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Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.
Date, Abhijit A; Rais, Rana; Babu, Taarika; Ortiz, Jairo; Kanvinde, Pranjali; Thomas, Ajit G; Zimmermann, Sarah C; Gadiano, Alexandra J; Halpert, Gilad; Slusher, Barbara S; Ensign, Laura M.
Affiliation
  • Date AA; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA.
  • Rais R; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Babu T; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Ortiz J; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA.
  • Kanvinde P; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA.
  • Thomas AG; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Zimmermann SC; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Gadiano AJ; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Halpert G; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA.
  • Slusher BS; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Psychiatry and Behavioral Sciences, Medicine, and Oncology, Johns Hopkins University Sch
  • Ensign LM; The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Department of C
J Control Release ; 263: 132-138, 2017 Oct 10.
Article in En | MEDLINE | ID: mdl-28159515
ABSTRACT
Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Organophosphorus Compounds / Inflammatory Bowel Diseases / Colitis / Glutamate Carboxypeptidase II / Enema Limits: Animals Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2017 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Organophosphorus Compounds / Inflammatory Bowel Diseases / Colitis / Glutamate Carboxypeptidase II / Enema Limits: Animals Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2017 Document type: Article Affiliation country: