Pharmacogenetic of cardiovascular system drugs focusing on implementation

• Grant number: 13/09295-3
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: October 01, 2013
• End date: September 30, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Paulo Caleb Júnior de Lima Santos
• Grantee: Paulo Caleb Júnior de Lima Santos
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexandre da Costa Pereira ; José Eduardo Krieger
• Associated scholarship(s): 17/26225-0 - Translational research: pharmacogenomic analysis of the response to crack and cocaine addiction, BP.DR; 16/22507-8 - Impact assessment of the inclusion of ABCB1 and CYP4F2 genes polymorphisms in pharmacogenetic-guided algorithm for personalized warfarin dosing, BP.MS; 16/23454-5 - Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients without stable dose, BP.DR; 13/24440-0 - Pharmacogenetics and pharmacometabolomics analyses for antihypertensive drugs, BP.DD; 13/20614-3 - Pharmacogenetic analyses for cardiovascular drugs focusing on implementation, BP.JP

Abstract

Cardiovascular diseases are the main causes of death worldwide and the pharmacological treatment implementation has been one of the most responsible for reductions in morbidity and mortality recent decades. Some pharmacogenetic tests are available to healthcare professionals, and increasingly, the regulatory agencies understand the relationship pharmaco-genomics. In this project, beside implementation of pharmacogenetic in a traditional institution, we will investigate the new field of research called pharrmacometabolomics. It can be conceptualized as a set of changes on metabolome resulting from pharmacological treatments and its approach can clarify mechanisms for variations to responses to treatment, or even understand how genetic alterations influence the responses. The main aims are: 1-for pharmacogenetic of warfarin: to compare anticoagulation guided by pharmacogenetic algorithm with traditional anticoagulation and to evaluate the impact of the algorithm on adverse events and cost-effectiveness in patients beginning anticoagulation; 2- for pharmacogenetic of anti-smoking drugs: to assess the effect of polymorphisms with therapeutic efficacy and adverse effects in patients treated with bupropion or varenicline; 3- for polymorphisms involved in nicotine dependence: to associate the effect of these polymorphisms with smoking habit and dependence degree; 4- for pharmacogenetic of antihypertensive drugs: to identify polymorphisms associated with efficacy in the treatment, adverse drug, and treatment resistance; 5- for metabolomic analysis in patients treated with antihypertensives: to identify metabolomic changes induced by the treatment, to associate metabolomic changes with responses to treatment, with adverse effects, with resistant hypertension, or with possible effects of the polymorphisms. Analyses of genotypes will be performed by polymerase chain reaction (PCR) followed by restriction enzyme digestion (RFLP), PCR followed by melting curve analysis (HRM), and by Taqman® OpenArray® technology. Metabolomic analysis will be performed by mass spectrometry. We will include: 200 patients, who initiate anticoagulation with warfarin; 500 smokers treated with bupropion and varenicline; for the analysis of nicotine dependence, 1000 smokers and 1000 control subjects; and 1500 patients with hypertension who were followed for a period of 24 weeks. Our expected results may show: 1- for pharmacogenetic of warfarin: there is not complete knowledge about its viability, thus, our study design may allow effective conclusions about cost-effectiveness. This information may be useful in designing preventive and therapeutic programs of personalized medicine in our public service; 2- for pharmacogenetic of anti-smoking drugs: may show significant associations on better treatment, increasing efficiency and reducing adverse events, an important for dropout and treatment failure; 3- for study of polymorphisms involved in nicotine dependence: may generate useful tools in the prevention, treatment and better understanding of smoking and level of dependency; 4- for pharmacogenetic of antihypertensive drugs: the possibility of personalized treatment and identification of resistant hypertension could result, on clinical and epidemiological scenario, in a reduction of complications due to hypertension and cardiovascular mortality; 5- for metabolomic analysis in patients treated with antihypertensives: may clarify mechanisms for variations to responses to treatment, or even understand how genetic alterations influence the responses. (AU)

Scientific publications

(20)

(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)

JUNIOR LIMA SANTOS, PAULO CALEB; MARCATTO, LEILIANE RODRIGUES; DUARTE, NUBIA ESTEBAN; GADI SOARES, RENATA ALONSO; CASSARO STRUNZ, CELIA MARIA; SCANAVACCA, MAURCIO; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA. Development of a pharmacogenetic-based warfarin dosing algorithm and its performance in Brazilian patients: highlighting the importance of population-specific calibration. PHARMACOGENOMICS, v. 16, n. 8, p. 865-876, 2015. (13/20614-3, 13/09295-3, 12/00316-5)

SILVA FONSECA, PAULA FERNANDA; CANCADO, RODOLFO DELFINI; UELLENDAHL LOPES, MARLY MARIA; CORREIA, EDILEIDE; LESCANO, MANUEL ANTONIO; JUNIOR LIMA SANTOS, PAULO CALEB. HAMP Gene Mutation Associated with Juvenile Hemochromatosis in Brazilian Patients. Acta Haematologica, v. 135, n. 4, p. 228-231, 2016. (13/20614-3, 13/09295-3)

