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Spalinger M, Schwarzfischer M, Niechcial A, Atrott K, Laimbacher A, Jirkof P, Scharl M. Evaluation of the effect of tramadol, paracetamol and metamizole on the severity of experimental colitis. Lab Anim 2023; 57:529-540. [PMID: 36960681 DOI: 10.1177/00236772231163957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
Application of dextran sodium sulfate (DSS) is often used to induce experimental colitis. Current state of the art is to refrain from the use of analgesics due to their possible interaction with the model. However, the use of analgesics would be beneficial to reduce the overall constraint imposed on the animals. Here, we analyzed the effect of the analgesics Dafalgan (paracetamol), Tramal (tramadol) and Novalgin (metamizole) on DSS-induced colitis. To study the effect of those analgesics in colitis mouse models, acute and chronic colitis was induced in female C57BL6 mice by DSS administration in the drinking water. Analgesics were added to the drinking water on days four to seven (acute colitis) or on days six to nine of each DSS cycle (chronic colitis). Tramadol and paracetamol had minor effects on colitis severity. Tramadol reduced water uptake and activity levels slightly, while mice receiving paracetamol presented with a better overall appearance. Metamizole, however, significantly reduced water uptake, resulting in pronounced weight loss. In conclusion, our experiments show that tramadol and paracetamol are viable options for the use in DSS-induced colitis models. However, paracetamol seems to be slightly more favorable since it promoted the overall wellbeing of the animals upon DSS administration without interfering with typical readouts of colitis severity.
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Affiliation(s)
- Marianne Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
| | - Anna Niechcial
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
| | - Andrea Laimbacher
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
| | - Paulin Jirkof
- Institute of Animal Welfare and 3R, University of Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Switzerland
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2
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Blaser LS, Duthaler U, Bouitbir J, Leuppi-Taegtmeyer AB, Liakoni E, Dolf R, Mayr M, Drewe J, Krähenbühl S, Haschke M. Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study. Front Pharmacol 2021; 12:620635. [PMID: 34557087 PMCID: PMC8453264 DOI: 10.3389/fphar.2021.620635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 08/17/2021] [Indexed: 11/13/2022] Open
Abstract
Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis.
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Affiliation(s)
- Lea S Blaser
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland
| | - Urs Duthaler
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Jamal Bouitbir
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Anne B Leuppi-Taegtmeyer
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Evangelia Liakoni
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Reto Dolf
- Office of Environment and Energy, Basel, Switzerland
| | - Michael Mayr
- Medical Outpatient Department, University Hospital Basel, Basel, Switzerland
| | - Jürgen Drewe
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland.,Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Manuel Haschke
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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3
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Bachmann F, Duthaler U, Meyer Zu Schwabedissen HE, Puchkov M, Huwyler J, Haschke M, Krähenbühl S. Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2. Clin Pharmacol Ther 2020; 109:1505-1516. [PMID: 33336382 PMCID: PMC8247900 DOI: 10.1002/cpt.2141] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/07/2020] [Indexed: 01/24/2023]
Abstract
Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79‐fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4‐MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4‐MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.
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Affiliation(s)
- Fabio Bachmann
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Urs Duthaler
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Maxim Puchkov
- Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Jörg Huwyler
- Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Manuel Haschke
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
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4
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Cismaru AL, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Carvajal A, Lucena MI, Martin J, Sancho Ponce E, Molokhia M, Eriksson N, Krähenbühl S, Largiadèr CR, Haschke M, Hallberg P, Wadelius M, Amstutz U. Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes (Basel) 2020; 11:genes11111275. [PMID: 33138277 PMCID: PMC7716224 DOI: 10.3390/genes11111275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022] Open
Abstract
Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.
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Affiliation(s)
- Anca Liliana Cismaru
- Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (A.L.C.); (C.R.L.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - Deborah Rudin
- Department of Clinical Pharmacology & Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; (D.R.); (S.K.)
- Department of Biomedicine, University of Basel, 4051 Basel, Switzerland
| | - Luisa Ibañez
- Clinical Pharmacology Service, Hospital Universitari Vall d’Hebron, Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Fundació Institut Català de Farmacología, 08035 Barcelona, Spain;
| | - Evangelia Liakoni
- Department of Clinical Pharmacology & Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (E.L.); (M.H.)
- Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland
| | - Nicolas Bonadies
- Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Reinhold Kreutz
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, 10117 Berlin, Germany;
| | - Alfonso Carvajal
- Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, 47005 Valladolid, Spain;
| | - Maria Isabel Lucena
- Servicio Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain;
| | - Javier Martin
- Instituto de Parasitología y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientiíficas, 18016 Granada, Spain;
| | - Esther Sancho Ponce
- Servei d’Hematologia i Banc de Sang, Hospital General de Catalunya, 08190 Sant Cugat del Vallès, Spain;
| | - Mariam Molokhia
- Department of Population Health Sciences, King’s College London, London WC2R 2LS, UK;
| | - Niclas Eriksson
- Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden;
| | | | - Stephan Krähenbühl
- Department of Clinical Pharmacology & Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; (D.R.); (S.K.)
| | - Carlo R. Largiadèr
- Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (A.L.C.); (C.R.L.)
| | - Manuel Haschke
- Department of Clinical Pharmacology & Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (E.L.); (M.H.)
- Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland
| | - Pär Hallberg
- Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (P.H.); (M.W.)
| | - Mia Wadelius
- Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; (P.H.); (M.W.)
| | - Ursula Amstutz
- Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (A.L.C.); (C.R.L.)
- Correspondence:
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5
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Cismaru AL, Grimm L, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Hallberg P, Wadelius M, Haschke M, Largiadèr CR, Amstutz U. High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis. Front Genet 2020; 11:951. [PMID: 32973882 PMCID: PMC7473498 DOI: 10.3389/fgene.2020.00951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/29/2020] [Indexed: 12/18/2022] Open
Abstract
Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n = 53), metamizole-tolerant (n = 39) and unexposed controls (n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A, -B, and -C using the HLA-specific mapper hla-mapper. Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C∗04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 109/L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA. Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.
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Affiliation(s)
- Anca Liliana Cismaru
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Livia Grimm
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Deborah Rudin
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Luisa Ibañez
- Clinical Pharmacology Service, Hospital Universitari Vall d'Hebron, Department of Pharmacology, Therapeutics and Toxicology, Fundació Institut Català de Farmacologia, Autonomous University of Barcelona, Barcelona, Spain
| | - Evangelia Liakoni
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Nicolas Bonadies
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Reinhold Kreutz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany
| | - Pär Hallberg
- Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Mia Wadelius
- Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | | | - Manuel Haschke
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Carlo R Largiadèr
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ursula Amstutz
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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6
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Purnomo E, Nugrahaningsih DAA, Agustriani N, Gunadi. Comparison of metamizole and paracetamol effects on colonic anastomosis and fibroblast activities in Wistar rats. BMC Pharmacol Toxicol 2020; 21:6. [PMID: 31931882 PMCID: PMC6958591 DOI: 10.1186/s40360-020-0383-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 12/31/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Leakage following colorectal anastomosis surgery causes various complications associated with high morbidity and mortality, especially in pediatric patients. It might be caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) as postoperative analgesics. This study aimed to compare the effect of metamizole and paracetamol on colonic anastomosis and fibroblast activities, including proliferation, migration, and collagen synthesis, in Wistar rats. METHODS Rats were divided into control, paracetamol and metamizole groups. The colonic anastomosis was evaluated by determining the integrity of the muscle layers, the formation of granulation tissue, and mucosal anastomosis. Fibroblast activities were analyzed by measuring the proliferation, migration, and collagen synthesis. RESULTS Metamizole caused more damage to muscle layer integrity, more inhibition of granulation tissue formation in the anastomosis area and lower mucosal anastomosis compared with paracetamol and control groups. Metamizole had a higher cytotoxic effect than paracetamol, which suppressed the proliferation and migration of fibroblasts. Furthermore, both drugs did not affect the synthesis of collagen. CONCLUSION Metamizole shows worse effects on the integrity of muscle layers, inhibition of granulation tissue formation, mucosal anastomosis, fibroblast proliferation, and migration, but not collagen synthesis, than paracetamol in Wistar rat intestines following colonic anastomosis. These findings might indicate that paracetamol is safer than metamizole as analgesic following colonic anastomosis.
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Affiliation(s)
- Eko Purnomo
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, 55291, Indonesia
| | - Dwi Aris Agung Nugrahaningsih
- Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia.
| | - Nunik Agustriani
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Gunadi
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia
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7
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Rudin D, Spoendlin J, Cismaru AL, Liakoni E, Bonadies N, Amstutz U, Meier CR, Krähenbühl S, Haschke M. Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients. Eur J Intern Med 2019; 68:36-43. [PMID: 31383393 DOI: 10.1016/j.ejim.2019.07.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/26/2019] [Accepted: 07/29/2019] [Indexed: 12/22/2022]
Abstract
Reports of metamizole-induced neutropenia have increased in Switzerland and Germany over the last decades, most likely reflecting increased use of metamizole. To date, there are no effective strategies to identify patients at increased risk of metamizole-induced neutropenia. In this observational, multi-center comparative study, characteristics of patients with metamizole-associated neutropenia were compared with patients treated with metamizole without developing adverse hematological reactions. Patients with metamizole-induced neutropenia treated at the University Hospitals Basel and Bern between 2005 and 2017 were included. Tolerant comparison patients with continuous metamizole treatment (≥500 mg/day for at least 28 days) were recruited from GP offices and community pharmacies. Forty-eight patients with metamizole-induced neutropenia, consisting of 23 and 25 cases with inpatient-acquired and outpatient-acquired neutropenia, respectively, were compared to 39 metamizole tolerant comparison patients. Median latency until first diagnosis of neutropenia was 6 days (1-61 days) in inpatient cases and 19 days (2-204 days) in outpatient cases. There was no association between non-myelotoxic and non-immunosuppressive co-medication (p = .6627), history of drug allergy (p = .1304), and preexisting auto-immune diseases (p = .2313) and the development of metamizole-induced neutropenia. Our results suggest that autoimmune diseases, history of drug allergy, and concomitant treatment with non-myelotoxic and non-immunosuppressive drugs are likely not individual risk factors for metamizole-associated neutropenia.
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Affiliation(s)
- Deborah Rudin
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
| | - Julia Spoendlin
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, University of Basel, St. Johanns-Vorstadt 27, 4031 Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, 4031 Basel, Switzerland.
| | - Anca L Cismaru
- Division of Clinical Chemistry, Inselspital Bern University Hospital, Freiburgstrasse 18, 3010 Bern, Switzerland.
| | - Evangelia Liakoni
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland; Institute of Pharmacology, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland.
| | - Nicolas Bonadies
- Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland.
| | - Ursula Amstutz
- Division of Clinical Chemistry, Inselspital Bern University Hospital, Freiburgstrasse 18, 3010 Bern, Switzerland.
| | - Christoph R Meier
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, University of Basel, St. Johanns-Vorstadt 27, 4031 Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, 4031 Basel, Switzerland.
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
| | - Manuel Haschke
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland; Institute of Pharmacology, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland.
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8
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Lutz M. Metamizole (Dipyrone) and the Liver: A Review of the Literature. J Clin Pharmacol 2019; 59:1433-1442. [DOI: 10.1002/jcph.1512] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/31/2019] [Indexed: 01/17/2023]
Affiliation(s)
- Mathias Lutz
- Department of Medicine AUniversity Hospital of Münster Münster Germany
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9
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Rudin D, Roos NJ, Duthaler U, Krähenbühl S. Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes. Toxicology 2019; 426:152254. [PMID: 31356851 DOI: 10.1016/j.tox.2019.152254] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/15/2019] [Accepted: 07/24/2019] [Indexed: 12/18/2022]
Abstract
Metamizole is an analgesic and antipyretic with a superior analgesic efficacy than paracetamol. Since metamizole can cause neutropenia and agranulocytosis, it is currently used in only few countries. In a previous study, we have shown that N-methyl-4-aminoantipyrine (MAA), the active metamizole metabolite, reacts with hemin and forms an electrophilic metabolite that is toxic for HL60 cells, but not for mature neutrophil granulocytes. In the current study, we investigated the toxicity of hemin (12.5 μM) and MAA (100 μM) on differentiating HL60 cells. In undifferentiated HL60 cells, hemin decreased the viability and this effect was significantly increased by MAA. Similarly, hemin/MAA was more toxic than hemin alone on human cord blood cells. At 3 days (metamyelocyte stage) and 5 days of differentiation (mature neutrophils), hemin/MAA was not toxic on HL60 cells, whereas hemin alone was still toxic. No toxicity was observed on freshly isolated human neutrophils. The protein expression of enzymes responsible for hemin metabolism increased with HL60 cell differentiation. Inhibition of heme oxygenase-1 or cytochrome P450 reductase increased the toxicity of hemin and hemin/MAA in undifferentiated, but only for hemin in differentiated HL60 cells. Similar to the enzymes involved in hemin metabolism, the protein expression of enzymes involved in antioxidative defense and the cellular glutathione pool increased with HL60 cell differentiation. In conclusion, HL60 cells become resistant to the toxicity of hemin/MAA and partly also of hemin during their differentiation. This resistance is associated with the development of heme metabolism and of the antioxidative defense system including the cellular glutathione pool.
