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A year-long extended release nanoformulated cabotegravir prodrug.
Kulkarni, Tanmay A; Bade, Aditya N; Sillman, Brady; Shetty, Bhagya Laxmi Dyavar; Wojtkiewicz, Melinda S; Gautam, Nagsen; Hilaire, James R; Sravanam, Sruthi; Szlachetka, Adam; Lamberty, Benjamin G; Morsey, Brenda M; Fox, Howard S; Alnouti, Yazen; McMillan, JoEllyn M; Mosley, R Lee; Meza, Jane; Domanico, Paul L; Yue, Tai-Yuen; Moore, Gary; Edagwa, Benson J; Gendelman, Howard E.
Afiliação
  • Kulkarni TA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
  • Bade AN; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Sillman B; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Shetty BLD; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Wojtkiewicz MS; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Gautam N; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
  • Hilaire JR; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Sravanam S; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Szlachetka A; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Lamberty BG; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Morsey BM; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Fox HS; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Alnouti Y; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
  • McMillan JM; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Mosley RL; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
  • Meza J; Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA.
  • Domanico PL; Department of Global Health Sciences, The Clinton Health Access Initiative, Boston, MA, USA.
  • Yue TY; Department of Global Health Sciences, The Clinton Health Access Initiative, Boston, MA, USA.
  • Moore G; Department of Global Health Sciences, The Clinton Health Access Initiative, Boston, MA, USA.
  • Edagwa BJ; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. benson.edagwa@unmc.edu.
  • Gendelman HE; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. hegendel@unmc.edu.
Nat Mater ; 19(8): 910-920, 2020 08.
Article em En | MEDLINE | ID: mdl-32341511
ABSTRACT
Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB's effectiveness.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridonas / Pró-Fármacos / Antirretrovirais / Nanoestruturas Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridonas / Pró-Fármacos / Antirretrovirais / Nanoestruturas Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article