarathy.1986.99">Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P, Santha T, Sivasubramanian S, Somasundaram PR, Tripathy SP. Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. <span><span class="ref-journal">Tubercle. </span>1986;<span class="ref-vol">67</span>:99–108.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3775870" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3775870</span></a>]<div>
|
||
<i>(Hepatitis occurred in 10% of patients with spinal tuberculosis, 16-39% of children with meningitis and 2-8% with pulmonary disease treated with rifampin and isoniazid, arising 1-6 months after starting therapy, more commonly in slow acetylators).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF27">Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore. A controlled clinical trial of 3- and 5-month regimens in the treatment of sputum-positive pulmonary tuberculosis in South India. <span><span class="ref-journal">Am Rev Respir Dis. </span>1986;<span class="ref-vol">134</span>:27–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3524334" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3524334</span></a>]<div>
|
||
<i>(Analysis of 3 regimens for therapy of active tuberculosis in 908 patients; jaundice occurred in 6-8% of subjects on rifampin, but only 1% of subjects on nonrifampin regimens [isoniazid, pyrazinamide and streptomycin], but no mention of rates of death or clinically apparent hepatitis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.swamy.1987.549">Swamy R, Acharyulu GS, Duraipandian M, Jawahar MS, Ramachandran R, Sarma GR. Liver function tests during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin & pyrazinamide. <span><span class="ref-journal">Indian J Med Res. </span>1987 Nov;<span class="ref-vol">86</span>:549–57.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3451899" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3451899</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.donald.1987.741">Donald PR, Schoeman JF, O'Kennedy A. Hepatic toxicity during chemotherapy for severe tuberculosis meningitis. <span><span class="ref-journal">Am J Dis Child. </span>1987;<span class="ref-vol">141</span>:741–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2884866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2884866</span></a>]<div>
|
||
<i>(Among 33 children with tuberculous meningitis treated with 3-4 agents, liver test abnormalities were common [85%], but usually mild and transient; only one child developed jaundice who was also IgM anti-HAV positive and who later tolerated therapy without recurrence).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.van_aalderen.1987.290">van Aalderen WMC, Knoester H, Knol K. Fulminant hepatitis during treatment with rifampicin, pyrazinamide and ethambutol. <span><span class="ref-journal">Eur J Pediatr. </span>1987;<span class="ref-vol">146</span>:290–1.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3595648" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3595648</span></a>]<div>
|
||
<i>(10 year old girl developed nausea and ALT elevations 2 weeks after starting isoniazid, rifampin, pyrazinamide and ethambutol, resolving with stopping all drugs, but severe recurrence with fever, rash and fatal acute liver failure 6 weeks after adding pyrazinamide back to rifampin, ethambutol and kanamycin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.roden.1990.43">Roden S, Lagneau M, Homasson JP. <span><span class="ref-journal">Rev Pneumol Clin. </span>1990;<span class="ref-vol">46</span>:43.</span> [Fulminant hepatitis induced by pyrazinamide] French. [<a href="https://pubmed.ncbi.nlm.nih.gov/2371480" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2371480</span></a>]<div>
|
||
<i>(68 year old woman developed jaundice 3.5 months after starting antituberculosis therapy with rifampin, pyrazinamide and ethambutol [bilirubin 9.6 mg/dL, ALT 1100 U/L, Alk P 185 U/L, prothrombin index 45%], with progressive hepatic failure leading to liver transplantation, by followed by death 10 days postoperatively).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kshirsagar.1992.13">Kshirsagar NA, Karande SC, Potkar CN. A prospective survey of drug induced hepatotoxicity in a large hospital. <span><span class="ref-journal">Indian J Gastroenterol. </span>1992;<span class="ref-vol">11</span>:13–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1551705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1551705</span></a>]<div>
|
||
<i>(Among 11 cases of drug induced liver disease, 9 were due to antituberculosis medications, usually combinations of isoniazid, rifampin and pyrazinamide, 2 deaths).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.padmini.1993.361">Padmini R, Srinivasan S, Nalini P, Mahadevan S. Short course chemotherapy for tuberculosis in children. <span><span class="ref-journal">J Trop Pediatr. </span>1993;<span class="ref-vol">39</span>:361–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8133559" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8133559</span></a>]<div>
|
||
<i>(Among 83 children [<12 years] treated for tuberculosis [using 2-4 agents, including pyrazinamide] in India between 1988-91, 4 developed hepatitis with jaundice [bilirubin 2.0-4.5 mg/dL, ALT >4 times ULN], but all resolved with decrease in dose of isoniazid and rifampin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.altman.1993.1212">Altman C, Biour M, Grangé JD. <span><span class="ref-journal">Presse Med. </span>1993;<span class="ref-vol">22</span>:1212–6.</span> [Hepatic toxicity of antitubercular agents. Role of different drugs. 199 cases] French. [<a href="https://pubmed.ncbi.nlm.nih.gov/8248040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8248040</span></a>]<div>
|
||
<i>(Analysis of 199 cases of hepatotoxicity from antituberculosis medications from literature [n=169] and French pharmacovigilance system [n=30]; overall mortality rate was 23%, rifampin cases had short latency [average 2 weeks] compared to isoniazid [11 weeks] and pyrazinamide [7 weeks] cases; there was no association with alcohol, but some with higher doses, particularly isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.robson.1993.432">Robson SC, Pillans P, Willcox PA. Treatment of tuberculosis in patients with pre-existing liver disease or following hepatotoxic drug reactions. <span><span class="ref-journal">S Afr Med J. </span>1993;<span class="ref-vol">83</span>:432–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8211464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8211464</span></a>]<div>
|
||
<i>(Review of problems of treating tuberculosis in patients with preexisting liver disease, recommended avoiding pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.van_der_kooi.1994.987">van der Kooi K, Mottet JJ, Regamey C. Isoniazid is not always the cause of hepatitis during treatment of tuberculosis. <span><span class="ref-journal">Clin Infect Dis. </span>1994;<span class="ref-vol">19</span>:987–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7893906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7893906</span></a>]<div>
|
||
<i>(46 year old man developed hepatitis [ALT 900 U/L] 2 weeks after starting isoniazid, rifampin, pyrazinamide and ethambutol, with positive challenge with pyrazinamide and not by isoniazid; no mention of fever, rash or bilirubin levels).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.t_rkta_.1994.58">Türktaş H, Unsal M, Tülek N, Orüç O. Hepatotoxicity of antituberculosis therapy (rifampicin, isoniazid and pyrazinamide) or viral hepatitis. <span><span class="ref-journal">Tuber Lung Dis. </span>1994;<span class="ref-vol">75</span>:58–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8161767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8161767</span></a>]<div>
|
||
<i>(Among 705 Turkish adults with tuberculosis, 57 [8%] developed hepatitis with jaundice during therapy with isoniazid and rifampin; serologic testing showed hepatitis A in none, B in 6 and C in 4).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.farrell.1994.2255">Farrell FJ, Keeffe EB, Man KM, Imperial JC, Esquivel CO. Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. <span><span class="ref-journal">Dig Dis Sci. </span>1994;<span class="ref-vol">39</span>:2255–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7924752" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7924752</span></a>]<div>
|
||
<i>(Two cases of acute liver failure attributed to isoniazid: 49 year old man on isoniazid for latent tuberculosis for 4 months developed jaundice [bilirubin 16.1 mg/dL, AST 2882 U/L]; and 60 year old woman developed jaundice 6 weeks after starting isoniazid, rifampin, and pyrazinamide for active tuberculosis [bilirubin 3.5 mg/dL, AST 548 U/L], both progressing to hepatic failure and undergoing successful liver transplantation).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.horn.1994.1241">Horn DL, Hewlett D Jr, Alfalla C, Peterson S, Opal SM. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis. <span><span class="ref-journal">N Engl J Med. </span>1994;<span class="ref-vol">330</span>:1241.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8139647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8139647</span></a>]<div>
|
||
<i>(Among 16 contacts of a case of multidrug resistant tuberculosis treated with pyrazinamide and ofloxacin, side effects were common; 4 had hepatitis [ALT 491-1776 U/L], only 2 completed therapy).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.singh.1995.359">Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. <span><span class="ref-journal">Postgrad Med J. </span>1995;<span class="ref-vol">71</span>:359–62.</span> [<a href="/pmc/articles/PMC2398146/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2398146</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7644398" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7644398</span></a>]<div>
|
||
<i>(Case control study of 60 patients with liver injury due to antituberculosis medications and 60 controls from India identified lower body mass index and use of pyrazinamide, but not age, sex, or acetylator status as risk factors).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.mitchell.1995.555">Mitchell I, Wendon J, Fitt S, Williams R. Anti-tuberculous therapy and acute liver failure. <span><span class="ref-journal">Lancet. </span>1995;<span class="ref-vol">345</span>:555–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7786350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7786350</span></a>]<div>
|
||
<i>(Four cases of acute liver failure in patients on isoniazid, rifampin and pyrazinamide; 3 women and 1 man, ages 31-61 years, jaundice after 1-6 weeks, two requiring liver transplantation, one recovered, one died; unclear which agent was responsible).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.noble.1995.867">Noble A. Antituberculous therapy and acute liver failure. <span><span class="ref-journal">Lancet. </span>1995 Apr 1;<span class="ref-vol">345</span>:867.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7898260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7898260</span></a>]<div>
|
||
<i>(Letter in response to Mitchell [1995] suggesting that patients be warned to stop the medication if they develop symptoms of liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.janes.1995.867">Janes SL, Behrens J. Antituberculous therapy and acute liver failure. <span><span class="ref-journal">Lancet. </span>1995;<span class="ref-vol">345</span>:867.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7898259" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7898259</span></a>]<div>
|
||
<i>(Letter in response to Mitchell [1995] reporting a 45 year old man who developed hepatitis 5 weeks after starting isoniazid and rifampin [bilirubin 3.3 mg/dL, ALT 1884 U/L], who recovered rapidly with prompt stopping of both).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ozick.1995.1978">Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, Felton CP. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. <span><span class="ref-journal">Am J Gastroenterol. </span>1995;<span class="ref-vol">90</span>:1978–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7485004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7485004</span></a>]<div>
|
||
<i>(Among 70 AIDS patients with active tuberculosis receiving isoniazid, rifampin and pyrazinamide for 2 months, ALT or AST levels >200 U/L occurred in 8 [11%] with peak bilirubin values 0.6-2.9 mg/dL).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.corbella.1995.93">Corbella X, Vadillo M, Cabellos C, Fernandez-Viladrich P, Rufi G. Hypersensitivity hepatitis due to pyrazinamide. <span><span class="ref-journal">Scand J Infect Dis. </span>1995;<span class="ref-vol">27</span>:93–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7784827" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7784827</span></a>]<div>
|
||
<i>(59 year old woman developed abdominal pain and fever 1 month after starting isoniazid, rifampin, ethambutol and pyrazinamide [bilirubin 7.9 mg/dL, ALT 1260 U/L, 14% eosinophils], with positive rechallenge to pyrazinamide [ALT 3240 U/L], later tolerating ethambutol, rifampin and streptomycin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.moitinho.1996.448">Moitinho E, Salmerón JM, Mas A, Bruguera M, Rodés J. <span><span class="ref-journal">Gastroenterol Hepatol. </span>1996;<span class="ref-vol">19</span>:448–51.</span> [Severe hepatotoxicity of tuberculostatic agents. Increase in the incidence] Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/8998667" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8998667</span></a>]<div>
|
||
<i>(Among 27 cases of severe acute hepatitis seen in 1994 in Barcelona, 5 cases were due to antituberculosis medications, 1 woman and 4 men, ages 25 to 62 years, 2 with HBsAg, 1 with anti-HCV, arising after 11-62 days [peak bilirubin 8-41 mg/dL; ALT 450-2320 U/L, Alk P 1.5-2 times ULN], 3 died, one required liver transplant, one recovered spontaneously).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.de_souza.1996.194">de Souza AF. de Oliveira e Silva A, Baldi J, de Souza TN, Rizzo PM. <span><span class="ref-journal">Arq Gastroenterol. </span>1996;<span class="ref-vol">33</span>:194–200.</span> [Hepatic functional changes induced by the combined use of isoniazid, pyrazinamide and rifampicin in the treatment of pulmonary tuberculosis] Portuguese. [<a href="https://pubmed.ncbi.nlm.nih.gov/9302332" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9302332</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.pande.1996.132">Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandom RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. <span><span class="ref-journal">Thorax. </span>1996;<span class="ref-vol">51</span>:132–6.</span> [<a href="/pmc/articles/PMC473016/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC473016</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8711642" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8711642</span></a>]<div>
|
||
<i>(Comparison of 86 patients with hepatitis due to antituberculosis therapy to 406 patients who tolerated therapy; risk factors for liver injury were older age, history of high alcohol intake [20% vs 5%], more extensive disease [14% vs 3.5%], slow acetylator status [83% vs 64%] and use of pyrazinamide [63% vs 25%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.al_sarraf.1996.251">al Sarraf KA, Michielsen PP, Hauben EI, Lefebure A, Ramon AM, Van Marck EA, Pelckmans PA. Hepatotoxicity after a short course of low-dose pyrazinamide. <span><span class="ref-journal">Acta Gastroenterol Belg. </span>1996;<span class="ref-vol">59</span>:251–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9085628" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9085628</span></a>]<div>
|
||
<i>(32 year old man with tuberculosis developed ALT elevations [50 times ULN] 10 weeks after starting isoniazid, resolving promptly on stopping, but rising again within 3 weeks of starting pyrazinamide and rifampin with worsening despite stopping both agents [peak bilirubin 1.2 mg/dL, ALT 1455 U/L, Alk P 107 U/L 10 weeks after withdrawal], resolving slowly and incompletely).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ormerod.1996.37">Ormerod LP, Horsfield N. Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. <span><span class="ref-journal">Tuber Lung Dis. </span>1996;<span class="ref-vol">77</span>:37–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8733412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8733412</span></a>]<div>
|
||
<i>(Among 1317 patients treated for active tuberculosis, hepatitis was attributed to rifampin in 1.4%, pyrazinamide in 1.2% and isoniazid in 0.3%, but none to ethambutol or streptomycin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ormerod.1996.111">Ormerod LP, Skinner C, Wales J. Hepatotoxicity of antituberculosis drugs. <span><span class="ref-journal">Thorax. </span>1996;<span class="ref-vol">51</span>:111–3.</span> [<a href="/pmc/articles/PMC473008/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC473008</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8711637" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8711637</span></a>]<div>
|
||
<i>(Review of the problem of hepatotoxicity of antituberculosis medications and recommendations on monitoring, with biochemical monitoring recommended only for patients with preexisting liver disease; in the UK between 1965-86 there were 243 reports of liver injury due to antituberculosis therapy and 45 fatalities).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.d_ssing.1996.335">Døssing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study. <span><span class="ref-journal">Tuber Lung Dis. </span>1996;<span class="ref-vol">77</span>:335–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8796249" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8796249</span></a>]<div>
|
||
<i>(Retrospective chart review on 765 Danish patients treated for tuberculosis with 3 or 4 drugs for 6-9 months; 16% had AST elevations >2 times ULN usually during first month, but only 2% required modified regimen; 7 with jaundice, no fatalities; risk factors for hepatotoxicity were female sex, age and severe tuberculosis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.durand.1996.394">Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J. Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. <span><span class="ref-journal">Drug Saf. </span>1996;<span class="ref-vol">15</span>:394–405.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8968694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8968694</span></a>]<div>
|
||
<i>(Review and recommendations from France regarding monitoring of serum enzymes during therapy of tuberculosis; isoniazid may have direct hepatotoxicity because of dose relatedness and usual absence of recurrence on rechallenge; rifampin is rare cause of liver injury, usually with short latency period; pyrazinamide is clearly hepatotoxic at higher doses which should be kept to a minimum and given for 2 months only).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.knobel.1997.264">Knobel B, Buyanowsky G, Dan M, Zaidel L. Pyrazinamide-induced granulomatous hepatitis. <span><span class="ref-journal">J Clin Gastroenterol. </span>1997;<span class="ref-vol">24</span>:264–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9252856" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9252856</span></a>]<div>
|
||
<i>(52 year old developed fever 1 month after starting pyrazinamide and streptomycin for suspected tuberculosis [bilirubin 0.6 mg/dL, ALT 136 U/L, Alk P 752 U/L] without rash or eosinophilia, resolving on stopping, biopsy showing granulomas).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ridzon.1997.1264">Ridzon R, Meador J, Maxwell R, Higgins K, Weismuller P, Onorato IM. Asymptomatic hepatitis in persons who received alternative preventive therapy with pyrazinamide and ofloxacin. <span><span class="ref-journal">Clin Infect Dis. </span>1997;<span class="ref-vol">24</span>:1264–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9195099" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9195099</span></a>]<div>
|
||
<i>(Among 22 contacts of patients with multidrug resistant tuberculosis given pyrazinamide and ofloxacin, 12 developed ALT elevations after 2-25 weeks resolving in 3-5 weeks of stopping; two above 35 years in age both developed elevations [ALT 1026 and 2,990 U/L], one had eosinophilia [35%] and jaundice [bilirubin 4.1 mg/dL]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.devoto.1997.197">Devoto FM, González C, Iannantuono R, Serra HA, González CD, Sáenz C. Risk factors for hepatotoxicity induced by antituberculosis drugs. <span><span class="ref-journal">Acta Physiol Pharmacol Ther Latinoam. </span>1997;<span class="ref-vol">47</span>:197–202.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9504179" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9504179</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.hwang.1997.87">Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CL, Lin TP, Lee SD. A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B. <span><span class="ref-journal">J Gastroenterol Hepatol. </span>1997;<span class="ref-vol">12</span>:87–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9076631" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9076631</span></a>]<div>
|
||
<i>(Prospective study of 240 patients treated for active tuberculosis with 3 drug regimen, found ALT elevations in 45% of 31 HBsAg carriers vs 26% of 209 controls; 1 death in a carrier, none in controls, but nevertheless concluded that HBsAg was not a risk factor for antituberculosis therapy associated liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ungo.1998.1871">Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>1998;<span class="ref-vol">157</span>:1871–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9620920" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9620920</span></a>]<div>
|
||
<i>(Among 134 patients with tuberculosis, 22 developed hepatotoxicity during therapy; risk factors were HCV infection [30% vs 11%] and HIV infection [27% vs 12%]; alpha interferon therapy of hepatitis C allowed for antituberculosis therapy without ALT elevations in some patients).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.rose.1998.779">Rose DN. Short-course prophylaxis against tuberculosis in HIV-infected persons. A decision and cost-effectiveness analysis. <span><span class="ref-journal">Ann Intern Med. </span>1998;<span class="ref-vol">129</span>:779–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9841583" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9841583</span></a>]<div>
|
||
<i>(Cost-effectiveness analysis of various regimens for treating latent tuberculosis in HIV infected persons using Markov model and various predictions of efficacy, safety, tuberculosis development and survival used rates of fatal hepatitis of 0.002% found prophylaxis to be “greatly” beneficial, including regimens using pyrazinamide and rifampin for 2 months).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.wada.1999.353">Wada M, Yoshiyama T, Ogata H, Ito K, Mizutani S, Sugita H. <span><span class="ref-journal">Kekkaku. </span>1999;<span class="ref-vol">74</span>:353–60.</span> [Six-months chemotherapy (2HRZS or E/4HRE) of new cases of pulmonary tuberculosis—six year experiences on its effectiveness, toxicity, and acceptability] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/10355221" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10355221</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.corrigan.1999.37">Corrigan D, Paton J. Hepatic enzyme abnormalities in children on triple therapy for tuberculosis. <span><span class="ref-journal">Pediatr Pulmonol. </span>1999;<span class="ref-vol">27</span>:37–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10023790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10023790</span></a>]<div>
|
||
<i>(Among 43 children prospectively monitored on rifampin, isoniazid and pyrazinamide therapy, 30% had abnormal liver tests, usually in first few weeks, 2 had symptoms, 1 jaundice; all patients continued or were restarted and finished therapy).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.gordin.2000.1445">Gordin F, Chaisson RE, Matts JP, Miller C, de Lourdes Garcia M, Hafner R, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. <span><span class="ref-journal">JAMA. </span>2000;<span class="ref-vol">283</span>:1445–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10732934" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10732934</span></a>]<div>
|
||
<i>(Controlled trial in 1583 patients with HIV infection and latent tuberculosis comparing rifampin/pyrazinamide [R/P] for 2 months to isoniazid [INH] for 12 months; active tuberculosis arose in 0.8% per year of R/P vs 1.1% of INH treated; ALT elevations >10 times ULN occurred in 1.3% of R/P vs 3.3% of INH treated; one “grade 4 hepatitis” in R/P versus 2 in INH treated).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.girotto.2000.249">Girotto L, Gjonovich A, Preciso G. <span><span class="ref-journal">Minerva Anestesiol. </span>2000;<span class="ref-vol">66</span>:249–51.</span> [Fulminant liver failure caused by antitubercular drugs. Report of a clinical case] Italian. [<a href="https://pubmed.ncbi.nlm.nih.gov/10832275" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10832275</span></a>]<div>
|
||
<i>(26 year old man with pulmonary tuberculosis treated with isoniazid, rifampin, ethambutol and pyrazinamide, presented after 1 month with fever, rash and jaundice [bilirubin 8.5 mg/dL, ALT 2757 U/L], renal insufficiency and hepatic and multiorgan failure; died after 10 days; autopsy showed massive liver necrosis and acute renal tubular necrosis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.meyers.2000.64">Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. <span><span class="ref-journal">Transplantation. </span>2000;<span class="ref-vol">69</span>:64–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10653382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10653382</span></a>]<div>
|
||
<i>(Toxicity was common in transplant patients treated for active tuberculosis using first line agents, but switching to second line agents was successful in treating the tuberculosis and well tolerated).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.centers_for_disease_control_and_prevention_cdc_.2001.289">Centers for Disease Control and Prevention (CDC). Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection—New York and Georgia, 2000. <span><span class="ref-journal">MMWR Morb Mortal Wkly Rep. </span>2001;<span class="ref-vol">50</span>:289–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11330495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11330495</span></a>]<div>
|
||
<i>(First alert: initial report of 2 cases of severe hepatitis during 2 month regimen of rifampin and pyrazinamide for latent tuberculosis; 53 year old man developed ALT elevation [1734 U/L] 33 days after starting regimen followed by jaundice [bilirubin 17.8 mg/dL] and fatal hepatic failure; 59 year old woman developed symptoms at end of therapy with bilirubin 11.4 mg/dL, ALT 1735 U/L, ANA 1:640, treated with prednisone and recovered; in both cases ALT monitoring did not prevent severe hepatitis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.centers_for_disease_control_and_prevention_cdc_.2001.733">Centers for Disease Control and Prevention (CDC). Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations—United States, 2001. <span><span class="ref-journal">MMWR Morb Mortal Wkly Rep. </span>2001;<span class="ref-vol">50</span>:733–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11787580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11787580</span></a>]<div>
|
||
<i>(Second alert: during a 6 month period, 21 cases of liver injury were reported to the CDC associated with 2 month regimens of rifampin-pyrazinamide; 5 died of liver failure, ages 32 to 68 years, onset in 2nd month; recommended use of 9 months of isoniazid as standard regimen and need for close monitoring if rifampin-pyrazinamide is used).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.de_maria.2001.983">de Maria A, Berardi M, Dignetti P, Ferrera L, Viassolo L, Canonica GW. Side effects of antituberculosis treatment. <span><span class="ref-journal">Thorax. </span>2001;<span class="ref-vol">56</span>:983.</span> [<a href="/pmc/articles/PMC1745978/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1745978</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11758512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11758512</span></a>]<div>
|
||
<i>(Letter arguing against use of fixed dose combination pills of pyrazinamide with isoniazid and rifampin because of the risk of hepatotoxicity and inability to adjust relative doses).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.burman.2001.1112">Burman WJ, Reves RR. Hepatotoxicity from rifampin plus pyrazinamide: lessons for policymakers and messages for care providers. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2001;<span class="ref-vol">164</span>:1112–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11673194" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11673194</span></a>]<div>
|
||
<i>(Editorial in response to MMWR report on 21 cases of severe hepatotoxicity and 5 deaths due to the combination of rifampin and pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.vu.2001.942">Vu D, Macdonald L. Antitubercular drugs (isoniazid, rifampin and pyrazinamide): hepatobiliary reactions. <span><span class="ref-journal">CMAJ. </span>2001;<span class="ref-vol">165</span>:942–3, 946-7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11599338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11599338</span></a>]<div>
|
||
