The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Kazuya Higashino - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo study on the conversion of allopurinol and Pyrazinamide.
Advances in experimental medicine and biology, 1994Co-Authors: Yumiko Nasako, Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Zenta Tsutsumi, Kazuya HigashinoAbstract:Allopurinol is widely used in the treatment of gout. The main metabolic pathway of allopurinol is its oxidation to oxypurinol. Pyrazinamide is an antituberculous drug. One of the main metabolic pathways of Pyrazinamide is its oxidation to 5-hydroxyPyrazinamide. The oxidation of allopurinol and Pyrazinamide is known to be attributed to xanthine oxidase1, 2. However, it has been suggested that aldehyde oxidase also participates in the oxidation of these agents3, 4. Therefore, we investigated whether aldehyde oxidase plays a role in the oxidation of allopurinol and Pyrazinamide by in vivo and in vitro studies.
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Effect of BOF-4272 on the oxidation of allopurinol and Pyrazinamide in vivo: Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and Pyrazinamide?
Biochemical pharmacology, 1993Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Takashi Nakano, Kazuya HigashinoAbstract:Abstract Allopurinol or Pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxyPyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of Pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of Pyrazinamide during the period after the administration of Pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and Pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidazed both allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyprazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyPyrazinamide.
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In vitro oxidation of Pyrazinamide and allopurinol by rat liver aldehyde oxidase.
Biochemical pharmacology, 1993Co-Authors: Yuji Moriwaki, Tetsuya Yamamoto, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Kazuya HigashinoAbstract:Abstract Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with Mr of 2.7 × 105 on polyacrylamide gel electrophoresis (PAGE) and Mr of 1.35 × 105 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, Pyrazinamide and pyrazinoic acid was investigated. Allopurinol and Pyrazinamide were oxidized to oxypurinol and 5-hydroxyPyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of Pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for Pyrazinamide was 160 μM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or Pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of Pyrazinamide to 5-hydroxyPyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and Pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and Pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrzinamide.
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A Case of Xanthinuria: A Study on the Metabolism of Pyrazinamide and Allopurinol.
Japanese journal of medicine, 1991Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Michio Suda, Kazuomi Kario, Kazuya HigashinoAbstract:A 74-year-old female was diagnosed as having xanthinuria by measurement of the uric acid level in plasma, purine bases in urine and activity of xanthine oxidase in the duodenal mucosa. The determination of the urinary excretion of purine bases in her family demonstrated a slightly increased urinary excretion of oxypurines in her younger brother, suggesting that he was a heterozygote. The Pyrazinamide-loading test and allopurinolloading test demonstrated that she could neither metabolize pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol, although there was a slight metabolizing of prazinamide into 5-hydroxyPyrazinamide. This suggested that she belonged to the subgroup which can neither metabolize Pyrazinamide into 5-hydroxyPyrazinamide, pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol.
Matsie Mphahlele - One of the best experts on this subject based on the ideXlab platform.
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Pyrazinamide resistance among south african multidrug resistant mycobacterium tuberculosis isolates
Journal of Clinical Microbiology, 2008Co-Authors: Matsie Mphahlele, Heidi Syre, Havard Valvatne, Ruth Stavrum, Turid Mannsaker, Tshilidzi Muthivhi, Karin WeyerAbstract:Pyrazinamide is important in tuberculosis treatment, as it is bactericidal to semidormant mycobacteria not killed by other antituberculosis drugs. Pyrazinamide is also one of the cornerstone drugs retained in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, due to technical difficulties, routine drug susceptibility testing of Mycobacterium tuberculosis for Pyrazinamide is, in many laboratories, not performed. The objective of our study was to generate information on Pyrazinamide susceptibility among South African MDR and susceptible M. tuberculosis isolates from pulmonary tuberculosis patients. Seventy-one MDR and 59 fully susceptible M. tuberculosis isolates collected during the national surveillance study (2001 to 2002, by the Medical Research Council, South Africa) were examined for Pyrazinamide susceptibility by the radiometric Bactec 460 TB system, pyrazinamidase activity (by Wayne's assay), and sequencing of the pncA gene. The frequency of Pyrazinamide resistance (by the Bactec system) among the MDR M. tuberculosis isolates was 37 of 71 (52.1%) and 6 of 59 (10.2%) among fully sensitive isolates. A total of 25 unique mutations in the pncA gene were detected. The majority of these were point mutations that resulted in amino acid substitutions. Twenty-eight isolates had identical mutations in the pncA gene, but could be differentiated from each other by a combination of the spoligotype patterns and 12 mycobacterial interspersed repetitive-unit loci. A high proportion of South African MDR M. tuberculosis isolates were resistant to Pyrazinamide, suggesting an evaluation of its role in patients treated previously for tuberculosis as well as its role in the treatment of MDR-TB.
