PAULO CALEB JUNIOR DE LIMA SANTOS
Projetos de Pesquisa
Unidades Organizacionais
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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bookPart Farmacogenômica(2021) TAVARES, Letícia Camargo; MARCATTO, Leiliane Rodrigues; SANTOS, Paulo Caleb Júnior de Lima- Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox(2017) LESCANO, Manuel A.; TAVARES, Leticia C.; SANTOS, Paulo C. J. L.Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g. 47G> A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [ serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 ae mol/g; reference value < 36 ae mol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.
- Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin(2018) MARCATTO, Leiliane Rodrigues; SACILOTTO, Luciana; TAVARES, Leticia Camargo; FACIN, Mirella; OLIVETTI, Natalia; STRUNZ, Celia Maria Cassaro; DARRIEUX, Francisco Carlos Costa; SCANAVACCA, Mauricio Ibrahim; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa; SANTOS, Paulo Caleb Junior LimaThromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist's warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range-TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient's INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2-3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 +/- 0.010 vs. 0.382 +/- 0.016; and 0.144 +/- 0.010 vs. 0.543 +/- 0.014, p < 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 +/- 0.015; 0.540 +/- 0.015, p < 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin.
- Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans(2021) STEINER, Heidi E.; GILES, Jason B.; PATTERSON, Hayley Knight; FENG, Jianglin; ROUBY, Nihal El; CLAUDIO, Karla; MARCATTO, Leiliane Rodrigues; TAVARES, Leticia Camargo; GALVEZ, Jubby Marcela; CALDERON-OSPINA, Carlos-Alberto; SUN, Xiaoxiao; HUTZ, Mara H.; SCOTT, Stuart A.; CAVALLARI, Larisa H.; FONSECA-MENDOZA, Dora Janeth; DUCONGE, Jorge; BOTTON, Mariana Rodrigues; SANTOS, Paulo Caleb Junior Lima; KARNES, Jason H.Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 x 10(-15)). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.
- Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population(2018) TAVARES, Leticia C.; DUARTE, Nubia E.; MARCATTO, Leiliane R.; SOARES, Renata A. G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.; SANTOS, Paulo Caleb Junior LimaPurposeInterpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population.MethodsTwo independent cohorts of patients treated with warfarin (n=832 and n=133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan (R) assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates.ResultsThe inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R-2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%).ConclusionAlthough our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.
- Genotype-guided warfarin therapy: current status(2018) TAVARES, Leticia C.; MARCATTO, Leiliane R.; SANTOS, Paulo C. J. L.Warfarin pharmacogenomics has been an extensively studied field in the last decades as it is focused on personalized therapy to overcome the wide interpatient warfarin response variability and decrease the risk of side effects. In this expert review, besides briefly summarizing the current knowledge about warfarin pharmacogenetics, we also present an overview of recent studies that aimed to assess the efficacy, safety and economic issues related to genotype-based dosing algorithms used to guide warfarin therapy, including randomized and controlled clinical trials, meta-analyses and cost-effectiveness studies. To date, the findings still present disparities, mostly because of standard limitations. Thus, further studies should be encouraged to try to demonstrate the benefits of the application of warfarin pharmacogenomic dosing algorithms in clinical practice.
bookPart Fármacos anticoagulantes(2021) MARCATTO, Leiliane Rodrigues; TAVARES, Letícia Camargo; SACILOTTO, Luciana; SANTOS, Paulo Caleb Júnior de Lima- Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients(2018) TAVARES, Leticia C.; MARCATTO, Leiliane R.; SOARES, Renata A. G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.; SANTOS, Paulo C. J. L.The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan((R)) genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup ( n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.