<i>(Review of 420 reports to the Canadian Monitoring Program of hepatotoxicity of antituberculosis drugs identified 258 due to isoniazid alone with 7 deaths; 27 to rifampin alone with 1 death; 110 to isoniazid and rifampin with 6 deaths; 25 related to pyrazinamide alone or in combination with 3 cases of death or hepatic failure; advises biochemical monitoring for patients above the age of 35).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.mccarthy.2001.816">McCarthy M. US guidelines for treatment of latent tuberculosis revised. <span><span class="ref-journal">Lancet. </span>2001;<span class="ref-vol">358</span>:816.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11564495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11564495</span></a>]<div>
|
||
<i>(Newsletter on the modification of the US guidelines on treatment of latent tuberculosis, recommending avoidance of rifampin/pyrazinamide regimens).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.tahao_lu.2001.65">Tahaoğlu K, Ataç G, Sevim T, Tärün T, Yazicioğlu O, Horzum G, Gemci I, et al. The management of anti-tuberculosis drug-induced hepatotoxicity. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2001;<span class="ref-vol">5</span>:65–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11263519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11263519</span></a>]<div>
|
||
<i>(Description of 45 patients with hepatotoxicity from antituberculosis therapy, ages 15 to 76 years, ALT 42-897 U/L, bilirubin 0.2-7.0 mg/dL, arising in 6-102 days, with resolution in 4-58 days. No recurrence in patients with gradual reintroduction of regimen without pyrazinamide compared to 6 cases [24%] in those with abrupt reintroduction).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.wada.2001.33">Wada M. <span><span class="ref-journal">Kekkaku. </span>2001;<span class="ref-vol">76</span>:33–43.</span> [Effectiveness and problems of PZA-containing 6-month regimen for the treatment of new pulmonary tuberculosis patients] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/11211781" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11211781</span></a>]</div></li><li><div class="bk_ref" id="Pyrazinamide.REF.papastavros.2002.131">Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb M. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. <span><span class="ref-journal">CMAJ. </span>2002;<span class="ref-vol">167</span>:131–6.</span> [<a href="/pmc/articles/PMC117089/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC117089</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12160118" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12160118</span></a>]<div>
|
||
<i>(Among 17 persons given pyrazinamide and levofloxacin for latent tuberculosis after contact with multidrug resistant tuberculosis, adverse reactions were common, 5 [29%] had ALT elevations [peak 80-504 U/L]; all recovered after stopping).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lee.2002.995">Lee AM, Mennone JZ, Jones RC, Paul WS. Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2002;<span class="ref-vol">6</span>:995–1000.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12475146" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12475146</span></a>]<div>
|
||
<i>(Among 148 patients with latent tuberculosis treated with rifampin/pyrazinamide, 14 [9.4%] had ALT elevations >5 times ULN, 12 were symptomatic [8%]; risk factors were female sex and recent infection).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.medinger.2002.1710">Medinger A. Death associated with rifampin and pyrazinamide 2-month treatment of latent Mycobacterium tuberculosis. <span><span class="ref-journal">Chest. </span>2002;<span class="ref-vol">121</span>:1710–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12006469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12006469</span></a>]<div>
|
||
<i>(68 year old man developed jaundice at end of 2 month course of rifampin and pyrazinamide for latent tuberculosis [bilirubin 19.2 mg/dL, ALT 1930 U/L, Alk P 207 U/L], with liver failure and death within 3 days of presentation: Case 2).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.castro.2003.967">Castro KG, Jereb JA, Koppaka VR, Cohn DL. Fatal liver injury associated with rifampin-pyrazinamide treatment of latent tuberculosis infection. <span><span class="ref-journal">Chest. </span>2003;<span class="ref-vol">123</span>:967.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12628913" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12628913</span></a>]<div>
|
||
<i>(Letter in response to Medinger [2002] on need to report cases of hepatotoxicity of antituberculosis therapy to the CDC).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.centers_for_disease_control_and_prevention_cdc_.2002.998">Centers for Disease Control and Prevention (CDC). Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. <span><span class="ref-journal">MMWR Morb Mortal Wkly Rep. </span>2002;<span class="ref-vol">51</span>:998–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12455909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12455909</span></a>]<div>
|
||
<i>(Third alert: 40 cases of severe hepatotoxicity [8 fatal] associated with rifampin/pyrazinamide therapy of latent tuberculosis reported to CDC; issued revised guidelines cautioning against use of this regimen and only with no preexisting liver disease or alcohol use, with ALT monitoring and provision of drugs in two week increments).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.jasmer.2002.640">Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, et al. Short-Course Rifampin and pyrazinamide for Tuberculosis Infection(SCRIPT) Study Investigators. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. <span><span class="ref-journal">Ann Intern Med. </span>2002;<span class="ref-vol">137</span>:640–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12379063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12379063</span></a>]<div>
|
||
<i>(Controlled trial of isoniazid [INH: 6 months] vs rifampin and pyrazinamide [RP: 2 months] in 589 patients with latent tuberculosis, similar completion rates [57% vs 61%]; ALT rose >5 times ULN in 1% on INH vs 7.7% on RP; none resulted in hospitalization or death; no mention of jaundice).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ohkawa.2002.220">Ohkawa K, Hashiguchi M, Ohno K, Kiuchi C, Takahashi S, Kondo S, Echizen H, et al. Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2002;<span class="ref-vol">72</span>:220–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12189369" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12189369</span></a>]<div>
|
||
<i>(Retrospective analysis of 99 children who received therapy for tuberculosis, 8 developed hepatotoxicity; risk factors identified were young age and pyrazinamide exposure).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.teleman.2002.699">Teleman MD, Chee CB, Earnest A, Wang YT. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2002;<span class="ref-vol">6</span>:699–705.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12150482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12150482</span></a>]<div>
|
||
<i>(Retrospective analysis of 1036 patients treated for active tuberculosis in Singapore during 1998 found 55 cases of liver injury [5.3%], 37 symptomatic [3.6%], 18 jaundiced [1.8%], 3 died [0.3%: all on pyrazinamide]; 48 able to restart therapy; risk factors were age >60 years and baseline liver test abnormalities).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.centers_for_disease_control_and_prevention_cdc_.2003.735">Centers for Disease Control and Prevention (CDC). American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. <span><span class="ref-journal">MMWR Morb Mortal Wkly Rep. </span>2003;<span class="ref-vol">52</span>:735–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12904741" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12904741</span></a>]<div>
|
||
<i>(Fourth alert and issuing of recommendations against use of rifampin/pyrazinamide for latent tuberculosis; with this regimen, estimated rate of ALT elevations >5 times ULN was 2.6%, hospitalization for hepatitis 0.3% and death 0.09%).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.american_thoracic_society.2003.1">American Thoracic Society. Centers for Disease Control and Prevention (CDC). Infectious Diseases Society of America. Treatment of tuberculosis. <span><span class="ref-journal">MMWR Recomm Rep. </span>2003;<span class="ref-vol">52</span>(RR-11):1–77.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12836625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12836625</span></a>]<div>
|
||
<i>(Detailed recommendations on therapy of tuberculosis including drug regimens, side effects, monitoring and optimal approaches to follow up).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kunimoto.2003.e158">Kunimoto D, Warman A, Beckon A, Doering D, Melenka L. Severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy requiring transplantation in an individual at low risk for hepatotoxicity. <span><span class="ref-journal">Clin Infect Dis. </span>2003;<span class="ref-vol">36</span>:e158–61.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12802781" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12802781</span></a>]<div>
|
||
<i>(37 year old man had AST elevations at end of 2 month course of rifampin/pyrazinamide, with levels rising thereafter to AST 2409 U/L and bilirubin 7.8 mg/dL and need for liver transplant 2 months later).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.nagayama.2003.339">Nagayama N, Masuda K, Baba M, Tamura A, Nagai H, Akagawa S, Kawabe Y, et al. <span><span class="ref-journal">Kekkaku. </span>2003;<span class="ref-vol">78</span>:339–46.</span> [Secular increase in the incidence rate of drug-induced hepatitis due to anti-tuberculosis chemotherapy including isoniazid and rifampicin] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/12739393" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12739393</span></a>]<div>
|
||
<i>(In Japan there was an apparent increase in rate of ALT elevations reported during isoniazid and rifampin therapy between the years 1980-83 [9%] and 1998-2000 [27%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.yee.2003.1472">Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2003;<span class="ref-vol">167</span>:1472–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12569078" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12569078</span></a>]<div>
|
||
<i>(Among 408 adult patients treated for tuberculosis, 37 [9%] had 46 serious adverse events including 12 [3%] instances of hepatitis [ALT >5 times ULN]; risk factors were age [hazard ratio 4.8-7.7], female sex [2.2] and Asian birthplace [2.2]; hepatitis arose in 2% on pyrazinamide and 1% on isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.mohan.2004.882">Mohan A, Sharma SK. Side effects of antituberculosis drugs. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2004;<span class="ref-vol">169</span>:882–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15044223" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15044223</span></a>]<div>
|
||
<i>(Letter in response to Yee [2003] requesting further information on doses and clinical features; reply by authors stating that high rate of hepatotoxicity in comparison to reports from India was not due to higher doses of pyrazinamide, but may have been partially due to patient age and diverse ethnic background of patients).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.mcneill.2003.102">McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. <span><span class="ref-journal">Chest. </span>2003;<span class="ref-vol">123</span>:102–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12527609" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12527609</span></a>]<div>
|
||
<i>(Between 1999-2002, 110 patients were treated with pyrazinamide/rifampin [P/R] for 2 months and 114 with isoniazid [INH] for 6 months for latent tuberculosis; completion rates were higher [71% vs 59%] as was hepatotoxicity [13% vs 4%] with PR than INH, and 2 patients had clinically apparent hepatitis [ALT 45-67 times ULN at 4 weeks] but both survived; after intensive monitoring, no further severe cases on P/R).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.stout.2003.824">Stout JE, Engemann JJ, Cheng AC, Fortenberry ER, Hamilton CD. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2003;<span class="ref-vol">167</span>:824–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12446275" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12446275</span></a>]<div>
|
||
<i>(Among 114 patients receiving 2 month course of rifampin/pyrazinamide, 67% completed therapy and 6 had hepatitis [5.3%] but all resolved; no hospitalizations or death).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.fern_ndezvillar.2004.1499">Fernández-Villar A, Sopeña B, Fernández-Villar J, Vázquez-Gallardo R, Ulloa F, Leiro V, Mosteiro M, et al. The influence of risk factors on the severity of anti-tuberculosis drug-induced hepatotoxicity. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2004;<span class="ref-vol">8</span>:1499–505.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15636498" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15636498</span></a>]<div>
|
||
<i>(Among 471 patients receiving antituberculosis therapy, 56 [12%] developed ALT elevations >3 times ULN, 16 [3.4%] and symptoms and 5 [1%] were jaundiced; no deaths. Rates of hepatotoxicity higher in patients with risk factors than without [18.2% vs 5.6%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.jasmer.2004.363">Jasmer RM, Snyder DC, Saukkonen JJ, Hopewell PC, Bernardo J, King MD, Kawamura LM, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a cost-effective analysis based on a multicenter clinical trial. <span><span class="ref-journal">Clin Infect Dis. </span>2004;<span class="ref-vol">38</span>:363–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14727206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14727206</span></a>]<div>
|
||
<i>(Cost effectiveness analysis of two regimens of therapy for latent tuberculosis, suggesting that isoniazid alone for 9 months is less expensive than a short course of rifampin and pyrazinamide and has similar long term efficacy [both regimens increased life expectancy by 1.2 years]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ijaz.2004.289">Ijaz K, McElroy PD, Navin TR. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a cost-effectiveness analysis based on a multicenter clinical trial. <span><span class="ref-journal">Clin Infect Dis. </span>2004;<span class="ref-vol">39</span>:289.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15307044" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15307044</span></a>]<div>
|
||
<i>(Letter in response to Jasmer [2004], stressing the recommendation that rifampin and pyrazinamide not be used to treat latent tuberculosis, a 9 month course of isoniazid being safer and more cost effective).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.gordin.2004.561">Gordin FM, Cohn DL, Matts JP, Chaisson RE, O'Brien RJ., Terry Beirn Community Programs for Clinical Research on AIDS. Adult AIDS Clinical Trials Group; Centers for Disease Control and Prevention. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? <span><span class="ref-journal">Clin Infect Dis. </span>2004;<span class="ref-vol">39</span>:561–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15356822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15356822</span></a>]<div>