MARCATTO, LEILIANE RODRIGUES; SACILOTTO, LUCIANA; TAVARES, LETICIA CAMARGO; FACIN, MIRELLA; OLIVETTI, NATALIA; CASSARO STRUNZ, CELIA MARIA; COSTA DARRIEUX, FRANCISCO CARLOS; SCANAVACCA, MAURICIO IBRAHIM; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; et al. Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin. FRONTIERS IN PHARMACOLOGY, v. 9, SEP 21 2018. (16/23454-5, 13/09295-3)

MARCATTO, LEILIANE RODRIGUES; SACILOTTO, LUCIANA; BUENO, CAROLINA TOSIN; FACIN, MIRELLA; CASSARO STRUNZ, CELIA MARIA; COSTA DARRIEUX, FRANCISCO CARLOS; SCANAVACCA, MAURICIO IBRAHIM; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; JUNIOR LIMA SANTOS, PAULO CALEB. Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial. BMC CARDIOVASCULAR DISORDERS, v. 16, NOV 17 2016. (13/09295-3)

DA COSTA JUNIOR, LUIZ CARLOS; DE CASTRO, CLARISSA LOURENCO; FREITAS-ALVES, DANIELY REGINA; VIANNA-JORGE, ROSANE; SANTOS, PAULO CALEB JUNIOR LIMA. ABCB1 and ERCC1 gene polymorphisms are associated with nephro- and hepatotoxicity to carboplatin/paclitaxel-based chemotherapy in patients with gynecologic cancers. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, v. 76, n. 10, JUN 2020. (13/09295-3)

TAVARES, LETICIA C.; DUARTE, NUBIA E.; MARCATTO, LEILIANE R.; SOARES, RENATA A. G.; KRIEGER, JOSE E.; PEREIRA, ALEXANDRE C.; JUNIOR LIMA SANTOS, PAULO CALEB. Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, v. 74, n. 12, p. 1555-1566, DEC 2018. (16/22507-8, 16/23454-5, 13/09295-3)

MARCATTO, LEILIANE RODRIGUES; SACILOTTO, LUCIANA; DA COSTA DARRIEUX, FRANCISCO CARLOS; HACHUL, DENISE TESSARIOL; SCANAVACCA, MAURICIO IBRAHIM; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; JUNIOR LIMA SANTOS, PAULO CALEB. Age is associated with time in therapeutic range for warfarin therapy in patients with atrial fibrillation. ONCOTARGET, v. 7, n. 34, p. 54194-54199, AUG 23 2016. (13/09295-3)

STEINER, HEIDI E.; GILES, JASON B.; PATTERSON, HAYLEY KNIGHT; FENG, JIANGLIN; EL ROUBY, NIHAL; CLAUDIO, KARLA; MARCATTO, LEILIANE RODRIGUES; TAVARES, LETICIA CAMARGO; GALVEZ, JUBBY MARCELA; CALDERON-OSPINA, CARLOS-ALBERTO; et al. Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans. FRONTIERS IN PHARMACOLOGY, v. 12, OCT 29 2021. (16/23454-5, 13/09295-3, 19/08338-7)

MARCATTO, LEILIANE RODRIGUES; SACILOTTO, LUCIANA; TAVARES, LETICIA CAMARGO; PEREIRA SOUZA, DEBORA STEPHANIE; OLIVETTI, NATALIA; CASSARO STRUNZ, CELIA MARIA; COSTA DARRIEUX, FRANCISCO CARLOS; SCANAVACCA, MAURICIO IBRAHIM; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; et al. Evaluation of the Long-Term Impact on Quality After the End of Pharmacist-Driven Warfarin Therapy Management in Patients With Poor Quality of Anticoagulation Therapy. FRONTIERS IN PHARMACOLOGY, v. 11, JUL 14 2020. (16/23454-5, 16/22507-8, 13/09295-3, 19/08338-7)

MARCATTO, LEILIANE; BOER, BRUNO; SACILOTTO, LUCIANA; OLIVETTI, NATALIA; DARRIEUX, FRANCISCO CARLOS COSTA; SCANAVACCA, MAURICIO IBRAHIM; PEREIRA, ALEXANDRE COSTA; SANTOS, PAULO CALEB JUNIOR LIMA. Impact of adherence to warfarin therapy during 12 weeks of pharmaceutical care in patients with poor time in the therapeutic range. JOURNAL OF THROMBOSIS AND THROMBOLYSIS, v. 51, n. 4, SI, p. 1043-1049, MAY 2021. (13/09295-3, 16/23454-5)

MARCATTO, LEILIANE; BOER, BRUNO; SACILOTTO, LUCIANA; OLIVETTI, NATALIA; DARRIEUX, FRANCISCO CARLOS COSTA; SCANAVACCA, MAURICIO IBRAHIM; PEREIRA, ALEXANDRE COSTA; SANTOS, PAULO CALEB JUNIOR LIMA. Impact of adherence to warfarin therapy during 12 weeks of pharmaceutical care in patients with poor time in the therapeutic range. JOURNAL OF THROMBOSIS AND THROMBOLYSIS, v. 51, n. 4, p. 7-pg., 2020-09-24. (13/09295-3, 16/23454-5)