Tetsuya Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo study on the conversion of allopurinol and Pyrazinamide.
Advances in experimental medicine and biology, 1994Co-Authors: Yumiko Nasako, Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Zenta Tsutsumi, Kazuya HigashinoAbstract:Allopurinol is widely used in the treatment of gout. The main metabolic pathway of allopurinol is its oxidation to oxypurinol. Pyrazinamide is an antituberculous drug. One of the main metabolic pathways of Pyrazinamide is its oxidation to 5-hydroxyPyrazinamide. The oxidation of allopurinol and Pyrazinamide is known to be attributed to xanthine oxidase1, 2. However, it has been suggested that aldehyde oxidase also participates in the oxidation of these agents3, 4. Therefore, we investigated whether aldehyde oxidase plays a role in the oxidation of allopurinol and Pyrazinamide by in vivo and in vitro studies.
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Effect of BOF-4272 on the oxidation of allopurinol and Pyrazinamide in vivo: Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and Pyrazinamide?
Biochemical pharmacology, 1993Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Takashi Nakano, Kazuya HigashinoAbstract:Abstract Allopurinol or Pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxyPyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of Pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of Pyrazinamide during the period after the administration of Pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and Pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidazed both allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyprazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyPyrazinamide.
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In vitro oxidation of Pyrazinamide and allopurinol by rat liver aldehyde oxidase.
Biochemical pharmacology, 1993Co-Authors: Yuji Moriwaki, Tetsuya Yamamoto, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Kazuya HigashinoAbstract:Abstract Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with Mr of 2.7 × 105 on polyacrylamide gel electrophoresis (PAGE) and Mr of 1.35 × 105 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, Pyrazinamide and pyrazinoic acid was investigated. Allopurinol and Pyrazinamide were oxidized to oxypurinol and 5-hydroxyPyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of Pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for Pyrazinamide was 160 μM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or Pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of Pyrazinamide to 5-hydroxyPyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and Pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and Pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrzinamide.
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A Case of Xanthinuria: A Study on the Metabolism of Pyrazinamide and Allopurinol.
Japanese journal of medicine, 1991Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Michio Suda, Kazuomi Kario, Kazuya HigashinoAbstract:A 74-year-old female was diagnosed as having xanthinuria by measurement of the uric acid level in plasma, purine bases in urine and activity of xanthine oxidase in the duodenal mucosa. The determination of the urinary excretion of purine bases in her family demonstrated a slightly increased urinary excretion of oxypurines in her younger brother, suggesting that he was a heterozygote. The Pyrazinamide-loading test and allopurinolloading test demonstrated that she could neither metabolize pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol, although there was a slight metabolizing of prazinamide into 5-hydroxyPyrazinamide. This suggested that she belonged to the subgroup which can neither metabolize Pyrazinamide into 5-hydroxyPyrazinamide, pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol.
Yuji Moriwaki - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo study on the conversion of allopurinol and Pyrazinamide.
Advances in experimental medicine and biology, 1994Co-Authors: Yumiko Nasako, Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Zenta Tsutsumi, Kazuya HigashinoAbstract:Allopurinol is widely used in the treatment of gout. The main metabolic pathway of allopurinol is its oxidation to oxypurinol. Pyrazinamide is an antituberculous drug. One of the main metabolic pathways of Pyrazinamide is its oxidation to 5-hydroxyPyrazinamide. The oxidation of allopurinol and Pyrazinamide is known to be attributed to xanthine oxidase1, 2. However, it has been suggested that aldehyde oxidase also participates in the oxidation of these agents3, 4. Therefore, we investigated whether aldehyde oxidase plays a role in the oxidation of allopurinol and Pyrazinamide by in vivo and in vitro studies.