|
||
<i>(Detailed reanalysis of results of randomized controlled trial comparing 12 months of isoniazid [INH] to 2 months of rifampin/pyrazinamide [R/P] for latent tuberculosis in HIV infected patients; comparing INH to RP recipients, bilirubin >2.5 mg/dL occurred in 0.6% vs 1.8% and AST >250 U/L in 1.6% vs 2.1%, but no hospitalizations or deaths due to hepatotoxicity occurred in the trial; older age was only risk factor identified).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.van_hest.2004.488">van Hest R, Baars H, Kik S, van Gerven P, Trompenaars MC, Kalisvaart N, Keizer S, et al. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment. <span><span class="ref-journal">Clin Infect Dis. </span>2004;<span class="ref-vol">39</span>:488–96.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15356811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15356811</span></a>]<div>
|
||
<i>(Retrospective analysis of patients starting preventive antituberculosis therapy; ALT elevations above 5 times ULN occurred in 8.4% of those receiving 2 months of rifampin/pyrazinamide vs 3.4% of those receiving 6 months of isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.marra.2004.905">Marra F, Cox VC, FitzGerald JM, Moadebi S, Elwood RK. Successful treatment of multidrug-resistant tuberculosis following drug-induced hepatic necrosis requiring liver transplant. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2004;<span class="ref-vol">8</span>:905–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15260286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15260286</span></a>]<div>
|
||
<i>(Patient with tuberculous lymphadenitis was treated with isoniazid, rifampin, ethambutol and pyrazinamide and was switched to ciprofloxacin with pyrazinamide and ethambutol when resistance testing was done; four days later she developed fever, rash and fatigue [bilirubin normal, ALT 285 U/L, Alk P normal], but then worsened [bilirubin 15.2 mg/dL, ALT 1165 U/L, Alk P 141 U/L], ultimately requiring liver transplant; she was later treated successfully with levofloxacin, amikacin and streptomycin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.camposfranco.2004.396">Campos-Franco J, Gonzalez-Quintela A, Alende-Sixto MR. Isoniazid-induced hyperacute liver failure in a young patient receiving carbamazepine. <span><span class="ref-journal">Eur J Intern Med. </span>2004;<span class="ref-vol">15</span>:396–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15522577" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15522577</span></a>]<div>
|
||
<i>(16 year old girl on long term carbamazepine and clobazam with ileocecal tuberculosis developed hepatitis and drowsiness with tremor, 5 days after starting isoniazid, rifampin and pyrazinamide [bilirubin 3.2 mg/dL, ALT 658 U/L, prothrombin index 12%], resolving spontaneously despite continuing anticonvulsants and later tolerating reintroduction of rifampin and pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.sharma.2004.167">Sharma SK. Antituberculosis drugs and hepatotoxicity. <span><span class="ref-journal">Infect Genet Evol. </span>2004;<span class="ref-vol">4</span>:167–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15157635" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15157635</span></a>]<div>
|
||
<i>(Review of hepatotoxicity of isoniazid, rifampin and pyrazinamide with focus on role of acetylator status).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kandula.2004.163">Kandula NR, Dworkin MS, Carroll MR, Lauderdale DS. Tuberculosis prevention in Mexican immigrants: limitations of short-course therapy. <span><span class="ref-journal">Am J Prev Med. </span>2004;<span class="ref-vol">26</span>:163–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14751331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14751331</span></a>]<div>
|
||
<i>(Among 34 immigrants and contacts of a patient with multidrug resistant tuberculosis treated with rifampin/pyrazinamide, 1 of 11 children [9%] and 4 of 23 adults [17%] developed hepatotoxicity [ALT 165-547 U/L] after 10-53 days; all recovered and were able to finish 4 months of rifampin; points out impracticality of biochemical monitoring in immigrant population).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.mcelroy.2005.1125">McElroy PD, Ijaz K, Lambert LA, Jereb JA, Iademarco MF, Castro KG, Navin TR. National survey to measure rates of liver injury, hospitalization, and death associated with rifampin and pyrazinamide for latent tuberculosis infection. <span><span class="ref-journal">Clin Infect Dis. </span>2005;<span class="ref-vol">41</span>:1125–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16163632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16163632</span></a>]<div>
|
||
<i>(Survey of 110 health care programs using the 2 month rifampin/pyrazinamide regimen for latent tuberculosis in 8087 patients between 2000-2; ALT elevations >5 times ULN occurred in 2.4% and hepatitis in 1.9% with 23 hospitalizations and 7 deaths [0.1%] due to acute liver injury; higher than historical rates with isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cook.2006.892">Cook PP. Rifampin and pyrazinamide for treatment of latent tuberculosis infection. <span><span class="ref-journal">Clin Infect Dis. </span>2006;<span class="ref-vol">42</span>:892–author reply 892-3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16477576" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16477576</span></a>]<div>
|
||
<i>(Letter in response to McElroy [2005] questioning use of ALT for AST values used to define hepatotoxicity rates; reply by authors suggesting use of “AT” to indicate both enzymes).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.younossian.2005.462">Younossian AB, Rochat T, Ketterer JP, Wacker J, Janssens JP. High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. <span><span class="ref-journal">Eur Respir J. </span>2005;<span class="ref-vol">26</span>:462–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16135729" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16135729</span></a>]<div>
|
||
<i>(Among 12 persons treated with pyrazinamide and ethambutol for latent tuberculosis and contact with a patient with multidrug resistant disease, 7 developed liver injury [ALT 82-1338 U/L], after 87-247 days, 3 with symptoms, no mention of bilirubin levels).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.potolidis.2005.155">Potolidis E, Mantadakis E, Zeniodi MH, Samonis G. Rifampin plus pyrazinamide-induced hepatitis requiring hospitalization in a 30-y-old male with latent tuberculosis. <span><span class="ref-journal">Scand J Infect Dis. </span>2005;<span class="ref-vol">37</span>:155–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15773037" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15773037</span></a>]<div>
|
||
<i>(30 year old man developed nausea and dehydration 6 weeks after starting rifampin and pyrazinamide for latent tuberculosis [bilirubin normal, ALT “in the range of 600 to 2000” U/L], resolving within 3 weeks of stopping).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lee.2005.1304">Lee BH, Koh WJ, Choi MS, Suh GY, Chung MP, Kim H, Kwon OJ. Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy. <span><span class="ref-journal">Chest. </span>2005;<span class="ref-vol">127</span>:1304–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15821209" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15821209</span></a>]<div>
|
||
<i>(Retrospective case control study of 110 HBsAg carriers and 97 controls from Korea who received 3-4 drug antituberculosis therapy; any ALT elevations occurred in 34% of carriers vs 20% of controls and were >3 times ULN in 8% vs 4%; no risk factors identified, most tolerated reintroduction of therapy without pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lobato.2005.1296">Lobato MN, Reves RR, Jasmer RM, Grabau JC, Bock NN, Shang N. 2RZ Study Group. Adverse events and treatment completion for latent tuberculosis in jail inmates and homeless persons. <span><span class="ref-journal">Chest. </span>2005;<span class="ref-vol">127</span>:1296–303.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15821208" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15821208</span></a>]<div>
|
||
<i>(Analysis of 2 month course of rifampin and pyrazinamide in jail and homeless populations found ALT elevations >5 times ULN in 6% of patients, one of whom died of acute liver failure, risk factors were older age and baseline ALT levels).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.idilman.2006.1427">Idilman R, Ersoz S, Coban S, Kumbasar O, Bozkaya H. Antituberculous therapy-induced fulminant hepatic failure: successful treatment with liver transplantation and nonstandard antituberculous therapy. <span><span class="ref-journal">Liver Transpl. </span>2006;<span class="ref-vol">12</span>:1427–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16933231" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16933231</span></a>]<div>
|
||
<i>(19 year old woman with peritoneal tuberculosis developed jaundice 4 days after starting isoniazid, rifampin, ethambutol and pyrazinamide [bilirubin 10.5 mg/dL, ALT 1332 U/L, protime 71 sec], undergoing living donor liver transplantation within 2 days and afterwards treated with streptomycin, ethambutol and cycloserine with no recurrence).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.yew.2006.699">Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. <span><span class="ref-journal">Respirology. </span>2006;<span class="ref-vol">11</span>:699–707.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17052297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17052297</span></a>]<div>
|
||
<i>(Review of incidence, causes, risk factors and management of hepatotoxicity of antituberculosis medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.senaratne.2006.9">Senaratne WV, Pinidiyapathirage MJ, Perera GA, Wickremasinghe AR. Anti-tuberculosis drug induced hepatitis – a Sri Lankan experience. <span><span class="ref-journal">Ceylon Med J. </span>2006;<span class="ref-vol">51</span>:9–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16898030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16898030</span></a>]<div>
|
||
<i>(Among 783 patients treated for active tuberculosis, 9.5% developed hepatitis; major risk factor being older age).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cook.2006.271">Cook PP, Maldonado RA, Yarnell CT, Holbert D. Safety and completion rate of short-course therapy for treatment of latent tuberculosis infection. <span><span class="ref-journal">Clin Infect Dis. </span>2006;<span class="ref-vol">43</span>:271–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16804838" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16804838</span></a>]<div>
|
||
<i>(Retrospective analysis of 459 patients treated in public health departments for latent tuberculosis; completion rates were 78% for 2 months of rifampin/pyrazinamide vs 66% for 9 months of isoniazid; any ALT elevations in 18% vs 11%; ALT >5 times ULN in 6% vs 2%; no deaths).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.schechter.2006.922">Schechter M, Zajdenverg R, Falco G, Barnes GL, Faulhaber JC, Coberly JS, Moore RD, et al. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2006;<span class="ref-vol">173</span>:922–6.</span> [<a href="/pmc/articles/PMC2662911/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2662911</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16474028" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16474028</span></a>]<div>
|
||
<i>(In trial comparing rifapentine with isoniazid for 3 months [n=206] vs rifampin and pyrazinamide for 2 months [n=193]; hepatotoxicity arose in 10% on pyrazinamide vs 1% on isoniazid combination, all resolved within two months, no hospitalizations or deaths).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.forget.2006.231">Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. <span><span class="ref-journal">Expert Opin Drug Saf. </span>2006;<span class="ref-vol">5</span>:231–49.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16503745" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16503745</span></a>]<div>
|
||
<i>(Review of side effects including hepatotoxicity of isoniazid, rifampin, ethambutol and pyrazinamide; overall rate of hepatotoxicity from pyrazinamide is 1.3-2.5%).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ijaz.2006.346">Ijaz K, Jereb JA, Lambert LA, Bower WA, Spradling PR, McElroy PD, Iademarco MF, et al. Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis infection. <span><span class="ref-journal">Clin Infect Dis. </span>2006;<span class="ref-vol">42</span>:346–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16392079" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16392079</span></a>]<div>
|
||
<i>(Analysis of 50 cases of severe hepatotoxicity from rifampin/pyrazinamide therapy of latent tuberculosis occurring in US between 1998-2004 and arising during or within 1 month of stopping therapy; fatality rate higher in older patients and with later onset; patients frequently on other potentially hepatotoxic medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.shigeto.2007.467">Shigeto E., Committee for Treatment Japanese Society for Tuberculosis. <span><span class="ref-journal">Kekkaku. </span>2007;<span class="ref-vol">82</span>:467–73.</span> [Survey of anti-tuberculosis drug-induced severe liver injury in Japan] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/17564126" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17564126</span></a>]<div>
|
||
<i>(Abstract: Survey questionnaire to 114 Japanese hospitals identified 70 cases of severe liver injury and 8 deaths due to antituberculosis therapy between 1994-2003).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.sabat_.2007.1401">Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. <span><span class="ref-journal">Aliment Pharmacol Ther. </span>2007;<span class="ref-vol">25</span>:1401–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17539979" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17539979</span></a>]<div>
|
||
<i>(Population based survey of 126 cases of acute liver injury due to drugs between 1993-1999 in Spain calculated relative risk of injury compared to the general population to be 1300 with use of triple therapy [isoniazid, rifampin and pyrazinamide] and 154 for isoniazid alone, ranking first and third).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.marra.2007.868">Marra F, Marra CA, Bruchet N, Richardson K, Moadebi S, Elwood RK, Fitzgerald JM. Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2007;<span class="ref-vol">11</span>:868–75.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17705952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17705952</span></a>]<div>