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Affiliation(s)
- Deborah Rudin
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
| | - Noëmi Johanna Roos
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
| | - Urs Duthaler
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), Missionsstrasse 64, 4055, Basel, Switzerland.
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Rudin D, Lanzilotto A, Bachmann F, Housecroft CE, Constable EC, Drewe J, Haschke M, Krähenbühl S. Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells. Biochem Pharmacol 2019; 163:345-356. [PMID: 30653950 DOI: 10.1016/j.bcp.2019.01.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 01/11/2019] [Indexed: 01/15/2023]
Abstract
Metamizole is an analgesic and antipyretic, but can cause neutropenia and agranulocytosis. We investigated the toxicity of the metabolites N-methyl-4-aminoantipyrine (MAA), 4-aminoantipyrine (AA), N-formyl-4-aminoantipyrine (FAA) and N-acetyl-4-aminoantipyrine (AAA) on neutrophil granulocytes and on HL60 cells (granulocyte precursor cell line). MAA, FAA, AA, and AAA (up to 100 µM) alone were not toxic for HL60 cells or granulocytes. In the presence of the myeloperoxidase substrate H2O2, MAA reduced cytotoxicity for HL60 cells at low concentrations (<50 µM), but increased cytotoxicity at 100 µM H2O2. Neutrophil granulocytes were resistant to H2O2 and MAA. Fe2+ and Fe3+ were not toxic to HL60 cells, irrespective of the presence of H2O2 and MAA. Similarly, MAA did not increase the toxicity of lactoferrin, hemoglobin or methemoglobin for HL60 cells. Hemin (hemoglobin degradation product containing a porphyrin ring and Fe3+) was toxic on HL60 cells and cytotoxicity was increased by MAA. EDTA, N-acetylcystein and glutathione prevented the toxicity of hemin and hemin/MAA. The absorption spectrum of hemin changed concentration-dependently after addition of MAA, suggesting an interaction between Fe3+ and MAA. NMR revealed the formation of a stable MAA reaction product with a reaction pathway involving the formation of an electrophilic intermediate. In conclusion, MAA, the principle metabolite of metamizole, increased cytotoxicity of hemin by a reaction involving the formation of an electrophilic metabolite. Accordingly, cytotoxicity of MAA/hemin could be prevented by the iron chelator EDTA and by the electron donors NAC and glutathione. Situations with increased production of hemin may represent a risk factor for metamizole-associated granulocytopenia.
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Affiliation(s)
- Deborah Rudin
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland
| | | | - Fabio Bachmann
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland
| | | | | | - Jürgen Drewe
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland
| | - Manuel Haschke
- Division of Clinical Pharmacology & Toxicology, Inselspital, Bern, Switzerland
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre of Applied Human Toxicology (SCAHT), Basel, Switzerland.
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Collares EF, Troncon LEA. Effects of dipyrone on the digestive tract. ACTA ACUST UNITED AC 2019; 52:e8103. [PMID: 30652827 PMCID: PMC6328969 DOI: 10.1590/1414-431x20188103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 10/31/2018] [Indexed: 12/14/2022]
Abstract
Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic pharmacological effects, which are mediated by poorly known mechanisms. In rats, intravenously administered dipyrone delays gastric emptying (GE) of liquids with the participation of capsaicin-sensitive afferent fibers. This effect seems to be mediated by norepinephrine originating from the sympathetic nervous system but not from the superior celiac-mesenteric ganglion complex, which activates β2-adrenoceptors. In rats, in contrast to nonselective non-hormonal anti-inflammatory drugs, dipyrone protects the gastric mucosa attenuating the development of gastric ulcers induced by a number of agents. Clinically, it has been demonstrated that dipyrone is effective in the control of colic-like abdominal pain originating from the biliary and intestinal tracts. Since studies in humans and animals have demonstrated the presence of β2-adrenoceptors in biliary tract smooth muscle and β2-adrenoceptor activation has been shown to occur in dipyrone-induced delayed GE, it is likely that this kind of receptors may participate in the reduction of smooth muscle spasm of the sphincter of Oddi induced by dipyrone. There is no evidence that dipyrone may interfere with small bowel and colon motility, and the clinical results of its therapeutic use in intestinal colic appear to be due to its analgesic effect.
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Affiliation(s)
- E F Collares
- Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - L E A Troncon
- Departamento de Clinica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Burmańczuk A, Milczak A, Grabowski T, Osypiuk M, Kowalski C. The using of a piglets as a model for evaluating the dipyrone hematological effects. BMC Vet Res 2016; 12:263. [PMID: 27884143 PMCID: PMC5123311 DOI: 10.1186/s12917-016-0891-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 11/17/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Dipyrone (MET, metamizole) is a non-steroidal anti-inflammatory drug commonly used both in human and in veterinary medicine. After oral administration, is broken down rapidly to metabolites which largely retain the activity of the parent drug. Its metabolites have analgesic, antipyretic and anti-inflammatory effects. RESULTS The subjects were eight healthy male Large White post-suckling piglets, weighing between 5.0 to 7.4 kg, of ages 35 ± 10 days. The animals were administered MET (100 mg/kg) by an intramuscular (I.M.) injection. The study calculated the value of several hemorheological parameters. Significant impact of MET treatment (p < 0.05) was proven in case: activated partial thromboplastin time; ratio of activated partial thromboplastin time; hemoglobin; hematocrit; mean corpuscular hemoglobin; mean corpuscular volume; red blood cells volume; white blood cells volume; prothrombin time index. CONCLUSIONS In summation, our observations suggest that a piglet model is useful for studying the impact of MET on hemorheological parameters.
