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Title: Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

Abstract

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg{sup -1} was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg{sup -1} buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N = 24) and arterial blood gases (N = 12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3] + buprenorphine [day 4]), (dexamethasone solvent [days 1-3] + buprenorphine [day 4]), (dexamethasone [days 1-3] + buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3] + buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P < 0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratorymore » parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg{sup -1} buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [4];  [1];  [1];  [5];  [6];  [6];  [1];  [3]
  1. INSERM U705, CNRS UMR 7157, Universite Paris 7, Universite Paris 5, Hopital Fernand Widal, 75010 Paris (France)
  2. INSERM U705, CNRS UMR 7157, Universite Paris 7, Universite Paris 5, Hopital Fernand Widal, 75010 Paris (France) and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris (France). E-mail: bruno-megarbane@wanadoo.fr
  3. (France)
  4. (United States)
  5. Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris (France)
  6. INSERM U481, Faculte de Medecine Xavier Bichat, 75018 Paris (France)
Publication Date:
OSTI Identifier:
20850509
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.011; PII: S0041-008X(06)00341-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLOOD; CARBON DIOXIDE; DEATH; DEXAMETHASONE; HEROIN; LIQUID COLUMN CHROMATOGRAPHY; LIVER; MAGNESIUM 30; MASS SPECTROSCOPY; METABOLISM; PARTIAL PRESSURE; POISONING; RATS; SOLVENTS; THERAPY

Citation Formats

Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.011.
Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., & Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression. United States. doi:10.1016/j.taap.2006.09.011.
Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Fri . "Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression". United States. doi:10.1016/j.taap.2006.09.011.
@article{osti_20850509,
title = {Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression},
author = {Hreiche, Raymond and Megarbane, Bruno and Pirnay, Stephane and Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris and Borron, Stephen W. and Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229 and Monier, Claire and Risede, Patricia and Milan, Nathalie and Descatoire, Veronique and Pessayre, Dominique and Baud, Frederic J. and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris},
abstractNote = {In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg{sup -1} was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg{sup -1} buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N = 24) and arterial blood gases (N = 12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3] + buprenorphine [day 4]), (dexamethasone solvent [days 1-3] + buprenorphine [day 4]), (dexamethasone [days 1-3] + buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3] + buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P < 0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg{sup -1} buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.},
doi = {10.1016/j.taap.2006.09.011},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}
  • The inducing effects of 1-nitropyrene (1-NP) on the microsomal cytochrome P-450 system were studied in rats. Intraperitoneal administration of 1-NP led to increases in cytochrome P-450 content and aryl hydrocarbon hydroxylase, ethoxycoumarin, and ethoxyresorufin-O-deethylase activities. These increases were does dependent. Cytochrome b/sub 5/ content aminopyrine and p-nitroanisole demethylase activities were not affected by treatment of rats with 1-NP. Substrate specificity, sensitivity to mixed-function oxidase inhibitors, and electrophoretic pattern of 1-NP-induced cytochrome(s) P-450 were compared to the major forms of cytochrome P-450 induced by phenobarbital and methylcholanthrene. Furthermore microsomes from 1-NP-induced rats showed greater ability to metabolize the chemical as comparedmore » with those from control animals; this result indicates that 1-NP induces a form(s) of cytochrome P-450 especially effective in the metabolism of the substance itself.« less
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  • Purpose: Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non-small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. Wemore » conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity. Methods and Materials: Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity. Results: Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases. Conclusions: Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.« less
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