|
||
<i>(Among 1061 patients treated for active tuberculosis in British Columbia between 2000-2005 [usually with 3-4 drugs for ~8 months], 148 [14%: 2% per month] developed hepatitis defined by ALT >5 times ULN or symptoms and ALT >3 times ULN]; independent risk factors were pyrazinamide, female sex, older age and baseline ALT levels, but not HBV, HCV or race).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kwon.2007.803">Kwon YS, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ. Hepatitis C virus infection and hepatotoxicity during antituberculosis chemotherapy. <span><span class="ref-journal">Chest. </span>2007;<span class="ref-vol">131</span>:803–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17356096" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17356096</span></a>]<div>
|
||
<i>(Retrospective analysis of 54 patients with HCV infection and 97 controls receiving therapy for active tuberculosis; ALT >3 times ULN occurred in 13% of HCV infected vs 4% of controls; none died or required hospitalization).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.huang.2007.1">Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. <span><span class="ref-journal">Expert Opin Drug Metab Toxicol. </span>2007;<span class="ref-vol">3</span>:1–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17269890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17269890</span></a>]<div>
|
||
<i>(Two gene variants have been linked to an increased risk of hepatotoxicity of antituberculosis medications; NAT2 and CYP 2E1, but the associations require further confirmation).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.aouam.2007.253">Aouam K, Chaabane A, Loussaïef C, Ben Romdhane F, Boughattas NA, Chakroun M. <span><span class="ref-journal">Med Mal Infect. </span>2007;<span class="ref-vol">37</span>:253–61.</span> [Adverse effects of antitubercular drugs: epidemiology, mechanisms, and patient management] French. [<a href="https://pubmed.ncbi.nlm.nih.gov/17336011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17336011</span></a>]<div>
|
||
<i>(Review of toxicities of antituberculosis agents; pyrazinamide is the most likely agent to cause side effects which can include hepatocellular injury, which is more common with higher doses and arising within the first 2 months of therapy).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.marzuki.2008.688">Marzuki OA, Fauzi AR, Ayoub S, Kamarul Imran M. Prevalence and risk factors of anti-tuberculosis drug-induced hepatitis in Malaysia. <span><span class="ref-journal">Singapore Med J. </span>2008;<span class="ref-vol">49</span>:688–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18830542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18830542</span></a>]<div>
|
||
<i>(Among 473 patients treated for tuberculosis, 46 [9.7%] developed ALT elevations >3 times ULN; in a case control analysis, concurrent HIV infection was a risk factor).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.makhlouf.2008.353">Makhlouf HA, Helmy A, Fawzy E, El-Attar M, Rashed HA. A prospective study of antituberculous drug-induced hepatotoxicity in an area endemic for liver diseases. <span><span class="ref-journal">Hepatol Int. </span>2008;<span class="ref-vol">2</span>:353–60.</span> [<a href="/pmc/articles/PMC2716885/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2716885</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19669265" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19669265</span></a>]<div>
|
||
<i>(Among 100 Middle Eastern patients treated for active tuberculosis, 15% had liver toxicity arising in 15-60 days, resolving in 15-45 days of stopping; bilirubin >2 in 5%, 1 death; able to restart therapy in all).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.leiro.2008.835">Leiro V, Fernández-Villar A, Valverde D, Constenla L, Vázquez R, Piñeiro L, González-Quintela A. Influence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population. <span><span class="ref-journal">Liver International. </span>2008;<span class="ref-vol">28</span>:835–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18397238" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18397238</span></a>]<div>
|
||
<i>(Case control study of 35 cases of hepatotoxicity from antituberculosis therapy and 60 controls; found higher rate of T1 GST variants in cases [49%] than controls [27%]; no difference for M1 variants [34% vs 42%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.possuelo.2008.673">Possuelo LG, Castelan JA, de Brito TC, Ribeiro AW, Cafrune PI, Picon PD, Santos AR, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. <span><span class="ref-journal">Eur J Clin Pharmacol. </span>2008;<span class="ref-vol">64</span>:673–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18421452" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18421452</span></a>]<div>
|
||
<i>(Among 17 persons given pyrazinamide and levofloxacin for latent tuberculosis after contact with multidrug resistant tuberculosis, adverse reactions were common, 5 [29%] had ALT elevations [peak 80-504 U/L]; all recovered).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.chang.2008.1391">Chang KC, Leung CC, Yew WW, Lau TY, Tam CM. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2008;<span class="ref-vol">177</span>:1391–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18388355" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18388355</span></a>]<div>
|
||
<i>(Among 3007 patients starting antituberculosis therapy over a six month period, 150 [5.0%] developed ALT elevations >3 times ULN including 48 that arose after 3 months; in a case control analysis, risk factors were hepatitis B and C and regimens with pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.vieira.2008.1049">Vieira DE, Gomes M. Adverse effects of tuberculosis treatment: experience at an outpatient clinic of a teaching hospital in the city of São Paulo, Brazil. <span><span class="ref-journal">J Bras Pneumol. </span>2008;<span class="ref-vol">34</span>:1049–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19180340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19180340</span></a>]<div>
|
||
<i>(Among 297 patients treated for tuberculosis between 2000 and 2006, 24 [10.6%] had hepatotoxicity, 7 [2.4%] symptomatic, no deaths).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.yimer.2008.e1809">Yimer G, Aderaye G, Amogne W, Makonnen E, Aklillu E, Lindquist L, Yamuah L, et al. Anti-tuberculosis therapy-induced hepatotoxicity among Ethiopian HIV-positive and negative patients. <span><span class="ref-journal">PLoS One. </span>2008;<span class="ref-vol">3</span>:e1809. </span> [<a href="/pmc/articles/PMC2265547/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2265547</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18350147" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18350147</span></a>]<div>
|
||
<i>(Between 2004-5, 103 HIV-positive and 94 HIV-negative patients were treated for tuberculosis; subclinical hepatotoxicity occurred in 17% and clinical apparent liver injury with jaundice in 4.1%; risk factors were HIV-positivity and other drug intake, but not age, sex, hepatitis or body mass index).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.sun.2008.994">Sun F, Chen Y, Xiang Y, Zhan S. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2008;<span class="ref-vol">12</span>:994–1002.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18713495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18713495</span></a>]<div>
|
||
<i>(Prospective study in 261 patients treated for tuberculosis; 16% developed hepatitis [ALT or AST > times 5 times ULN or >3 times with symptoms/jaundice], predictive factors were preexisting elevations or low albumin; 49% had at least one ALT or AST elevation, 25% >2 times, 17% >3 times and 10% >5 times ULN).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kaneko.2008.13">Kaneko Y, Nagayama N, Kawabe Y, Shimada M, Suzuki J, Kunogi M, Matsui Y, et al. <span><span class="ref-journal">Kekkaku. </span>2008;<span class="ref-vol">83</span>:13–9.</span> [Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/18283910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18283910</span></a>]<div>
|
||
<i>(Abstract: there was a substantial increase in frequency of ALT elevations in patients with chronic hepatitis C associated with pyrazinamide therapy).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.p_v_k.2008.51">P V K. Palaian S, Ojha P, P R S. Pattern of adverse drug reactions experienced by tuberculosis patients in a tertiary care teaching hospital in Western Nepal. <span><span class="ref-journal">Pak J Pharm Sci. </span>2008;<span class="ref-vol">21</span>:51–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18166520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18166520</span></a>]<div>
|
||
<i>(Abstract: Retrospective analysis of 326 Nepalese patients treated for tuberculosis identified 24 [7.4%] with AST elevations; no fatalities from liver disease).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.tostmann.2008.192">Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WC, van der Ven AJ, Dekhuijzen R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. <span><span class="ref-journal">J Gastroenterol Hepatol. </span>2008;<span class="ref-vol">23</span>:192–202.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17995946" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17995946</span></a>]<div>
|
||
<i>(Review of incidence, pathogenesis, clinical course, risk factors and management of drug induced liver disease due to antituberculosis medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.centers_for_disease_control_and_prevention_cdc_.2009.249">Centers for Disease Control and Prevention(CDC). Trends in tuberculosis—United States, 2008. <span><span class="ref-journal">MMWR Morb Mortal Wkly Rep. </span>2009;<span class="ref-vol">58</span>:249–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19300406" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19300406</span></a>]<div>
|
||
<i>(In 2008, 12,898 cases of active tuberculosis in US were reported, lowest rate since reporting began in 1953; incidence rate=3/100,000; 1.2% with multidrug resistant strains).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.chalasani.2008.1924">Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. <span><span class="ref-journal">Gastroenterology. </span>2008;<span class="ref-vol">135</span>:1924–34.</span> [<a href="/pmc/articles/PMC3654244/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3654244</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18955056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18955056</span></a>]<div>
|
||
<i>(Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008; isoniazid accounted for 13 cases [4%, ranking 2nd in frequency], pyrazinamide 1, rifampin 1, and isoniazid combined with other agents 2).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.semfke.2009.159">Semfke A, Wackernagel C, Vier H, Schütz A, Wiechmann V, Gillissen A. Histologically proven isoniazid hepatoxicity in complicated tuberculous salpingitis. <span><span class="ref-journal">Ther Adv Respir Dis. </span>2009;<span class="ref-vol">3</span>:159–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19723821" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19723821</span></a>]<div>
|
||
<i>(49 year old woman with suspected tuberculous salpingitis developed fever and ALT elevations 1 month after starting isoniazid, rifampin and pyrazinamide, resolved only when she stopped isoniazid, later tolerating rifampin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ho.2009.1526">Ho CC, Chen YC, Hu FC, Yu CJ, Yang PC, Luh KT. Safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens. <span><span class="ref-journal">Clin Infect Dis. </span>2009;<span class="ref-vol">48</span>:1526–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19400686" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19400686</span></a>]<div>
|
||
<i>(Among 1191 patients treated for active tuberculosis, 134 [11%] developed liver injury [risk factors were baseline ALT levels and pyrazinamide use]; then treated with ethambutol with or without streptomycin and randomized to also receive levofloxacin or moxifloxacin, only 1 in each group continued to have ALT elevations and most were then able to restart isoniazid and rifampin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.walker.2009.918">Walker NF, Kliner M, Turner D, Bhagani S, Cropley I, Hopkins S, Lipman M. Hepatotoxicity and antituberculosis therapy: time to revise UK guidance? <span><span class="ref-journal">Thorax. </span>2009;<span class="ref-vol">64</span>:918.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19786720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19786720</span></a>]<div>
|
||
<i>(During a one year period, 14 of 94 patients [15%] with active tuberculosis developed ALT elevations >3 times ULN during therapy; more common in HIV-positive [35%] than -negative [7%]; recommended routine HIV screening and biochemical monitoring in high risk groups).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.tostmann.2010.268">Tostmann A, van den Boogaard J, Semvua H, Kisonga R, Kibiki GS, Aarnoutse RE, Boeree MJ. Antituberculosis drug-induced hepatotoxicity is uncommon in Tanzanian hospitalized pulmonary TB patients. <span><span class="ref-journal">Trop Med Int Health. </span>2010;<span class="ref-vol">15</span>:268–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20409289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20409289</span></a>]<div>
|
||
<i>(Among 112 Tanzanian patients with tuberculosis monitored during first 2 months of therapy with isoniazid, rifampin, pyrazinamide and ethambutol, only 7 [6.3%] had ALT elevations [peak level 87 U/L], but none required dose modification).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.sharma.2010.833">Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, Sreenivas V, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. <span><span class="ref-journal">Clin Infect Dis. </span>2010;<span class="ref-vol">50</span>:833–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20156055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20156055</span></a>]<div>
|
||
<i>(175 patients with hepatic injury [ALT or AST >5 times ULN or symptoms with ALT elevations] attributed to antituberculosis medications were randomized to 3 different approaches to restarting therapy after initial episode resolved; 11% had recurrence with rates similar for all three regimens [starting agents at full doses or gradual escalation], onset in 5-35 days, none fatal and few with jaundice).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.saukkonen.2010.840">Saukkonen J. Challenges in reintroducing tuberculosis medications after hepatotoxicity. <span><span class="ref-journal">Clin Infect Dis. </span>2010;<span class="ref-vol">50</span>:840–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20156056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20156056</span></a>]<div>
