Clinical pharmacogenetics of ibuprofen enantiomers after lower third molar surgeries

• Grant number: 18/04157-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 01, 2018
• End date: January 31, 2019
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Ferreira dos Santos
• Grantee: Giovana Maria Weckwerth
• Supervisor: Devin Michael Absher
• Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Institution abroad: HudsonAlpha Institute for Biotechnology, United States
• Associated to the scholarship: 16/12671-5 - Clinical Pharmacogenetic of ibuprofen enantiomers after lower third molar surgeries, BP.DR

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are over-the-counter agents frequently consumed by the population in order to control chronic pain and also acute pain after inflammatory processes. Extraction of lower third molars is recommended for evaluation of the NSAIDs effect since it generates pain, swelling and trismus. Metabolism of NSAIDs is mainly dependent on the family of cytochrome P450 (CYP), more precisely CYP2C8 and CYP2C9 genes. The most common coding mutations occurring in these genes that are associated with reduced enzyme activity on CYP2C8 and CYP2C9 genes exhibit frequencies around 22% and 31%, respectively, in the Caucasian population. Due to this high frequency of variations in these genes, the evaluation of their role could help to understand the variability in responses to clinical treatment and the development of adverse effects to the use of NSAIDs. In this context, pharmacogenetics, which studies the contribution of polymorphisms and genetic factors to the individual variability of responses to drug metabolism, is growing and starting to show results regarding the clinical use of drugs. In addition, the possible influence of genetic and tissue biomarkers at the descending inhibitory system of pain, may also impact the response and effects of NSAIDS, and this inhibitory system could be checked through the modulation of conditioned pain. In this aspect, the OPRM1 opioid receptor has been widely studied by pharmacogenetics, due to the structural variation, and its function in a variety of painful disorders. The ¼-opioid receptor (MOR), encoded by the OPRM1 gene naturally regulates the analgesic response to pain. Genetic variabilities in the OPRM1 gene, particularly A118G SNP have been associated with a number of functional purposes. Thus, the aim of this study is to assess the link between the different haplotypes of CYP2C8, CYP2C9 and OPRM1 genes and the clinical efficacy of ibuprofen after lower third molar extractions regarding pain, swelling and trismus, adverse reactions, the amount of pain medication used, the patient's satisfaction with the drug and the influence of the ability on preoperative modulation of conditioned pain. Lyophilized DNA, derived from the saliva of the 200 patients from this PhD research collected in Brazil, will be used for the genetic sequencing and analysis of the CYP2C8, CYP2C9 and OPRM1 genes, related to the metabolism of NSAIDS, pain and modulation of pain and all data collected will be compared with the haplotypes found in the Brazilian population. For the genetic sequencing of CYP2C8, CYP2C9 and OPRM1 MiSeq® System (Illumina®) instruments with a 2 x 78bp read length will be utilized. The research internship abroad (BEPE) will be conducted under the coordination of Professor Devin Absher, Faculty Investigator of HudsonAlpha, Institute for Biotechnology, Huntsville, Alabama, USA, where genetic testing will be conducted. This research will also have the collaboration of Dr. Troy Moore, Chief Scientific Officer of Kailos Genetics, Inc., Huntsville, Alabama, USA, which is located in the same complex of HudsonAlpha (same address). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

WECKWERTH, GIOVANA MARIA; DIONISIO, THIAGO JOSE; COSTA, YURI MARTINS; ZUPELARI-GONCALVES, PAULO; OLIVEIRA, GABRIELA MORAES; TORRES, ELZA ARAUJO; BONJARDIM, LEONARDO RIGOLDI; FARIA, FLAVIO AUGUSTO CARDOSO; CALVO, ADRIANA MARIA; MOORE, TROY; et al. Multifocal Analysis of Acute Pain After Third Molar Removal. FRONTIERS IN PHARMACOLOGY, v. 12, APR 15 2021. (17/12725-0, 18/04157-5)

WECKWERTH, GIOVANA M.; DIONISIO, THIAGO J.; COSTA, YURI M.; COLOMBINI-ISHIQUIRIAMA, BELLA L.; OLIVEIRA, GABRIELA M.; TORRES, ELZA A.; BONJARDIM, LEONARDO R.; CALVO, ADRIANA M.; MOORE, TROY; ABSHER, DEVIN M.; et al. CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, v. 77, n. 5, NOV 2020. (16/12671-5, 18/04157-5)