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| Author(s): |
Carolina Tosin Bueno
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2018-11-09 |
| Examining board members: |
Paulo Caleb Júnior de Lima Santos;
Eduardo Costa de Figueiredo;
Andréa Roseli Vançan Russo Horimoto;
Gustavo José da Silva Pereira
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| Advisor: | Paulo Caleb Júnior de Lima Santos |
| Abstract | |
Background: Resistant hypertensive (RH) patients are individuals with uncontrolled blood pressure - despite treatment with one diuretic and two antihypertensives with different mechanisms of action in adequate doses. There are two areas of interest in this context: genetic ancestry that could initially impact on blood pressure controls, and pharmacometabolomics, which conceptually is a set of changes in metabolite concentrations - a new field that can clarify mechanisms of pharmacological response variation. Thus, our main objectives were: to associate serum measurements of antihypertensive drugs and their metabolites to the pharmacotherapeutic responses in hypertensive patients and to analyze genetic ancestry in hypertensive patients in order to verify a possible association with pharmacotherapeutic responses and resistant hypertension. Methods: Samples of 1,597 patients were used, being 187 RH. Sample preparation and analysis were performed using a column with restricted access carbon nanotubes (RACNTs) in a liquid chromatography coupled to mass spectrometer (UPLC-MS/MS) in column switching mode. Genetic ancestry was performed using a panel of 192 polymorphic markers; three references were used (European, Amerindian and African). The race was determined by self-declaration, according to IBGE (white, brown, black and others). Results: The method has been fully validated according to the guidelines of the Food and Drug Administration (FDA). The total run time for each analysis was 12.0 min including sample preparation. No significant differences were found in the concentrations of each analyte according to responsive and nonresponsive patients, possibly because of the still low number of samples (total n of 171 samples). The means of the measurements in the responders group were: clonidine 1.308microg/L; amlodipine 44.044microg/L; enalapril 67.706microg/L; enalaprilat 44.144microg/L; losartan 202.622microg/L; losartan carboxylic acid 65.99microg/L, N-2 glucuronide of losartan 43,4microg/L and spironolactone 85.87microg/L. For the group of non-responders, we obtained: clonidine 1.4 microg/L; amlodipine 78.89microg/L; enalapril 87.821microg/L; enalaprilat 78.878microg/L; losartana 148.026microg/L, losartan carboxylic acid 83.535microg/L, N-2 glucanide of losartan 122.452microg/L and spironolactone 79.72microg/L. Self-reported race was associated with the components of the genetic ancestry of these patients (p<0.001). Genetic ancestry, available for 1,503 patients, had an overall mean of 0.53 for European; 0.11 for Amerindian; and 0.35 for African. No statistical differences were found in the means of ancestry according to responder or RH groups. Conclusion: The analytical method was validated and genetic ancestry was performed, both unrelated to pharmacotherapeutic and resistant hypertension (AU) | |
| FAPESP's process: | 13/24440-0 - Pharmacogenetics and pharmacometabolomics analyses for antihypertensive drugs |
| Grantee: | Carolina Tosin Bueno |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |