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A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies.
Srivastava, Shashikant; Pasipanodya, Jotam G; Ramachandran, Geetha; Deshpande, Devyani; Shuford, Stephen; Crosswell, Howland E; Cirrincione, Kayle N; Sherman, Carleton M; Swaminathan, Soumya; Gumbo, Tawanda.
Afiliação
  • Srivastava S; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
  • Pasipanodya JG; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
  • Ramachandran G; Tuberculosis Research Center Chennai, India.
  • Deshpande D; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
  • Shuford S; KIYATEC Inc., Greenville, SC, USA.
  • Crosswell HE; KIYATEC Inc., Greenville, SC, USA.
  • Cirrincione KN; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
  • Sherman CM; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
  • Swaminathan S; Tuberculosis Research Center Chennai, India.
  • Gumbo T; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA; Tuberculosis Research Center Chennai, India. Electronic address: tawanda.gumbo@BSWhealth.org.
EBioMedicine ; 6: 126-138, 2016 Apr.
Article em En | MEDLINE | ID: mdl-27211555
ABSTRACT
Treatment of disseminated tuberculosis in children≤6years has not been optimized. The pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due to hepatotoxicity worries, there are no dose-response studies in children. We designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for efficacy and toxicity. We utilized pediatric pharmacokinetics of pyrazinamide and acetaminophen to determine dose-dependent pyrazinamide efficacy and hepatotoxicity. Acetaminophen concentrations that cause hepatotoxicity in children led to elevated liver function tests, while 100mg/kg pyrazinamide did not. Surprisingly, pyrazinamide did not kill intracellular Mycobacterium tuberculosis up to fourfold the standard dose as monotherapy or as combination therapy, despite achieving high intracellular concentrations. Host-pathogen RNA-sequencing revealed lack of a pyrazinamide exposure transcript signature in intracellular bacteria or of phagolysosome acidification on pH imaging. Artificial intelligence algorithms confirmed that pyrazinamide was not predictive of good clinical outcomes in children≤6years who had extrapulmonary tuberculosis. Thus, adding a drug that works inside macrophages could benefit children with disseminated tuberculosis. Our in vitro model can be used to identify such new regimens that could accelerate cure while minimizing toxicity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazinamida / Tuberculose / Doença Hepática Induzida por Substâncias e Drogas / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Child, preschool / Humans / Infant / Newborn Idioma: En Revista: EBioMedicine Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazinamida / Tuberculose / Doença Hepática Induzida por Substâncias e Drogas / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Child, preschool / Humans / Infant / Newborn Idioma: En Revista: EBioMedicine Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos