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Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation. However, rare cases of haemochromatosis (non-HFE haemochromatosis) can also be caused by pathogenic variants in other genes (such as HJV, HAMP, TFR2 and SLC40A1). A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity. The aim of the present review is to provide an update on classification, pathophysiology and therapeutic recommendations.
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Hereditary hyperferritinemia-cataract syndrome is a rare autosomal dominant disease caused by a genetic mutation in the iron responsive element in the 5' untranslated region of the ferritin light chain gene. Hereditary hyperferritinemia-cataract syndrome is characterized by elevated serum ferritin levels and bilateral cataract development early in life and may be misdiagnosed as hemochromatosis. This case report describes a Brazilian family with a clinical diagnosis of hereditary hyperferritinemia-cataract syndrome, which was submitted to ferritin light chain gene sequencing. The genetic mutation c.-164C>G was identified in the 5' untranslated region. In conclusion, genetic testing can be used for accurate diagnosis of hereditary hyperferritinemia-cataract syndrome to avoid misdiagnosis of hemochromatosis, other diseases associated with iron overload or ophthalmic diseases.
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Catarata , Hemocromatose , Humanos , Apoferritinas/genética , Hemocromatose/genética , Regiões 5' não Traduzidas , Brasil , Catarata/diagnóstico , Catarata/genética , Ferro , LinhagemRESUMO
BACKGROUND: Hemochromatosis is a genetic condition of iron overload caused by deficiency of hepcidin. In a previous stage of this study, patients with suspected hemochromatosis had their quality of life (QL) measured. We observed that QL scores differed among genotypic groups of patients. In this reported final phase of the study, the aims were to compare QL scores after a treatment period of approximately 3 years and to analyze a possible association of the serum ferritin values with QL scores. METHODS: Sixty-five patients were enrolled in this final phase and divided into group 1 (patients that showed primary iron overload and homozygous genotype for the HFE p.Cys282Tyr mutation) and group 2 (other kinds of genotypes). Short Form 36 (SF-36) was performed and consisted of eight domains with a physical and also a mental component. RESULTS: Both groups had a significant decrease in serum ferritin concentrations: group 1 had a variation from 1844 ± 1313 ng/mL to 281 ± 294 ng/mL, and group 2 had a variation from 1216 ± 631 ng/mL to 236 ± 174 ng/mL. Group 1 had a smaller mean value for these six SF-36 domains compared with group 2, indicating a worse QL. CONCLUSIONS: In this final stage, six domains demonstrated a difference among genotypic groups (role emotional and mental health, adding to the four of the initial phase), reassuring the impact of the identified genotype on the QL of hemochromatosis patients. Furthermore, despite that both patient groups demonstrated similar and significant decreases in serum ferritin values, no association was found between the decrease in this biological parameter and the SF-36 domains.
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Ferritinas/sangue , Proteína da Hemocromatose/genética , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteínas de Membrana/genética , Mutação , Qualidade de Vida , Predisposição Genética para Doença , Genótipo , Hemocromatose/sangue , HumanosRESUMO
ABSTRACT Hereditary hyperferritinemia-cataract syndrome is a rare autosomal dominant disease caused by a genetic mutation in the iron responsive element in the 5' untranslated region of the ferritin light chain gene. Hereditary hyperferritinemia-cataract syndrome is characterized by elevated serum ferritin levels and bilateral cataract development early in life and may be misdiagnosed as hemochromatosis. This case report describes a Brazilian family with a clinical diagnosis of hereditary hyperferritinemia-cataract syndrome, which was submitted to ferritin light chain gene sequencing. The genetic mutation c.-164C>G was identified in the 5' untranslated region. In conclusion, genetic testing can be used for accurate diagnosis of hereditary hyperferritinemia-cataract syndrome to avoid misdiagnosis of hemochromatosis, other diseases associated with iron overload or ophthalmic diseases.
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Pharmacogenetic testing is available to healthcare professionals to guide drug selection and prevent adverse events. However, its implementation in the clinical practice of psychiatry/neurology still has barriers, mainly due to a lack of evidence. We conducted a literature search on Cochrane Library, Embase and Pubmed, from their inception to 18 June 2020. We included 16 published systematic reviews. The most studied drug categories were anticonvulsants and selective serotonin reuptake inhibitors associated with human leukocyte antigen and cytochrome P450 genes (HLA-A, HLA-B, CYP2C9, CYP2D6, CYP2C19), classified as critically low quality/low quality. There is a need for more robust studies with adequate design to assess the potential benefits of adopting pharmacogenetics in health systems and services.
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Neurologia/métodos , Testes Farmacogenômicos/métodos , Psiquiatria/métodos , Anticonvulsivantes/uso terapêutico , Sistema Enzimático do Citocromo P-450/genética , Humanos , Farmacogenética/métodos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Poor adherence to warfarin treatment is a contributor to poor quality of treatment, which increases the risk of bleeding and thromboembolic events. This study aims to evaluate the impact of adherence to warfarin therapy on anticoagulation quality during 12 weeks of pharmaceutical care and after 1 year of follow-up for patients with atrial fibrillation and with poor TTR. The Arrhythmia Unit of tertiary hospital in Brazil. We included 262 patients with AF and poor quality of anticoagulation therapy with warfarin (TTR < 50%). Pharmacist-driven therapy management was performed for 12 weeks and patients were also evaluated 1 year after the end of the follow-up with a pharmacist. Adherence was classified into high adherence, medium adherence and low adherence. Impact of adherence to warfarin therapy after pharmaceutical care. Of the 262 patients, 160 were high adherence, 71 were medium adherence and 31 were low adherence. No statistically significant difference is found between adherence groups in demographic and clinical variables. The TTR basal means were not different among adherence groups (p = 0.386). However, the means of TTR 12 weeks and TTR 1 year after the end of protocol were statistically different among adherence groups (p < 0.001 and p = 0.002, respectively). When we compared TTR values at different times within the adherence group, we observed that there is a statistical difference between the three TTR means (basal versus 12 weeks versus 1 year after) within the adherence group (p < 0.001). Patients with poor anticoagulation control, who adhered to the treatment with warfarin during the pharmaceutical care had better anticoagulation quality compared to those who did not adhere to the therapy with warfarin.