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Affiliation(s)
- Artur Burmańczuk
- Department of Pharmacology, Faculty of Veterinary Medicine, University of Life Sciences, Akademicka 12, 20-033, Lublin, Poland.
| | - Andrzej Milczak
- Department and Clinic of Animal Internal Diseases, Sub-Department of Companion Animal Internal Medicine, Faculty of Veterinary Medicine, University of Life Sciences, Głęboka 30, 20- 612, Lublin, Poland
| | | | - Monika Osypiuk
- Department of Pharmacology, Faculty of Veterinary Medicine, University of Life Sciences, Akademicka 12, 20-033, Lublin, Poland
| | - Cezary Kowalski
- Department of Pharmacology, Faculty of Veterinary Medicine, University of Life Sciences, Akademicka 12, 20-033, Lublin, Poland
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Pharmacological and toxicological evaluations of the new pyrazole compound (LQFM-021) as potential analgesic and anti-inflammatory agents. Inflammopharmacology 2016; 24:265-275. [DOI: 10.1007/s10787-016-0282-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023]
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Goswami SK, Wan D, Yang J, Trindade da Silva CA, Morisseau C, Kodani SD, Yang GY, Inceoglu B, Hammock BD. Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers. J Pharmacol Exp Ther 2016; 357:529-36. [PMID: 26989141 DOI: 10.1124/jpet.116.232108] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/16/2016] [Indexed: 12/18/2022] Open
Abstract
Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.
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Affiliation(s)
- Sumanta Kumar Goswami
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Debin Wan
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Jun Yang
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Carlos A Trindade da Silva
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Christophe Morisseau
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Sean D Kodani
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Guang-Yu Yang
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Bora Inceoglu
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Bruce D Hammock
- Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California-Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Nassini R, Fusi C, Materazzi S, Coppi E, Tuccinardi T, Marone IM, De Logu F, Preti D, Tonello R, Chiarugi A, Patacchini R, Geppetti P, Benemei S. The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives. Br J Pharmacol 2015; 172:3397-411. [PMID: 25765567 DOI: 10.1111/bph.13129] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 02/23/2015] [Accepted: 03/07/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect. EXPERIMENTAL APPROACH Calcium responses and currents were studied in cultured TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice. KEY RESULTS Pyrazolone and PDs selectively inhibited calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists and TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuated TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuated carrageenan-evoked mechanical allodynia, without affecting PGE2 levels. The main metabolites of PDs did not target TRPA1 and did not affect TRPA1-dependent nociception and allodynia. CONCLUSIONS AND IMPLICATIONS Evidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans and that TRPA1 antagonists could be novel analgesics, devoid of the adverse haematological effects of PDs.
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Affiliation(s)
- Romina Nassini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Camilla Fusi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Serena Materazzi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Elisabetta Coppi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | | | - Ilaria M Marone
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Francesco De Logu
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Delia Preti
- Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Raquel Tonello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.,Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Alberto Chiarugi
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Riccardo Patacchini
- Department of Corporate Drug Development, Chiesi Farmaceutici SpA, Parma, Italy
| | - Pierangelo Geppetti
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Silvia Benemei
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
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Comparison of a new metamizole formulation and carprofen for extended post-operative analgesia in dogs undergoing ovariohysterectomy. Vet J 2015; 204:99-104. [DOI: 10.1016/j.tvjl.2015.01.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/29/2015] [Accepted: 01/30/2015] [Indexed: 11/19/2022]
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Nikolova I, Petkova V, Tencheva J, Benbasat N, Voinikov J, Danchev N. Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part II: Clinical Profile. BIOTECHNOL BIOTEC EQ 2014. [DOI: 10.5504/bbeq.2012.0135] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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18
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Nikolova I, Tencheva J, Voinikov J, Petkova V, Benbasat N, Danchev N. Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part I: Pharmaceutical and Nonclinical Profile. BIOTECHNOL BIOTEC EQ 2014. [DOI: 10.5504/bbeq.2012.0089] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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19
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Abstract
Abstract
Metamizole (dipyrone) is a popular analgetic, non-opioid drug, commonly used in human and veterinary medicine. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug (NSAID). Metamizole is a pro-drug, which spontaneously breaks down after oral administration to structurally related pyrazolone compounds. Apart from its analgesic effect, the medication is an antipyretic and spasmolytic agent. The mechanism responsible for the analgesic effect is a complex one, and most probably rests on the inhibition of a central cyclooxygenase-3 and activation of the opioidergic system and cannabinoid system. Metamizole can block both PG-dependent and PG-independent pathways of fever induced by LPS, which suggests that this drug has a profile of antipyretic action distinctly different from that of NSAIDs. The mechanism responsible for the spasmolytic effect of metamizole is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate. Metamizole is predominantly applied in the therapy of pain of different etiology, of spastic conditions, especially affecting the digestive tract, and of fever refractory to other treatments. Co-administration of morphine and metamizole produces superadditive, antinociceptive effects. Metamizole is a relatively safe pharmaceutical preparation although it is not completely free from undesirable effects. Among these side-effects, the most serious one that raises most controversy is the myelotoxic effect. It seems that in the past the risk of metamizole- induced agranulocytosis was exaggerated. Despite the evidence showing no risk of teratogenic and embryotoxic effects, the drug must not be administered to pregnant women, although it is allowed to be given to pregnant and lactating animals. This paper seeks to describe the characteristics of metamizole in the light of current knowledge.
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Fornai M, Antonioli L, Colucci R, Pellegrini C, Giustarini G, Testai L, Martelli A, Matarangasi A, Natale G, Calderone V, Tuccori M, Scarpignato C, Blandizzi C. NSAID-induced enteropathy: are the currently available selective COX-2 inhibitors all the same? J Pharmacol Exp Ther 2013; 348:86-95. [PMID: 24135073 DOI: 10.1124/jpet.113.207118] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E2 (PGE2) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.
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Affiliation(s)
- Matteo Fornai
- Department of Clinical and Experimental Medicine (M.F., L.A., R.C., C.P., G.G., M.T., C.B.), Department of Pharmacy (L.T., A.Mar., V.C.), Department of Translational Research and New Technologies in Medicine and Surgery (A.Mat., G.N.), University of Pisa, Pisa, Italy; Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy (C.S.)