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Effect of BOF-4272 on the oxidation of allopurinol and Pyrazinamide in vivo: Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and Pyrazinamide?
Biochemical pharmacology, 1993Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Takashi Nakano, Kazuya HigashinoAbstract:Abstract Allopurinol or Pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxyPyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of Pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of Pyrazinamide during the period after the administration of Pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and Pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidazed both allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyprazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and Pyrazinamide to 5-hydroxyPyrazinamide.
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In vitro oxidation of Pyrazinamide and allopurinol by rat liver aldehyde oxidase.
Biochemical pharmacology, 1993Co-Authors: Yuji Moriwaki, Tetsuya Yamamoto, Sumio Takahashi, Toshikazu Hada, Yumiko Nasako, Michio Suda, Keisai Hiroishi, Kazuya HigashinoAbstract:Abstract Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with Mr of 2.7 × 105 on polyacrylamide gel electrophoresis (PAGE) and Mr of 1.35 × 105 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, Pyrazinamide and pyrazinoic acid was investigated. Allopurinol and Pyrazinamide were oxidized to oxypurinol and 5-hydroxyPyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of Pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for Pyrazinamide was 160 μM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or Pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of Pyrazinamide to 5-hydroxyPyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and Pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and Pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrzinamide.
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A Case of Xanthinuria: A Study on the Metabolism of Pyrazinamide and Allopurinol.
Japanese journal of medicine, 1991Co-Authors: Tetsuya Yamamoto, Yuji Moriwaki, Sumio Takahashi, Michio Suda, Kazuomi Kario, Kazuya HigashinoAbstract:A 74-year-old female was diagnosed as having xanthinuria by measurement of the uric acid level in plasma, purine bases in urine and activity of xanthine oxidase in the duodenal mucosa. The determination of the urinary excretion of purine bases in her family demonstrated a slightly increased urinary excretion of oxypurines in her younger brother, suggesting that he was a heterozygote. The Pyrazinamide-loading test and allopurinolloading test demonstrated that she could neither metabolize pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol, although there was a slight metabolizing of prazinamide into 5-hydroxyPyrazinamide. This suggested that she belonged to the subgroup which can neither metabolize Pyrazinamide into 5-hydroxyPyrazinamide, pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol.
Ying Zhang - One of the best experts on this subject based on the ideXlab platform.
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Pyrazinamide May Improve Fluoroquinolone-Based Treatment of Multidrug-Resistant Tuberculosis
Antimicrobial agents and chemotherapy, 2012Co-Authors: Kwok Chiu Chang, Chi Chiu Leung, Wai Yew, Eric Chung Ching Leung, Wai Man Leung, Cheuk Ming Tam, Ying ZhangAbstract:The role of Pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by Pyrazinamide use and susceptibility, there were 83 users with Pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with Pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with Pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with Pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to Pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among Pyrazinamide nonusers might have underestimated the role of Pyrazinamide. Comparison of Pyrazinamide users showed that Pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding Pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.