|
||
<i>(Editorial in response to Sharma [2010], discussing the paradox of why the injury does not recur more often, whether rechallenge should be with one agent at a time, and whether such rechallenge is warranted in patients with severe hepatotoxicity).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.pasipanodya.2010.2847">Pasipanodya JG, Gumbo T. Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used. <span><span class="ref-journal">Antimicrob Agents Chemother. </span>2010;<span class="ref-vol">54</span>:2847–54.</span> [<a href="/pmc/articles/PMC2897291/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2897291</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20439617" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20439617</span></a>]<div>
|
||
<i>(The investigators conducted a systematic review of the literature and metaanalysis; findings indicated lack of association between high dose/exposure and liver toxicity; they concluded that attributable toxicity is idiosyncratic).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ferrajolo.2010.721">Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. <span><span class="ref-journal">Br J Clin Pharmacol. </span>2010;<span class="ref-vol">70</span>:721–8.</span> [<a href="/pmc/articles/PMC2997312/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2997312</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21039766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21039766</span></a>]<div>
|
||
<i>(Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, 2 antituberculosis agents were among the top 40 cases, including isoniazid [24th, 47 cases], and rifampin [35th, 37 cases]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.reuben.2010.2065">Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. <span><span class="ref-journal">Hepatology. </span>2010;<span class="ref-vol">52</span>:2065–76.</span> [<a href="/pmc/articles/PMC3992250/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3992250</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20949552" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20949552</span></a>]<div>
|
||
<i>(Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury and 25 to antituberculosis agents, including 15 to isoniazid alone [ranking first], 6 to isoniazid combined with other agents, 3 to rifampin and pyrazinamide and 1 to dapsone).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.devarbhavi.2010.2396">Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. <span><span class="ref-journal">Am J Gastroenterol. </span>2010;<span class="ref-vol">105</span>:2396–404.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20648003" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20648003</span></a>]<div>
|
||
<i>(Among 313 cases of drug induced liver injury seen between 1997 and 2008 at a large hospital in Bangalore, India, 181 [58%] were attributed to antituberculosis agents which accounted for 39 of 54 [72%] fatal cases).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.molleston.2011.182">Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N. Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. <span><span class="ref-journal">J Pediatr Gastroenterol Nutr. </span>2011;<span class="ref-vol">53</span>:182–9.</span> [<a href="/pmc/articles/PMC3634369/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3634369</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21788760" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21788760</span></a>]<div>
|
||
<i>(Among 30 children with suspected drug induced liver injury, 3 were attributed to isoniazid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.coca.2010.624">Coca NS, Oliveira MS, Voieta I, Antunes CM, Lambertucci JR. Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity. <span><span class="ref-journal">Rev Soc Bras Med Trop. </span>2010;<span class="ref-vol">43</span>:624–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21181011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21181011</span></a>]<div>
|
||
<i>(Using different definitions, rates of hepatotoxicity during antituberculosis therapy were either the same or higher among HIV infected than noninfected subjects).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ichai.2010.1136">Ichai P, Saliba F, Antoun F, Azoulay D, Sebagh M, Antonini TM, Escaut L, Delvart V, Castaing D, Samuel D. Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation. <span><span class="ref-journal">Liver Transpl. </span>2010;<span class="ref-vol">16</span>:1136–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20879012" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20879012</span></a>]<div>
|
||
<i>(Description of 14 patients with acute liver failure due to antituberculosis therapy presenting between 1986 and 2008, including 4 men and 10 women, ages 17 to 64 years, on therapy for 1 week to 9 months with isoniazid alone [n=1] or in combination with rifampin, pyrazinamide and ethambutol [bilirubin 1.8 to 39 mg/dL, ALT 214-2020], 7 recovering spontaneously, 6 undergoing liver transplantation, and one dying without transplant).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.baniasadi.2010.1235">Baniasadi S, Eftekhari P, Tabarsi P, Fahimi F, Raoufy MR, Masjedi MR, Velayati AA. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. <span><span class="ref-journal">Eur J Gastroenterol Hepatol. </span>2010;<span class="ref-vol">22</span>:1235–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20461008" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20461008</span></a>]<div>
|
||
<i>(Among 60 patients started on antituberculosis therapy using 4 drugs with or without concurrent N-acetylcysteine [NAC: 600 mg twice daily], hepatotoxicity arose in 37% of controls vs 0% of NAC treated subjects, the injury usually arising within the first week and resolving within 8 days of stopping).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lobue.2010.603">Lobue P, Menzies D. Treatment of latent tuberculosis infection: An update. <span><span class="ref-journal">Respirology. </span>2010;<span class="ref-vol">15</span>:603–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20409026" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20409026</span></a>]<div>
|
||
<i>(Extensive review of the efficacy and safety of various regimens used in the treatment of latent tuberculosis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.leung.2011.690">Leung CC, Rieder HL, Lange C, Yew WW. Treatment of latent infection with Mycobacterium tuberculosis: update 2010. <span><span class="ref-journal">Eur Respir J. </span>2011;<span class="ref-vol">37</span>:690–711.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20693257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20693257</span></a>]<div>
|
||
<i>(Review of the efficacy, adherence rates, cost effectiveness and safety of various regimens for the therapy of latent tuberculosis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.nader.2010.70">Nader LA, de Mattos AA, Picon PD, Bassanesi SL, De Mattos AZ, Pineiro Rodriguez M. Hepatotoxicity due to rifampicin, isoniazid and pyrazinamide in patients with tuberculosis: is anti-HCV a risk factor? <span><span class="ref-journal">Ann Hepatol. </span>2010;<span class="ref-vol">9</span>:70–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20308724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20308724</span></a>]<div>
|
||
<i>(Retrospective analysis of 534 patients treated for tuberculosis between 1998 and 2006 found that HIV positivity and high doses of isoniazid were independently associated with a higher risk of hepatotoxicity).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.donald.2011.e16">Donald PR. Antituberculosis drug-induced hepatotoxicity in children. <span><span class="ref-journal">Pediatr Rep. </span>2011;<span class="ref-vol">3</span>:e16. </span> [<a href="/pmc/articles/PMC3133498/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3133498</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21772953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21772953</span></a>]<div>
|
||
<i>(Extensive review of the literature on hepatotoxicity of antituberculosis medications in children concluded that liver injury occurs in children with isoniazid, pyrazinamide and rifampin, but at a lower rate than in adults).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.thongraung.2012.1119">Thongraung W, Sittidach M, Khwansuwan P, Sariyasuntorn K, Wongsampan S. Evaluation of the physicians' approach to the diagnosis and treatment of patients with antituberculosis drug-induced hepatotoxicity. <span><span class="ref-journal">J Eval Clin Pract. </span>2012;<span class="ref-vol">18</span>:1119–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21696520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21696520</span></a>]<div>
|
||
<i>(Survey of physician practices in Southern Thailand found variability in diagnosis and management of tuberculosis which were not always in compliance with published guidelines).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.perriot.2011.542">Perriot J, Chambonnet E, Eschalier A. <span><span class="ref-journal">Rev Mal Respir. </span>2011;<span class="ref-vol">28</span>:542–55.</span> [Managing the adverse events of antitubercular agents] French. [<a href="https://pubmed.ncbi.nlm.nih.gov/21549908" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21549908</span></a>]<div>
|
||
<i>(Review of the side effects of antituberculosis medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.devarbhavi.2011.167">Devarbhavi H. Antituberculous drug-induced liver injury: current perspective. <span><span class="ref-journal">Trop Gastroenterol. </span>2011;<span class="ref-vol">32</span>:167–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22332331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22332331</span></a>]<div>
|
||
<i>(Review of hepatotoxicity of antituberculosis medications).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.leirofernandez.2011.1403">Leiro-Fernandez V, Valverde D, Vázquez-Gallardo R, Botana-Rial M, Constenla L, Agúndez JA, Fernández-Villar A. N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2011;<span class="ref-vol">15</span>:1403–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22283902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22283902</span></a>]<div>
|
||
<i>(Analysis of N-acetyltransferase 2 polymorphisms in 50 Spanish patients with ALT elevations on antituberculosis therapy and in 67 controls found no difference in acetylation status).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.donald.2011.e16_1">Donald PR. Antituberculosis drug-induced hepatotoxicity in children. <span><span class="ref-journal">Pediatr Rep. </span>2011;<span class="ref-vol">3</span>:e16. </span> [<a href="/pmc/articles/PMC3133498/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3133498</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21772953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21772953</span></a>]<div>
|
||
<i>(Review of the hepatotoxicity and antituberculosis medications in children; rates of hepatotoxicity are lower in children than adults, ALT elevations occurring in 10% and jaundice in 0.8% of those receiving antituberculosis therapy and at lower rates with chemo-prophylaxis).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.whitney.2011.2780">Whitney J, Hurwitz M, Mojtahed A, Hwang C, Gallo A. Acute liver failure in a pediatric patient with disseminated tuberculosis. <span><span class="ref-journal">Dig Dis Sci. </span>2011;<span class="ref-vol">56</span>:2780–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21695402" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21695402</span></a>]<div>
|
||
<i>(7 year old boy developed jaundice and mental confusion 2 months after starting therapy with isoniazid, pyrazinamide, rifampin, ethambutol, fluconazole and ceftriaxone [bilirubin 6.5 mg/dL, ALT 396 U/L, GGT 207 U/L, INR 3.6], resolving spontaneously after stopping the regimen and switching to amikacin, cycloserine, ethambutol, levofloxacin and linezolid).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kim.2012.809">Kim SH, Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, Park JS, et al. TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis. <span><span class="ref-journal">Liver Int. </span>2012;<span class="ref-vol">32</span>:809–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22151084" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22151084</span></a>]<div>
|
||
<i>(Analysis of polymorphisms of TNF alpha in 77 Korean patients who developed ALT elevations >3 times ULN on antituberculosis therapy and 229 who did not , found slightly higher rate of variant allele [-308G/A] associated with hepatotoxicity [26% vs 15%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.malla.2012.e35">Malla I, Fauda M, Casanueva E, Fernández MI, Amante M, Cheang Y, Giacove G, et al. <span><span class="ref-journal">Arch Argent Pediatr. </span>2012;<span class="ref-vol">110</span>:e35–8.</span> [Fulminant hepatic failure due to tuberculostatic drugs: case report] Spanish. [<a href="https://pubmed.ncbi.nlm.nih.gov/22760756" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22760756</span></a>]<div>
|
||
<i>(10 year old girl developed jaundice 40 days after starting isoniazid, pyrazinamide and rifampin [bilirubin 13 mg/dL, ALT 37 times ULN, INR 8.5], developing progressive hepatic failure and undergoing successful liver transplantation 2 days after admission).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cai.2012.e47769">Cai Y, Yi J, Zhou C, Shen X. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. <span><span class="ref-journal">PLoS One. </span>2012;<span class="ref-vol">7</span>:e47769. </span> [<a href="/pmc/articles/PMC3474796/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3474796</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23082213" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23082213</span></a>]<div>
|
||
<i>(Metaanalysis of studies of genetic polymorphisms and hepatotoxicity of drugs for tuberculosis identified 38 publications including 2225 patients and 4906 controls; modest association was found between slow NAT2 acetylation genotypes and glutathione-S-transferase genotypes and hepatotoxicity, but largely in Asian populations).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.zhou.2013.825">Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. <span><span class="ref-journal">Eur J Gastroenterol Hepatol. </span>2013;<span class="ref-vol">25</span>:825–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23510965" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23510965</span></a>]<div>
|
||
<i>(Systematic review of the Chinese literature on drug induced liver injury from 1994 to 2011 identified 1119 reports on 21,789 patients; antituberculosis agents were the most commonly implicated drugs [31%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.nomi.2013.647">Nomi F, Hosaka K, Kurosawa T. <span><span class="ref-journal">Kekkaku. </span>2013 Sep;<span class="ref-vol">88</span>(9):647–51.</span> [A clinical investigation of seven patients with pulmonary tuberculosis who developed mixed liver injury during oral anti-tuberculosis treatment] Japanese. [<a href="https://pubmed.ncbi.nlm.nih.gov/24298690" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24298690</span></a>]<div>
|
||
<i>(Among 321 patients with tuberculosis treated at a single referral hospital during a 5 year period, 7 [2%] developed liver injury with a mixed pattern of enzyme elevations, onset averaging 28 days and resulting in fatality in one).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kato.2013.2209">Kato H, Horita N, Miyazawa N, Yoshiyama T, Ueda A, Ishigatsubo Y. Risk factors for liver injury with an elevated serum bilirubin concentration caused by antituberculous drugs. <span><span class="ref-journal">Intern Med. </span>2013;<span class="ref-vol">52</span>:2209–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24088753" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24088753</span></a>]<div>
|
||
<i>(In a retrospective analysis of potential risk factors for liver injury with jaundice due to antituberculosis agents, the level of activity of daily living and concurrent cardiac disease was found to be most strongly associated with occurrence of liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.miyazawa.2013.297">Miyazawa N, Horita N, Tomaru K, Tsukahara T, Takahashi R, Sasaki M, Ishigatsubo Y. <span><span class="ref-journal">Kekkaku. </span>2013;<span class="ref-vol">88</span>:297–300.</span> [Comparison of drug-induced hepatitis occurring in elderly and younger patients during anti-tuberculosis treatment with a regimen including pyrazinamide] [<a href="https://pubmed.ncbi.nlm.nih.gov/23672170" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23672170</span></a>]<div>
|
||
<i>(Among 36 Japanese patients with tuberculosis treated with isoniazid, pyrazinamide, rifampin and ethambutol, liver injury occurred in 12.5% over 80 and 14% less than 80 years of age).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.bj_rnsson.2013.1419">Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. <span><span class="ref-journal">Gastroenterology. </span>2013;<span class="ref-vol">144</span>:1419–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23419359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23419359</span></a>]<div>
|
||
<i>(In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, 2 [2%] of which were attributed to anti-tuberculosis agents, 1 isoniazid and 1 rifampin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.gupta.2013.959">Gupta VH, Singh M, Amarapurkar DN, Sasi P, Joshi JM, Baijal R. Association of GST null genotypes with anti-tuberculosis drug induced hepatotoxicity in Western Indian population. <span><span class="ref-journal">Ann Hepatol. </span>2013;<span class="ref-vol">12</span>:959–65.</span> H R PK, et al. [<a href="https://pubmed.ncbi.nlm.nih.gov/24114827" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24114827</span></a>]<div>
|
||
<i>(Among 296 patients being treated for tuberculosis, 17% developed ALT elevations during therapy and evidence of liver injury was associated with homozygous null mutations at both glutathione S transferase M1 and T1 gene loci).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.li.2013.859">Li C, Long J, Hu X, Zhou Y. GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis. <span><span class="ref-journal">Eur J Clin Microbiol Infect Dis. </span>2013;<span class="ref-vol">32</span>:859–68.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23377313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23377313</span></a>]<div>
|
||
<i>(Metaanalysis of studies on the association of tuberculosis drug associated liver injury and polymorphisms of the glutathione S-transferase genes found weak associations only).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.kumar.2014.5760">Kumar N, Kedarisetty CK, Kumar S, Khillan V, Sarin SK. Antitubercular therapy in patients with cirrhosis: challenges and options. <span><span class="ref-journal">World J Gastroenterol. </span>2014;<span class="ref-vol">20</span>:5760–72.</span> [<a href="/pmc/articles/PMC4024786/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4024786</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24914337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24914337</span></a>]<div>
|
||
<i>(Review of the frequency, pathogenesis and management of hepatotoxicity of antituberculosis therapy in patients with preexisting cirrhosis, who appear to have an increased risk of liver injury from these agents as well as an increased risk of severe outcomes).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.shin.2014.347">Shin HJ, Lee HS, Kim YI, Lim SC, Jung JP, Ko YC, Kwon YS. Hepatotoxicity of anti-tuberculosis chemotherapy in patients with liver cirrhosis. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2014;<span class="ref-vol">18</span>:347–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24670574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24670574</span></a>]<div><i>(Among 50 patients with cirrhosis and 147 controls without cirrhosis who had active tuberculosis and were treated with</i> <i>isoniazid</i><i>, rifampin ethambutol and pyrazinamide, abnormal liver tests arose in 72% of cirrhotics vs 46% of controls, and predefined "hepatotoxicity" arose in 8% vs 3%, but no patient required hospitalization or died).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.huang.2014.169">Huang YS. Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury. <span><span class="ref-journal">J Chin Med Assoc. </span>2014;<span class="ref-vol">77</span>:169–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24593909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24593909</span></a>]<div>
|
||
<i>(Critical review of studies on genetic variations associated with antituberculosis drug induced liver injury focusing on N-acetyltransferase (NAT), CYP 2E1, glutathione S transferase and manganese superoxide dismutase, the strongest association being with NAT and slow acetylator status).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.satyaraddi.2014.188">Satyaraddi A, Velpandian T, Sharma SK, Vishnubhatla S, Sharma A, Sirohiwal A, Makharia GK, et al. Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2014;<span class="ref-vol">18</span>:188–95.</span> i-iii. [<a href="https://pubmed.ncbi.nlm.nih.gov/24429311" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24429311</span></a>]<div><i>(Among 110 patients being treated for tuberculosis, 15 developed evidence of liver injury [enzyme or bilirubin elevations or symptoms]; plasma free rifampin, but not</i> <i>isoniazid</i> <i>or pyrazinamide, levels were higher in patients who developed liver injury than in those who did not).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.xiang.2014.e85905">Xiang Y, Ma L, Wu W, Liu W, Li Y, Zhu X, Wang Q, et al. The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. <span><span class="ref-journal">PLoS One. </span>2014;<span class="ref-vol">9</span>:e85905. </span> [<a href="/pmc/articles/PMC3900431/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3900431</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24465778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24465778</span></a>]<div>
|
||
<i>(Among 2244 patients treated for tuberculosis, 89 [4%] had aminotransferase elevations above 2 times and 0.4% above 5 times ULN after 2 months of treatment; evidence of liver injury was more common in persons with NAT2*5*CT genotype, slow acetylator phenotype, but not with CYP 2E1 polymorphisms).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.hern_ndez.2014.231">Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. <span><span class="ref-journal">Ann Hepatol. </span>2014;<span class="ref-vol">13</span>:231–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24552865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24552865</span></a>]<div>
|
||
<i>(Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 13 [7%] due to antituberculosis agents including 6 to isoniazid, 1 to pyrazinamide, 1 to rifampin and 5 to combinations).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.li.2015.e1665">Li X, Liu Y, Zhang E, He Q, Tang YB. Liver transplantation in antituberculosis drugs-induced fulminant hepatic failure: a case report and review of the literature. <span><span class="ref-journal">Medicine (Baltimore). </span>2015;<span class="ref-vol">94</span>:e1665. </span> [<a href="/pmc/articles/PMC5008466/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5008466</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656321" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656321</span></a>]<div>
|
||
<i>(39 year old Chinese woman developed jaundice 3 months after starting isoniazid, rifampin and pyrazinamide for latent tuberculosis [bilirubin 0.6 rising to 41.1 mg/dL, ALT 1414 U/L, Alk P xxx U/L, protime 71 sec], with progressive hepatic failure undergoing liver transplantation 4 months after onset complicated by acute and ultimately fatal chronic rejection).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.jeong.2015.167">Jeong I, Park JS, Cho YJ, Yoon HI, Song J, Lee CT, Lee JH. Drug-induced hepatotoxicity of anti-tuberculosis drugs and their serum levels. <span><span class="ref-journal">J Korean Med Sci. </span>2015;<span class="ref-vol">30</span>:167–72.</span> [<a href="/pmc/articles/PMC4310943/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4310943</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25653488" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25653488</span></a>]<div>
|
||
<i>(Among 195 Korean patients with tuberculosis treated with a 4-drug regimen of isoniazid, rifampin, ethambutol and pyrazinamide, drug levels taken within the first week of treatment did not correlate with subsequent rate or severity of antituberculosis drug induced liver injury [n=12: 6%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.sharma.2015.8">Sharma P, Tyagi P, Singla V, Bansal N, Kumar A, Arora A. Clinical and biochemical profile of tuberculosis in patients with liver cirrhosis. <span><span class="ref-journal">J Clin Exp Hepatol. </span>2015;<span class="ref-vol">5</span>:8–13.</span> [<a href="/pmc/articles/PMC4415191/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4415191</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25941429" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25941429</span></a>]<div>
|
||
<i>(Among 67 patients with cirrhosis treated for tuberculosis with isoniazid, rifampin, ethambutol and either orofloxacin or pyrazinamide, evidence of drug induced liver injury arose in 35% of cases, but none were attributed to ethambutol or pyrazinamide and there were no deaths attributed to drug toxicity).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.horita.2015.2315">Horita N, Miyazawa N, Yoshiyama T, Kojima R, Ishigatsubo Y, Kaneko T. Currently used low-dose pyrazinamide does not increase liver-injury in the first two months of tuberculosis treatment. <span><span class="ref-journal">Intern Med. </span>2015;<span class="ref-vol">54</span>:2315–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26370854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26370854</span></a>]<div>
|
||
<i>(Among 383 Chinese patients with tuberculosis treated with isoniazid, rifampin and ethambutol with or without pyrazinamide analyzed in a retrospective study, liver injury arising within the first two months of therapy was less frequent with four drug [8%] than 3-drug regimen [24%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.chalasani.2015.1340">Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. <span><span class="ref-journal">Gastroenterology. </span>2015;<span class="ref-vol">148</span>:1340–52.e7.</span> [<a href="/pmc/articles/PMC4446235/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4446235</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25754159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25754159</span></a>]<div>
|
||
<i>(Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 54 [6%] were attributed to antituberculosis agents including 48 to isoniazid, 2 to rifampin, 2 [0.2%] to pyrazinamide, 1 to ethambutol and 1 to isoniazid and rifampin).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.brightthomas.2016.1621">Bright-Thomas RJ, Gondker AR, Morris J, Ormerod LP. Drug-related hepatitis in patients treated with standard anti-tuberculosis chemotherapy over a 30-year period. <span><span class="ref-journal">Int J Tuberc Lung Dis. </span>2016;<span class="ref-vol">20</span>:1621–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27931337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27931337</span></a>]<div><i>(Among 2070 patients with tuberculosis treated over a 30 year period at a single UK referral center, 63 [3%] developed hepatitis requiring discontinuation of therapy of whom two died; the hepatitis rate was higher in whites than Asians and in females than males, and occurred more commonly with older age; 57% of cases were attributed to pyrazinamide, 32% to rifampin and 11% to</i> <i>isoniazid</i><i>).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.ji.2016.27706680">Ji GY, Wang Y, Wu SQ, Liu QQ, Wu JC, Zhang MM, Sandford AJ, et al. Association between TXNRD1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a prospective study. <span><span class="ref-journal">Genet Mol Res. </span>2016;<span class="ref-vol">15</span>:27706680. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27706680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27706680</span></a>]<div>
|
||
<i>(Among 248 patients with treated for tuberculosis, 24 [10%] developed evidence of drug induced liver injury, among whom thioredoxin reductase 1 gene variants [involved resistance to oxidative damage] were no different in distribution than among those who did not develop liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.guaoua.2016.680">Guaoua S, Ratbi I, El Bouazzi O, Hammi S, Tebaa A, Bourkadi JE, Bencheikh RS, et al. NAT2 genotypes in Moroccan patients with hepatotoxicity due to antituberculosis drugs. <span><span class="ref-journal">Genet Test Mol Biomarkers. </span>2016;<span class="ref-vol">20</span>:680–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27541622" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27541622</span></a>]<div>
|
||
<i>(Among 42 Moroccan patients with liver injury during antituberculosis therapy, there were no differences in frequency of acetylator status or in NAT2 genotypes compared to controls).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.wang.2016.334">Wang FJ, Wang Y, Niu T, Lu WX, Sandford AJ, He JQ. Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies. <span><span class="ref-journal">J Clin Pharm Ther. </span>2016;<span class="ref-vol">41</span>:334–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27062377" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27062377</span></a>]<div>