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Chouhan S, Sharma S. Diclofenac Mediated Demodulation of Alkaline Phosphatase and Renal Cortical Damage in Experimental Albino Mice. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s12595-013-0068-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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22
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Kinsey SG, Wise LE, Ramesh D, Abdullah R, Selley DE, Cravatt BF, Lichtman AH. Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 2013; 345:492-501. [PMID: 23412396 DOI: 10.1124/jpet.112.201426] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 (≥16 mg/kg) for 6 days displayed decreased CB1 receptor density and function in the brain, as assessed in [(3)H]SR141716A binding and CP55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, respectively. In contrast, normal CB1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB1 receptor tachyphylaxis/tolerance or cannabinoid dependence.
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Affiliation(s)
- Steven G Kinsey
- Department of Psychology, West Virginia University, Morgantown, West Virginia, USA
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Azevedo MS, De La Côrte FD, Brass KE, Dalmora SL, Machado FT, Pompermayer E, Dau SL, Santa'Ana LA. Bioavailability and Tolerability of Topical and Oral Diclofenac Sodium Administration in Healthy Ponies. J Equine Vet Sci 2013. [DOI: 10.1016/j.jevs.2012.04.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Kinsey SG, Nomura DK, O'Neal ST, Long JZ, Mahadevan A, Cravatt BF, Grider JR, Lichtman AH. Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther 2011; 338:795-802. [PMID: 21659471 DOI: 10.1124/jpet.110.175778] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB(1)), cannabinoid receptor type 2 (CB(2)), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, Δ(9)-tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E(2) and D(2). MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor α, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB(1) or CB(2) revealed that the gastroprotective effects of JZL184 and THC were mediated via CB(1). The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties.
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Affiliation(s)
- Steven G Kinsey
- Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
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Martins TL, Kahvegian MAP, Noel-Morgan J, Leon-Román MA, Otsuki DA, Fantoni DT. Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy. Am J Vet Res 2010; 71:1019-26. [PMID: 20807140 DOI: 10.2460/ajvr.71.9.1019] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To compare analgesic effects of tramadol, codeine, and ketoprofen administered alone and in combination and their effects on concentrations of blood glucose, serum cortisol, and serum interleukin (IL)-6 in dogs undergoing maxillectomy or mandibulectomy. ANIMALS 42 dogs with oral neoplasms. PROCEDURES 30 minutes before the end of surgery, dogs received SC injections of tramadol (2 mg/kg), codeine (2 mg/kg), ketoprofen (2 mg/kg), tramadol+ketoprofen, or codeine+ketoprofen (at the aforementioned dosages). Physiologic variables, analgesia, and sedation were measured before (baseline) and 1, 2, 3, 4, 5, and 24 hours after surgery. Blood glucose, serum cortisol, and serum IL-6 concentrations were measured 1, 3, 5, and 24 hours after administration of analgesics. RESULTS All treatments provided adequate postoperative analgesia. Significant increases in mean+/-SD blood glucose concentrations were detected in dogs receiving tramadol (96+/-14 mg/dL), codeine (120+/-66 mg/dL and 96+/-21 mg/dL), ketoprofen (105+/-22 mg/dL), and codeine+ketoprofen (104+/-16 mg/dL) at 5, 1 and 3, 5, and 3 hours after analgesic administration, respectively, compared with preoperative (baseline) values. There were no significant changes in physiologic variables, serum IL-6 concentrations, or serum cortisol concentrations. Dogs administered codeine+ketoprofen had light but significant sedation at 4, 5, and 24 hours. CONCLUSIONS AND CLINICAL RELEVANCE Opioids alone or in combination with an NSAID promoted analgesia without adverse effects during the 24-hour postoperative period in dogs undergoing maxillectomy or mandibulectomy for removal of oral neoplasms.
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Affiliation(s)
- Teresinha L Martins
- Postgraduate Program of Anesthesiology of Faculdade de Medicina, Department of Surgery, Universidade de São Paulo, São Paulo, CEP 05403-900, Brazil
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The determination of the concentrations of metamizol sodium in inflamed joints of pigs after intravenous and iontophoretic application. ACTA VET-BEOGRAD 2010. [DOI: 10.2298/avb1004371d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Naidu PS, Booker L, Cravatt BF, Lichtman AH. Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J Pharmacol Exp Ther 2008; 329:48-56. [PMID: 19118134 DOI: 10.1124/jpet.108.143487] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The present study investigated whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide catabolism, produces antinociception in the acetic acid-induced abdominal stretching model of visceral nociception. Genetic deletion or pharmacological inhibition of FAAH reduced acetic acid-induced abdominal stretching. Transgenic mice that express FAAH exclusively in the nervous system displayed the antinociceptive phenotype, indicating the involvement of peripheral fatty acid amides. The cannabinoid receptor 1 (CB(1)) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB(2)) receptor antagonist, SR144528, blocked the antinociceptive phenotype of FAAH(-/-) mice and the analgesic effects of URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) or OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane), respective irreversible and reversible FAAH inhibitors, administered to C57BL/6 mice. The opioid receptor antagonist, naltrexone, did not block the analgesic effects of either FAAH inhibitor. URB597, ED(50) [95% confidence interval (CI) = 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED(50) (95% CI) = 9.8 (8.2-11.7) mg/kg], dose-dependently inhibited acetic acid-induced abdominal stretching. Combinations of URB597 and diclofenac yielded synergistic analgesic interactions according to isobolographic analysis. It is important that FAAH(-/-) mice and URB597-treated mice displayed significant reductions in the severity of gastric irritation caused by diclofenac. URB597 lost its gastroprotective effects in CB(1)(-/-) mice, whereas it maintained its efficacy in CB(2)(-/-) mice, indicating a CB(1) mechanism of action. Taken together, the results of the present study suggest that FAAH represents a promising target for the treatment of visceral pain, and a combination of FAAH inhibitors and NSAIDs may have great utility to treat visceral pain, with reduced gastric toxicity.