XAVIER TOMAZ, PAULO ROBERTO; KAJITA, MARIANA SOARES; SANTOS, JULIANA ROCHA; SCHOLZ, JAQUELINE; ABE, TANIA OGAWA; GAYA, PATRICIA VIVIANE; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; JUNIOR LIMA SANTOS, PAULO CALEB. Cytochrome P450 2A6 and 2B6 polymorphisms and smoking cessation success in patients treated with varenicline. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, v. 75, n. 11, p. 1541-1545, NOV 2019. (13/09295-3)

BUENO, CAROLINA TOSIN; PEREIRA, ALEXANDRE COSTA; SANTOS, HADASSA CAMPOS; GOMEZ GOMEZ, LUZ MARINA; VANCAN RUSSO HORIMOTO, ANDREA ROSELI; KRIEGER, EDUARDO MOACYR; KRIEGER, JOSE EDUARDO; LIMA SANTOS, PAULO CALEB JUNIOR. Association of the genetic ancestry with resistant hypertension in the ReHOT (Resistant Hypertension Optimal Treatment) randomized study. SCIENTIFIC REPORTS, v. 10, n. 1, JAN 30 2020. (13/09295-3, 13/24440-0)

EL ROUBY, NIHAL; RODRIGUES MARCATTO, LEILIANE; CLAUDIO, KARLA; CAMARGO TAVARES, LETICIA; STEINER, HEIDI; BOTTON, MARIANNA R.; LUBITZ, STEVE A.; FALLON, ECHO N.; YEE, KEVIN; KAYE, JUSTIN; et al. Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, v. 14, n. 1, SEP 2020. (16/22507-8, 13/09295-3)

SANTOS, JULIANA ROCHA; XAVIER TOMAZ, PAULO ROBERTO; SCHOLZ, JAQUELINE RIBEIRO; GAYA, PATRICIA VIVIANE; ABE, TANIA OGAWA; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; DE LIMA SANTOS, PAULO CALEB JUNIOR. Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment. GENES, v. 11, n. 7, JUL 2020. (13/09295-3, 19/08338-7)

TAVARES, LETICIA C.; MARCATTO, LEILIANE R.; SANTOS, PAULO C. J. L.. Genotype-guided warfarin therapy: current status. PHARMACOGENOMICS, v. 19, n. 7, p. 667-685, MAY 2018. (16/23454-5, 13/09295-3, 16/22507-8)

DE FARIA, HENRIQUE DIPE; BUENO, CAROLINA TOSIN; KRIEGER, JOSE EDUARDO; KRIEGER, EDUARDO MOACYR; PEREIRA, ALEXANDRE COSTA; JUNIOR LIMA SANTOS, PAULO CALEB; FIGUEIREDO, EDUARDO COSTA. Online extraction of antihypertensive drugs and their metabolites from untreated human serum samples using restricted access carbon nanotubes in a column switching liquid chromatography system. Journal of Chromatography A, v. 1528, p. 41-52, DEC 15 2017. (13/09295-3, 13/24440-0)

TAVARES, LETICIA C.; MARCATTO, LEILIANE R.; SOARES, RENATA A. G.; KRIEGER, JOSE E.; PEREIRA, ALEXANDRE C.; SANTOS, PAULO C. J. L.. Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients. FRONTIERS IN PHARMACOLOGY, v. 9, MAY 23 2018. (16/23454-5, 13/09295-3, 16/22507-8)

SILVA FONSECA, PAULA FERNANDA; CANCADO, RODOLFO DELFINI; NAOUM, FLAVIO AUGUSTO; DINARDO, CARLA LUANA; HENCKLAIN FONSECA, GUILHERME HENRIQUE; MENOSI GUALANDRO, SANDRA FATIMA; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA; BRISSOT, PIERRE; JUNIOR LIMA SANTOS, PAULO CALEB. Quality of life scores differs between genotypic groups of patients with suspected hereditary hemochromatosis. BMC MEDICAL GENETICS, v. 19, JAN 5 2018. (13/20614-3, 13/09295-3)

DINARDO, CARLA LUANA; JUNIOR LIMA SANTOS, PAULO CALEB; SCHETTERT, ISOLMAR TADEU; GADI SOARES, RENATA ALONSO; KRIEGER, JOSE EDUARDO; PEREIRA, ALEXANDRE COSTA. Investigation of Genetic Disturbances in Oxygen Sensing and Erythropoietin Signaling Pathways in Cases of Idiopathic Erythrocytosis. GENETICS RESEARCH INTERNATIONAL, v. 2013, p. 4-pg., 2013-01-01. (10/17881-1, 13/20614-3, 13/09295-3)

Filed patent(s) as a result of this research project