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Aspirin and ibuprofen enhance Pyrazinamide treatment of murine tuberculosis
The Journal of antimicrobial chemotherapy, 2006Co-Authors: Sean T. Byrne, Steven M. Denkin, Ying ZhangAbstract:Objectives: Aspirin (acetylsalicylic acid) or ibuprofen [2-(4-isobutyl-phenyl)-propionic acid] was administered to mice undergoing treatment of tuberculosis infection with Pyrazinamide to determine if these non-steroidal anti-inflammatory drugs (NSAIDs) enhance Pyrazinamide activity in vivo. Methods: BALB/c mice were infected with Mycobacterium tuberculosis H37Rv through aerosol exposure. Mice were treated orally with aspirin, ibuprofen or Pyrazinamide, alone and in combination. The impact of daily administration of these drugs for 1 month was determined by enumerating viable bacteria in the lung and spleen. Results: Aspirin or ibuprofen alone at 20 mg/kg per day had little effect on tuberculosis infection after 1 month of treatment, while Pyrazinamide at 150 mg/kg per day led to a reduction of about 1.5 log10 cfu in the lung and 2 log10 cfu in the spleen compared with the control. Simultaneous administration of either aspirin or ibuprofen with Pyrazinamide resulted in a further decrease of about 0.4 log10 cfu in the lung and more than 1 log10 cfu in the spleen compared with mice receiving Pyrazinamide alone. All spleens in the Pyrazinamide-only treatment group were positive for infection. Of mice treated with both aspirin and Pyrazinamide, two of five spleens were negative for colony formation, with a lower limit of detection of 0.90 log10 cfu per organ. Three of five mice given ibuprofen and Pyrazinamide had culturenegative spleens. Conclusions: Aspirin and ibuprofen enhance the effect of Pyrazinamide during the initial phase of tuberculosis treatment in the mouse model. Further investigation is necessary to determine the impact of NSAIDs on long-term treatment with Pyrazinamide and other antituberculosis drugs in the mouse model of tuberculosis infection and the clinical implications of these findings on tuberculosis treatment in humans.
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Iron enhances the antituberculous activity of Pyrazinamide
The Journal of antimicrobial chemotherapy, 2004Co-Authors: Akos Somoskovi, Zhonghe Sun, Mary Margaret Wade, Ying ZhangAbstract:Background: Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high in vivo steril- izing activity but poor in vitro activity. This separation in Pyrazinamide activity reflects differences between the in vivo tissue environment and in vitro culture conditions. The well-known acid pH requirement for pyrazin- amide activity was discovered previously based on such reasoning but does not completely explain the discrepancy between in vivo and in vitro activity of Pyrazinamide. This study examined the effect of iron, which could potentially be elevated in local inflammatory lesions, on Pyrazinamide activity in vitro. Materials and methods: The effect of iron on the activity of Pyrazinamide or its active derivative pyrazinoic acid against Mycobacterium tuberculosis was assessed in liquid medium in a drug exposure assay or in solid medium with Pyrazinamide plus iron or Pyrazinamide alone. The effect of iron on Pyrazinamide or pyrazinoic acid was expressed as percentage of growth inhibition. Results: We have shown that iron enhances the activity of Pyrazinamide and pyrazinoic acid against M. tuberculosis in both liquid and solid media at acid pH 5.6. Iron enhanced the activity of pyrazinoic acid but not Pyrazinamide against the naturally Pyrazinamide-resistant Mycobacterium bovis BCG. Other metal ions such as magnesium, calcium and zinc did not enhance the activity of Pyrazinamide or pyrazinoic acid. Conclusions: Iron increased the activity of Pyrazinamide or pyrazinoic acid against M. tuberculosis in vitro. These findings may have implications for the study of mechanism of action of Pyrazinamide and possible iron supplement for improving the activity of Pyrazinamide.
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mode of action of Pyrazinamide disruption of mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid
Journal of Antimicrobial Chemotherapy, 2003Co-Authors: Ying Zhang, Mary Margaret Wade, Angelo Scorpio, Hao Zhang, Zhonghe SunAbstract:Pyrazinamide is an important sterilizing drug that shortens tuberculosis (TB) therapy. However, the mechanism of action of Pyrazinamide is poorly understood because of its unusual properties. Here we show that pyrazinoic acid, the active moiety of Pyrazinamide, disrupted membrane energetics and inhibited membrane transport function in Mycobacterium tuberculosis. The preferential activity of Pyrazinamide against old non-replicating bacilli correlated with their low membrane potential and the disruption of membrane potential by pyrazinoic acid and acid pH. Inhibitors of membrane energetics increased the antituberculous activity of Pyrazinamide. These findings shed new light on the mode of action of Pyrazinamide and may help in the design of new drugs that shorten therapy.