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Affiliation(s)
- Pattipati S Naidu
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA
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Antinociceptive action of 4-methyl-5-trifluoromethyl-5-hydroxy-4, 5-dihydro-1H-pyrazole methyl ester in models of inflammatory pain in mice. Life Sci 2008; 83:739-46. [DOI: 10.1016/j.lfs.2008.09.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Revised: 09/13/2008] [Accepted: 09/17/2008] [Indexed: 01/06/2023]
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Hoeger B, Dietrich DR, Schmid D, Hartmann A, Hitzfeld B. Distribution of intraperitoneally injected diclofenac in brown trout (Salmo trutta f. fario). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2008; 71:412-418. [PMID: 18068779 DOI: 10.1016/j.ecoenv.2007.10.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2007] [Revised: 10/21/2007] [Accepted: 10/27/2007] [Indexed: 05/25/2023]
Abstract
The detection of low levels of pharmaceuticals in aquatic environments has lately raised concerns regarding possible adverse effects of these highly active substances on aquatic organisms. The non-steroidal anti-inflammatory drug diclofenac (DCF) is one of the pharmaceutical substances regularly detected in surface waters and has lately been demonstrated to elicit adverse effects in salmonid species at environmentally relevant concentrations. The aim of the present study was to investigate the distribution of DCF in indigenous brown trout (Salmo trutta f. fario) following intraperitoneal (i.p.) injection of a single dose of (14)C-labelled DCF. A distribution kinetic over 36 h provides information on possible accumulation of DCF in different organs as well as on DCF detoxification in trout, possibly enabling identification of sites of preferential toxicity. Approximately 57% of the total single DCF dose appeared in the bile 6 h after i.p. application. Subsequently, DCF was observed to undergo enterohepatic cycling with an amount of (14)C-activity comparable to the 6 h bile values reappearing in bile 36 h after application. Results for (14)C-activity in intestine and pylori support the observation of enterohepatic cycling with a small peak in intestine at 3 h post i.p. injection and a low peak in intestine and pylori at 6 h post i.p. injection, reflecting presence of the drug substance in bile. The highest activity in intestine was found 24 h post-injection coinciding with low levels in bile, followed by a gradual decrease of activity in intestine mirroring the re-uptake of DCF into bile. The finding of enterohepatic cycling of DCF in brown trout is suggestive of a prolonged retention of DCF in brown trout.
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Affiliation(s)
- Birgit Hoeger
- Human and Environmental Toxicology, University of Konstanz, 78464 Konstanz, Germany.
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Haap T, Triebskorn R, Köhler HR. Acute effects of diclofenac and DMSO to Daphnia magna: immobilisation and hsp70-induction. CHEMOSPHERE 2008; 73:353-359. [PMID: 18649920 DOI: 10.1016/j.chemosphere.2008.05.062] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2007] [Revised: 05/19/2008] [Accepted: 05/27/2008] [Indexed: 05/26/2023]
Abstract
To determine the toxicity of the anti-rheumatic drug diclofenac to Daphnia magna, acute toxicity tests according to the OECD guideline 202 were combined with biochemical investigations of the hsp70 level as a biomarker for proteotoxicity. Particular attention was paid to the impact of the solvent DMSO as a confounding factor to diclofenac toxicity by means of testing different variations of producing stock solutions. In the acute immobilisation tests, diclofenac was most toxic as a singular test substance, with indication of a slight antagonistic interaction between the two substances. The highest EC50 values were obtained in those approaches using diclofenac pre-dissolved in DMSO. Thus, the observed antagonism seems to be intensified by pre-dissolution. Hsp70 levels of 12- to 19-days-old D. magna were determined after 48h exposure using a highly reproducible immunological protocol. Hsp70 induction occurred at a LOEC of 30mgl(-1) diclofenac plus 0.6mll(-1) DMSO, and at a LOEC of 40mgl(-1) for diclofenac alone. In summary, DMSO showed only slight confounding effects on diclofenac action in the applied range of concentrations.
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Affiliation(s)
- Timo Haap
- Animal Physiological Ecology, University of Tübingen, Konrad-Adenauer-Street 20, D-72072 Tübingen, Germany.
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Mino-Kenudson M, Tomita S, Lauwers GY. Mucin expression in reactive gastropathy: an immunohistochemical analysis. Arch Pathol Lab Med 2007; 131:86-90. [PMID: 17227128 DOI: 10.5858/2007-131-86-meirga] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2006] [Indexed: 11/06/2022]
Abstract
CONTEXT Reactive gastropathy is the second most common diagnosis made on gastric biopsies. Increased epithelial proliferation and modifications of epithelial cytokeratin profile, distinct from those of Helicobacter pylori gastritis, have been previously reported. However, the evaluation of mucins, important components of the protective mucosal mucous layer, has not been reported. OBJECTIVE To investigate alterations of membrane and secreted mucins in reactive gastropathy of various etiologies using antibodies against mucin glycoproteins. DESIGN Thirty-eight gastric biopsies diagnosed as reactive gastropathy, related to nonsteroidal anti-inflammatory drugs (n = 18) or bile reflux (n = 6) or of indeterminate etiology (n = 14), were evaluated using antibodies to MUC1, MUC5AC, MUC6, and MUC2. All cases were confirmed to be negative for H. pylori. The biopsies were classified in 3 groups based on the severity of cytoarchitectural changes (mild, moderate, and severe). Mucin expression and its distribution were recorded and the results correlated with the cytoarchitectural alterations and etiologies. RESULTS Loss of MUC1, either patchy or complete, was noted in 67% of the cases. Aberrant expression of MUC5AC in pyloric glands was observed in 81% of the cases, and aberrant expression of MUC6 in the upper foveolar epithelium was diffusely seen in 14% of the cases. Aberrant expression of MUC2 in non-goblet cells was observed in a single case. Aberrant expression of MUC6 was less extensive in the nonsteroidal anti-inflammatory drugs group than in other 2 groups (P = .03). Concurrently, the diffuse distribution of aberrant MUC6 expression was seen only in the cases of severe gastropathy (P = .09). There was no correlation between modifications in expression of other mucins and either the etiologies or the severity of cytoarchitectural changes. CONCLUSIONS Expressions of membrane (MUC1) and secreted (MUC5AC, MUC6) mucins are frequently modified in reactive gastropathy. The alteration of MUC1, which is involved in cell adhesion and polarity, may play a role in the development of the serrated profile of reactive gastropathy. Milder modifications of the secreted mucins may be explained by the reactive/regenerative nature of the process. Importantly, theses changes are different from the increase in MUC6 and reduction of MUC5AC expression reported in H. pylori gastritis, underlying their mechanistic differences. It is worth noting that similar alterations of mucin expression are shared by various etiologies, that is, nonsteroidal anti-inflammatory drugs and bile reflux, consistent with the nonspecific nature of reactive gastropathy.
