title: In vivo administration of ritonavir worsens intestinal damage caused by cyclooxygease inhibitors.
abstract: The protease inhibitor ritonavir is part of the highly active anti-retroviral therapy (HAART) successfully used in the treatment of human immunodeficiency virus (HIV)-1 infection. There is evidence that ritonavir alters intestinal permeability and induces damage to the small intestine. Because HIV infected patients taking HAART are at high risk for developing cardiovascular complications, there might be a need for the use of low dose of aspirin (ASA) to prevent ischemic events. Similarly, long term survival exposes HIV infected persons to detrimental interactions of ritonavir with non-steroidal anti-inflammatory drugs (NSAIDs). In the present work we tested whether ritonavir worsens intestinal injury caused by NSAIDs and ASA. C57BL6 mice were treated for 25 days with ritonavir and for a further 5 days with the combination of ritonavir plus ASA or ritonavir plus naproxen. In a second set of experiments C57BL6 mice were cotreated with ritonavir plus misoprostol, a PGE1 analog. We found that ritonavir administration caused intestinal damage and its co-administration with naproxen or ASA exacerbated the severity of injury and intestinal inflammation, as assessed by measuring haematocrit, MPO, mucosal levels of PGE2 and mRNA levels of iNOS, MCP-1 and VLA-1. Co-administration of misoprostol protected against intestinal damage induced by naproxen and ritonavir. In conclusion we demonstrated that ritonavir causes intestinal damage and that its association with NSAIDs or ASA worsens the damage caused by COX-inhibitors. Misoprostol rescues from intestinal damage caused by ritonavir. Further studies are need to clarify whether this observation has a clinical readout.
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy. Electronic address: barbara.renga@unipg.it.
authors: Barbara
authors: B
authors: Renga
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Andrea
authors: A
authors: Mencarelli
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Sabrina
authors: S
authors: Cipriani
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Claudio
authors: C
authors: D'Amore
authors: Dipartimento di Medicina e Scienze Biochimice, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Daniela
authors: D
authors: Francisci
authors: Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Luca
authors: L
authors: Santucci
authors: Dipartimento di Medicina e Scienze Biochimice, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Franco
authors: F
authors: Baldelli
authors: Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Eleonora
authors: E
authors: Distrutti
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori 1S. Andrea delle Fratte, Perugia 06132, Italy.
authors: Stefano
authors: S
authors: Fiorucci
mesh_terms: D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D019073:HT29 Cells; D006801:Humans; D039222:Integrin alpha1beta1 / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007660:Ketoprofen / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016595:Misoprostol / Q000494:pharmacology; D009288:Naproxen / Q000009:adverse effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019438:Ritonavir / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016861:Cyclooxygenase Inhibitors; D017320:HIV Protease Inhibitors; D039222:Integrin alpha1beta1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016595:Misoprostol; D009288:Naproxen; D007660:Ketoprofen; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000527:Alprostadil; D015232:Dinoprostone; D019438:Ritonavir; D001241:Aspirin
keywords: Acetylsalicylic acid; Intestinal damage; Ketoprofen; Misoprostol; Naproxen; Non-steroidal anti-inflammatory drugs; Ritonavir