|
||
<i>(Metaanalysis of 26 studies involving 7423 patients found that the CYP2E1 RsaI/PstI c1/c1 polymorphism was associated with an increased risk for liver injury caused by antituberculosis therapy with an odds ratio of 1.32).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lin.2016.299">Lin HS, Cheng CW, Lin MS, Chou YL, Chang PJ, Lin JC, Ye JJ. The clinical outcomes of oldest old patients with tuberculosis treated by regimens containing rifampicin, isoniazid, and pyrazinamide. <span><span class="ref-journal">Clin Interv Aging. </span>2016;<span class="ref-vol">11</span>:299–306.</span> [<a href="/pmc/articles/PMC4795580/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4795580</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27042029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27042029</span></a>]<div><i>(Among 700 Taiwanese patients with active tuberculosis treated with</i> <i>isoniazid</i><i>, rifampin and pyrazinamide, hepatitis arose in 83 [12%] and was more frequent in those above the age of 80 years [17.4%] compared to younger [10.2%], but details on severity and clinical features were not provided).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.chen.2017.434">Chen G, Wu SQ, Feng M, Wang Y, Wu JC, Ji GY, Zhang MM, et al. Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han. <span><span class="ref-journal">Int J Immunopathol Pharmacol. </span>2017;<span class="ref-vol">30</span>:434–8.</span> [<a href="/pmc/articles/PMC5806809/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5806809</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28934901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28934901</span></a>]<div>
|
||
<i>(Among 247 Chinese patients who received antituberculosis therapy for at least 3 months, 24 [10%] developed evidence of hepatic injury, but there was no association with polymorphisms of UGT2B7 a major hepatic enzyme responsible for glucuronidation and excretion of drugs and xenobiotics).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.zenner.2017.248">Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of latent tuberculosis infection: an updated network meta-analysis. <span><span class="ref-journal">Ann Intern Med. </span>2017;<span class="ref-vol">167</span>:248–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28761946" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28761946</span></a>]<div><i>(A metaanalysis of 61 studies on regimens for therapy of "latent tuberculosis" found evidence of lower rates of hepatotoxicity with rifampin only or short courses of</i> <i>isoniazid</i> <i>and rifampin compared to longer</i> <i>isoniazid</i> <i>only regimens).</i></div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.wang.2017.198">Wang Y, Xiang X, Wu SQ, Chen G, Zhang MM, Wang MG, Wang FJ, et al. Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population. <span><span class="ref-journal">Infect Genet Evol. </span>2017;<span class="ref-vol">51</span>:198–202.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28389387" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28389387</span></a>]<div>
|
||
<i>(Among 343 Chinese patients treated for tuberculosis, several CYP2B6 gene polymorphisms were found to be associated with a reduced risk for hepatotoxicity).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.angamo.2018.790">Angamo MT, Chalmers L, Curtain CM, Yilma D, Bereznicki L. Mortality from adverse drug reaction-related hospitalizations in south-west Ethiopia: A cross-sectional study. <span><span class="ref-journal">J Clin Pharm Ther. </span>2018;<span class="ref-vol">43</span>:790–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29722039" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29722039</span></a>]<div>
|
||
<i>(Among 1001 patients admitted to an Ethiopian hospital over a 1 year period, 103 were admitted for an adverse drug reaction, 15 of which were fatal, with 7 due to liver failure, implicated agents being isoniazid, pyrazinamide, efavirenz and tenofovir).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.lee.2019.1207">Lee LN, Huang CT, Hsu CL, Chang HC, Jan IS, Liu JL, Sheu JC, et al. Mitochondrial DNA variants in patients with liver injury due to anti-tuberculosis drugs. <span><span class="ref-journal">J Clin Med. </span>2019;<span class="ref-vol">8</span>:1207.</span> [<a href="/pmc/articles/PMC6723168/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6723168</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31412578" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31412578</span></a>]<div>
|
||
<i>(Among 38 patients who developed liver injury during antituberculosis therapy, sequencing of mitochondrial DNA identified a higher frequency of point mutations in complex I NADH subunits 1 and 5 in isoniazid cases [n=8] but not in pyrazinamide [n=14] or rifampin [n=16] associated cases).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.hagiwara.2019.1026">Hagiwara E, Suido Y, Asaoka M, Katano T, Okuda R, Sekine A, Kitamura H, et al. Safety of pyrazinamide-including regimen in late elderly patients with pulmonary tuberculosis: A prospective randomized open-label study. <span><span class="ref-journal">J Infect Chemother. </span>2019;<span class="ref-vol">25</span>:1026–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31229376" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31229376</span></a>]<div>
|
||
<i>(Among 89 elderly patients [80 years or older] with tuberculosis treated with isoniazid, rifampin and ethambutol with or without pyrazinamide, rates of discontinuation were similar between the two groups [33% vs 35%] as well as rates of ALT or AST elevations above 2.5 times ULN [18% vs 23%]).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.wang.2019.2217">Wang Y, Xiang X, Huang WW, Sandford AJ, Wu SQ, Zhang MM, Wang MG, et al. Association of PXR and CAR polymorphisms and antituberculosis drug-induced hepatotoxicity. <span><span class="ref-journal">Sci Rep. </span>2019;<span class="ref-vol">9</span>:2217.</span> [<a href="/pmc/articles/PMC6379441/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6379441</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30778091" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30778091</span></a>]<div>
|
||
<i>(Among 502 patients with tuberculosis treated with isoniazid, rifampin, ethambutol and pyrazinamide 19% developed ALT elevations above 10 times ULN, several polymorphisms of PXR [but not CAR] were associated with a lower incidence of liver injury).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.dheda.2019.820">Dheda K, Gumbo T, Maartens G, Dooley KE, Murray M, Furin J, Nardell EA, Warren RM. Lancet Respiratory Medicine drug-resistant tuberculosis Commission group. The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis. <span><span class="ref-journal">Lancet Respir Med. </span>2019;<span class="ref-vol">7</span>:820–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31486393" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31486393</span></a>]<div>
|
||
<i>(Review of the epidemiology, pathogenesis, diagnosis and management of multidrug resistant tuberculosis; does not discuss hepatotoxicity of therapeutic drug regimens).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.oscanoa.2020.516">Oscanoa T, Moscol S, Amado J. Clinical characteristics of pyrazinamide-associated hepatotoxicity in patients at a hospital in Lima, Peru. <span><span class="ref-journal">Rev Peru Med Exp Salud Publica. </span>2020;<span class="ref-vol">37</span>:516–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33295555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33295555</span></a>]<div>
|
||
<i>(Among 10 patients with suspected pyrazinamide hepatotoxicity, the average age was 41 years and average time to onset 41 days [range 11 to 130 days], 20% with rash and 40% with jaundice, hepatocellular enzyme elevations in 5, resolving in all patients).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.zhao.2020.e920350">Zhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-induced liver injury from anti-tuberculosis treatment: a retrospective cohort study. <span><span class="ref-journal">Med Sci Monit. </span>2020;<span class="ref-vol">26</span>:e920350. </span> [<a href="/pmc/articles/PMC7077058/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7077058</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32145061" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32145061</span></a>]<div>
|
||
<i>(Among 140 patients with liver injury due to antituberculosis therapy seen between 2009 and 2015, the median age was 40, time to onset ranged from 7-90 days [mean=24], 35% had fever, 16% rash, 68% were hepatocellular, 21% were severe and 7% died; most patients had received isoniazid, rifampin and pyrazinamide).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.soni.2020.171">Soni H, Kumar-M P, Mishra S, Bellam BL, Singh H, Mandavdhare HS, Medhi B, et al. Risk of hepatitis with various reintroduction regimens of anti-tubercular therapy: a systematic review and network meta-analysis. <span><span class="ref-journal">Expert Rev Anti Infect Ther. </span>2020;<span class="ref-vol">18</span>:171–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31923369" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31923369</span></a>]<div>
|
||
<i>(Systematic review of the risk of recurrence of hepatotoxicity on reintroduction of antituberculosis agents after occurrence of drug induced liver injury indicated that sequential and incremental introduction is preferable to rechallenge with both agents concurrently).</i>
|
||
</div></div></li><li><div class="bk_ref" id="Pyrazinamide.REF.cdc">CDC. <a href="https://www.cdc.gov/tb/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>.cdc.gov/tb/</a><div><i>(CDC website with up-to-date recommendations on therapy of tuberculosis).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK547856/?report=reader">PubReader</a></li><li><a href="/books/NBK547856/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK547856" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK547856" style="display:none" title="Cite this Page"><div class="bk_tt">LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Pyrazinamide. [Updated 2020 Dec 20].<span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK547856/pdf/Bookshelf_NBK547856.pdf">PDF version of this page</a> (332K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>New and Updated</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22LiverTox%22+AND+pmcbook&sort=date&size=200" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">In PubMed</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/29/31/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download LiverTox data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Overviews</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/livertox/intro/">Introduction</a></li><li><a href="/books/n/livertox/ClinicalCourse/">Clinical Course</a></li><li><a href="/books/n/livertox/ClinicalOutcome/">Clinical Outcomes</a></li><li><a href="/books/n/livertox/ImmuneFeatures/">Immune Features</a></li><li><a href="/books/n/livertox/Phenotypes_intro/">Phenotypes</a></li><li><a href="/books/n/livertox/Causality/">Causality</a></li><li><a href="/books/n/livertox/DrugCategory/">Likelihood Scale</a></li><li><a href="/books/n/livertox/Severity/">Severity Grading</a></li><li><a href="/books/n/livertox/CaseReport/">Writing a Case Report</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Support Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/livertox/">LiverTox Homepage</a></li><li><a href="/books/n/livertox/masterlistintro/">Master List of LiverTox Drugs [with Metadata]</a></li><li><a href="/books/n/livertox/drugliverinjury/">LiverTox Drugs by Drug Class</a></li><li><a href="/books/n/livertox/aboutus/">About LiverTox</a></li><li><a href="/books/n/livertox/editorsandreviewers/">Editors and Review Committee</a></li><li><a href="/books/n/livertox/alert/">Meetings and News</a></li><li><a href="/books/n/livertox/abbreviation/">Abbreviations Used</a></li><li><a href="/books/n/livertox/glossary/">Glossary</a></li><li><a href="/books/n/livertox/resource/">Information Resources</a></li><li><a href="/books/n/livertox/disclaimer/">User/Medical Advice Disclaimer</a></li><li><a href="/books/n/livertox/Contactus/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>OTHER REFERENCE LINKS</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a href="https://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pubmed&pubmedfilters=true&term=(Pyrazinamide/AE)+AND+Human%5BMH%5D+AND+(drug+induced+liver+injury+OR+jaundice/CI+OR+bile+duct+diseases/CI+OR+liver/DE+OR+liver+diseases/CI)+AND+(%221900/1/1%22%5BEDat%5D:%222999/12/31%22%5BEDat%5D)" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Recent References on Pyrazinamide: from PubMed.gov</a>
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<a href="https://clinicaltrials.gov/ct2/results?term=Pyrazinamide" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Trials on Pyrazinamide: from ClinicalTrials.gov</a>
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Epub 2005 Sep 9.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/8902462" ref="ordinalpos=1&linkpos=4&log$=relatedarticles&logdbfrom=pubmed">Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis.</a><span class="source">[Eur Respir J. 1996]</span><div class="brieflinkpop offscreen_noflow">Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Schaberg T, Rebhan K, Lode H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Eur Respir J. 1996 Oct; 9(10):2026-30. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/345572" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.</a><span class="source">[Tubercle. 1978]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Girling DJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Tubercle. 1978 Mar; 59(1):13-32. </em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=31643193" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=31643193" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67c8e13ff4a390645e34c871">Pyrazinamide - LiverTox</a><div class="ralinkpop offscreen_noflow">Pyrazinamide - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67c8e13da68b6b5afc777159">Pyrantel - LiverTox</a><div class="ralinkpop offscreen_noflow">Pyrantel - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67c8e13da68b6b5afc776e07">Purine Analogues - LiverTox</a><div class="ralinkpop offscreen_noflow">Purine Analogues - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67c8e13cab82281a803f9892">Pulmonary Arterial Hypertension Agents - LiverTox</a><div class="ralinkpop offscreen_noflow">Pulmonary Arterial Hypertension Agents - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67c8e13bab82281a803f934b">Psoriasis Agents - LiverTox</a><div class="ralinkpop offscreen_noflow">Psoriasis Agents - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
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