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Affiliation(s)
- Mari Mino-Kenudson
- Massachusetts General Hospital Department of Pathology, Boston, MA 02114-2696, USA
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Krischak GD, Augat P, Sorg T, Blakytny R, Kinzl L, Claes L, Beck A. Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Arch Orthop Trauma Surg 2007; 127:3-9. [PMID: 16865399 DOI: 10.1007/s00402-006-0202-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2005] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Potential adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on bone metabolism and fracture healing are contradictive to their wide application in post-traumatic treatment. Our objective was to investigate changes to periosteal callus formation with respect to NSAID and central analgesic drug application. Our hypothesis was that callus formation is delayed in animals treated with the non-specific NSAID diclofenac. MATERIALS AND METHODS The left tibia of forty male Wistar rats were osteotomized, stabilized with a Kirschner wire, and randomized into four groups of ten animals. Group 1 received a placebo, group 2 received the central analgesic tramadol (20 mg/kg per day) throughout the study, and groups 3 and 4 were treated with sodium diclofenac (5 mg/kg per day). Group 3 received diclofenac for seven days, followed by placebo until sacrifice (short-term), while group 4 animals received diclofenac for the full period (long-term). Animals were sacrificed 21 days after osteotomy. RESULTS Under light microscopy, all osteotomies healed successfully and independently of the drug treatment. Histomorphometry revealed delayed callus maturation in long-term diclofenac treated animals, with significantly higher amounts of cartilage and less bone, particularly in the outermost region of periosteal callus. Short-term NSAID and tramadol application did not significantly alter callus differentiation. CONCLUSION Callus maturation in vivo was impaired after long-term application of diclofenac which corresponds to the in vitro findings of a dose-dependent effect of NSAIDs on osteoblast proliferation.
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Affiliation(s)
- Gert D Krischak
- Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, University of Ulm, Steinhoevelstr. 9, 89075 Ulm, Germany.
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Hoeger B, Köllner B, Dietrich DR, Hitzfeld B. Water-borne diclofenac affects kidney and gill integrity and selected immune parameters in brown trout (Salmo trutta f. fario). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2005; 75:53-64. [PMID: 16139376 DOI: 10.1016/j.aquatox.2005.07.006] [Citation(s) in RCA: 209] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Revised: 06/23/2005] [Accepted: 07/02/2005] [Indexed: 05/02/2023]
Abstract
The detection of residues of various pharmaceuticals in surface waters during the last two decades has prompted concerns about possible adverse effects of this kind of pollution on aquatic organisms. The objective of the present study was to investigate effects of the non-steroidal anti-inflammatory drug diclofenac, one of the pharmaceuticals most prevalent in surface waters, on brown trout (Salmo trutta f. fario), a salmonid species native to German rivers. Brown trout were exposed to 0.5, 5 and 50 microg/L diclofenac for 7, 14 and 21 days, whereby the lowest exposure concentration is comparable with concentrations commonly found in the aquatic environment. Fish exposed to diclofenac displayed significantly reduced haematocrit levels after 7 and 14 days of exposure. After 21 days, trout were examined for histopathological alterations, whereby diclofenac exposure resulted in increased monocyte infiltration in the liver, telangiectasis in gills, and the occurrence of interstitial hyaline droplets, interstitial proteinaceous fluid and mild tubular necrosis in trunk kidney. Concurrent immunohistological analysis revealed an increase of granulocyte numbers in primary gill filaments, as well as granulocyte accumulation and increased major histocompatibility complex (MHC) II expression in kidney, suggestive of an inflammatory process in these organs. Moreover, the ability of diclofenac to hinder the stimulation of prostaglandin E2 synthesis was shown in head kidney macrophages of brown trout in vitro. These findings support the hypothesis that environmental exposure of fish to diclofenac provokes the same mechanism of action in these non-target organisms as previously described for mammalian species and can thus lead to similar (possibly adverse) effects. In general, the present study suggests that exposure of brown trout to diclofenac in concentration ranges commonly found in the environment can result in adverse effects in various organs and possibly compromise the health of affected fish populations.
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Affiliation(s)
- Birgit Hoeger
- Environmental Toxicology, University of Konstanz, Konstanz, Germany
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Cheng P, Gong J, Wang T, Chen J, Liu GS, Zhang R. Gene expression in rats with Barrett’s esophagus and esophageal adenocarcinoma induced by gastroduodenoesophageal reflux. World J Gastroenterol 2005; 11:5117-22. [PMID: 16127739 PMCID: PMC4320382 DOI: 10.3748/wjg.v11.i33.5117] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the different gene expression profiles in rats with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA) induced by gastro-duodeno-esophageal reflux.
METHODS: Esophagoduodenostomy was performed in 8-wk old Sprague-Dawley rats to induce gastro-duodeno-esophageal reflux, and a group of rats that received sham operation served as control. Esophageal epithelial pathological tissues were dissected and frozen in liquid nitrogen immediately. The expression profiles of 4 096 genes in EA and BE tissues were compared to normal esophagus epithelium in normal control (NC) by cDNA microarray.
RESULTS: Four hundred and forty-eight genes in BE were more than three times different from those in NC, including 312 upregulated and 136 downregulated genes. Three hundred and seventy-seven genes in EA were more than three times different from those in NC, including 255 upregulated and 142 downregulated genes. Compared to BE, there were 122 upregulated and 156 downregulated genes in EA. In the present study, the interested genes were those involved in carcinogenesis. Among them, the upregulated genes included cathepsin C, aminopeptidase M, arachidonic acid epoxygenase, tryptophan-2,3-dioxygenase, ubiquitin-conjugating enzyme, cyclic GMP-stimulated phosphodiesterase, tissue inhibitor of metalloproteinase-1, betaine-homocysteine methyltra-nsferase, lysozyme, complement 4b binding protein, complement 9 protein, insulin-like growth factor binding protein, UDP-glucuronosyltransferase, tissue inhibitor of metalloproteinase-3, aldolase B, retinoid X receptor gamma, carboxylesterase and testicular cell adhesion molecule 1. The downregulated genes included glutathione synthetase, lecithin-cholesterol acyltransferase, p55CDC, heart fatty acid binding protein, cell adhesion regulator and endothelial cell selectin ligand.
CONCLUSION: Esophageal epithelium exposed excessively to harmful ingredients of duodenal and gastric reflux may develop into BE and even EA gradually. The gene expression level is different between EA and BE, and may be related to the occurrence and progression of EA.
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Affiliation(s)
- Peng Cheng
- Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Cheng P, Gong J, Wang T, Chen J, Liu GS, Zhang R. Gene expression in rats with Barrett's esophagus and esophageal adenocarcinoma induced by gastroduodenoesophageal reflux. World J Gastroenterol 2005. [PMID: 16127739 DOI: 10.3748/wjg.v11.i21.5117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To study the different gene expression profiles in rats with Barrett's esophagus (BE) and esophageal adenocarcinoma (EA) induced by gastro-duodeno-esophageal reflux. METHODS Esophagoduodenostomy was performed in 8-wk old Sprague-Dawley rats to induce gastro-duodeno-esophageal reflux, and a group of rats that received sham operation served as control. Esophageal epithelial pathological tissues were dissected and frozen in liquid nitrogen immediately. The expression profiles of 4096 genes in EA and BE tissues were compared to normal esophagus epithelium in normal control (NC) by cDNA microarray. RESULTS Four hundred and forty-eight genes in BE were more than three times different from those in NC, including 312 upregulated and 136 downregulated genes. Three hundred and seventy-seven genes in EA were more than three times different from those in NC, including 255 upregulated and 142 downregulated genes. Compared to BE, there were 122 upregulated and 156 downregulated genes in EA. In the present study, the interested genes were those involved in carcinogenesis. Among them, the upregulated genes included cathepsin C, aminopeptidase M, arachidonic acid epoxygenase, tryptophan-2,3-dioxygenase, ubiquitin-conjugating enzyme, cyclic GMP-stimulated phosphodiesterase, tissue inhibitor of metalloproteinase-1, betaine-homocysteine methyltransferase, lysozyme, complement 4b binding protein, complement 9 protein, insulin-like growth factor binding protein, UDP-glucuronosyltransferase, tissue inhibitor of metalloproteinase-3, aldolase B, retinoid X receptor gamma, carboxylesterase and testicular cell adhesion molecule 1. The downregulated genes included glutathione synthetase, lecithin-cholesterol acyltransferase, p55CDC, heart fatty acid binding protein, cell adhesion regulator and endothelial cell selectin ligand. CONCLUSION Esophageal epithelium exposed excessively to harmful ingredients of duodenal and gastric reflux may develop into BE and even EA gradually. The gene expression level is different between EA and BE, and may be related to the occurrence and progression of EA.
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Affiliation(s)
- Peng Cheng
- Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Cheng P, Gong J, Wang T, Jie C, Liu GS, Zhang R. Gene expression in Barrett’s esophagus and reflux esophagitis induced by gastroduodenoesophageal reflux in rats. World J Gastroenterol 2005; 11:3277-80. [PMID: 15929182 PMCID: PMC4316063 DOI: 10.3748/wjg.v11.i21.3277] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the difference of gene expression profiles between Barrett’s esophagus and reflux eso-phagitis induced by gastroduodenoesophageal reflux in rats.
METHODS: Eight-week-old Sprague-Dawley rats were treated esophagoduodenostomy to produce gastroduode-noesophageal reflux, and another group received sham operation as control. Esophageal epithelial tissues were dissected and frozen in liquid nitrogen immediately for pathology 40 wk after surgery. The expression profiles of 4096 genes in reflux esophagitis and Barrett’s esophagus tissues were compared with normal esophageal epithelium by cDNA microarray.
RESULTS: Four hundred and forty-eight genes in Barrett’s esophagus were more than three times different from those in normal esophageal epithelium, including 312 up-regulated and 136 down-regulated genes. Two hundred and thirty-two genes in RE were more than three times different from those in normal esophageal epithelium, 90 up-regulated and 142 down-regulated genes. Compared to reflux esophagitis, there were 214 up-regulated and 142 down-regulated genes in Barrett’s esophagus.
CONCLUSION: Esophageal epithelium exposed excessively to harmful ingredients of duodenal and gastric reflux can develop esophagitis and Barrett’s esophagus gradually. The gene expression level is different between reflux esophagitis and Barrett’s esophagus and the differentially expressed genes might be related to the occurrence and development of Barrett’s esophagus and the promotion or progression in adenocarcinoma.
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Affiliation(s)
- Peng Cheng
- Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Hernández-Delgadillo GP, Cruz SL. Dipyrone potentiates morphine-induced antinociception in dipyrone-treated and morphine-tolerant rats. Eur J Pharmacol 2005; 502:67-73. [PMID: 15464091 DOI: 10.1016/j.ejphar.2004.08.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2004] [Revised: 08/09/2004] [Accepted: 08/18/2004] [Indexed: 11/21/2022]
Abstract
Coadministration of morphine and dipyrone produces acute and chronic antinociceptive potentiation in drug-naive rats. In this work, the effectiveness of the combination was determined in rats pretreated with morphine or dipyrone. Nine groups of male rats received (i.v.) 3.1 mg/kg morphine, 600 mg/kg dipyrone, or the morphine-dipyrone combination twice a day for five administrations (three groups per treatment). From the 6th to the 10th administration, one group out of each treatment continued without change, while the other two were switched to one of the other two possible treatments. In morphine-tolerant rats, morphine plus dipyrone produced a transient antinociceptive potentiation. In dipyrone-treated animals, this combination produced a long-lasting potentiation. In animals only treated with the combination, antinociception was clear since the beginning, although it decreased after the 6th injection. No cross-tolerance was seen between morphine and dipyrone. These data suggest that dipyrone potentiates morphine-induced antinociception in dipyrone-treated as well as in morphine-tolerant rats.
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Affiliation(s)
- Gloria P Hernández-Delgadillo
- Department of Pharmacobiology, Cinvestav, IPN. Calzada de los Tenorios #235, Col. Granjas Coapa, México, D.F. 14330, Mexico
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