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Fibrilação Atrial , Assistência Farmacêutica , Varfarina/uso terapêutico , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Coeficiente Internacional Normatizado , Resultado do Tratamento , Varfarina/farmacologiaRESUMO
BACKGROUND: Warfarin is the most common oral anticoagulant drug, especially in low-income and emerging countries, because of the high cost of direct oral anticoagulant (DOACs), or when warfarin is the only proven therapy (mechanical prosthetic valve and kidney dysfunction). The quality of warfarin therapy is directly associated with dose management. Evidence shows that pharmaceutical care achieves a better quality of therapy with warfarin. However, there are no studies showing this intervention in a specific patient group with poor quality of anticoagulation in a long period after the end of the follow-up by a pharmacist. Thus, the aim of this study was to evaluate whether the quality of warfarin therapy driven by a pharmacist remains stable in the long term after the end of follow up with a pharmacist, in AF patients with poor quality of anticoagulation. METHODS: This is a prospective study, which evaluated about 2,620 patients and selected 262 patients with AF and poor quality of anticoagulation therapy with warfarin (TTR<50% - based on the last three values of international normalized ratio). Pharmacist-driven therapy management was performed up to 12 weeks. Data from patients were evaluated 1 year after the end of the follow-up with pharmacist. RESULTS: Comparison between mean TTR after 12 weeks of pharmaceutical care (54.1%) and mean TTR one year after the end of the pharmaceutical care (56.5%; p=0.081) did not achieve statistical difference, demonstrating that the increment of quality due to intervention of 12 weeks was maintained for 1 year after intervention. CONCLUSION: The long-term impact of pharmaceutical care was beneficial for patients with AF and poor quality of warfarin anticoagulation. This design might be an important strategy to treat a subgroup of patients without proven effectiveness of warfarin.
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BACKGROUND: Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in ERCC1, ABCB1, CYP2C8, and CYP3A5 genes on the incidence of severe toxicities, including nephro- and hepatotoxicity. METHODS: A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin was recruited at the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consultations or from electronic medical records. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR. RESULTS: ABCB1 c.1236C>T was associated with moderate-to-severe (grades 2-4) nephrotoxicity (ORadjusted 2.40; 95% CI 1.39-4.15), even after adjustment for age (≥ 65) and diabetes. The risk association between ABCB1 c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (ORadjusted 2.16; 95% CI 1.22-3.82). ERCC1 c.118C>T was the only individual variable associated with an increased risk for moderate-to-severe (grades 2-4) hepatotoxicity (OR 3.71; 95% CI 1.08-12.77), severe nausea (OR 4.18; 95% CI 1.59-10.95), and severe myalgia (OR 1.95; 95% CI 1.12-3.40). CONCLUSIONS: ABCB1 c.1236C>T and ERCC1 c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Brasil , Carboplatina/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Estudos de Coortes , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Humanos , Nefropatias/induzido quimicamente , Nefropatias/genética , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Resistant hypertension (RH) is defined as uncontrolled blood pressure despite treatment with three or more antihypertensive medications, including, if tolerated, a diuretic in adequate doses. It has been widely known that race is associated with blood pressure control. However, intense debate persists as to whether this is solely explained by unadjusted socioeconomical variables or genetic variation. In this scenario, the main aim was to evaluate the association between genetic ancestry and resistant hypertension in a large sample from a multicenter trial of stage II hypertension, the ReHOT study. Samples from 1,358 patients were analyzed, of which 167 were defined as resistant hypertensive. Genetic ancestry was defined using a panel of 192 polymorphic markers. The genetic ancestry was similar in resistant (52.0% European, 36.7% African and 11.3% Amerindian) and nonresistant hypertensive patients (54.0% European, 34.4% African and 11.6% Amerindian) (p > 0.05). However, we observed a statistically suggestive association of African ancestry with resistant hypertension in brown patient group. In conclusion, increased African genetic ancestry was not associated with RH in Brazilian patients from a prospective randomized hypertension clinical trial.
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Vasoespasmo Coronário/genética , Hipertensão/genética , População Negra/genética , Brasil/epidemiologia , Vasoespasmo Coronário/epidemiologia , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Hipertensão/epidemiologia , Indígenas Sul-Americanos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , População Branca/genéticaRESUMO
The growth of the elderly population is a worldwide phenomenon and it is associated with chronic diseases, including dementia. In this scenario, the present study aimed to evaluate a possible association of estrogen receptor α polymorphisms with dementia in a Brazilian cohort. The subject sample was divided into two groups, control (n = 105) and case (n = 73), according to analysis of two predictive dementia tests (MMSE and CDR). The genotyping for the ERα PvuII (c.454-397T>C, rs2234693) and XbaI (c.454-351A>G, rs9340799) polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. The ERα PvuII pp genotype was associated with higher odds ratio for dementia (OR = 3.42, 95% CI = 1.33-8.77, p = 0.01, in a model including covariates. A linear regression model identified significant associations of the ERα PvuII genotypes (independent variable) with CDR scale (dependent variable), ß = 0.26 and p = 0.001. In conclusion, estrogen receptor α PvuII polymorphism is associated with dementia in a Brazilian cohort. This finding may be useful for the identification of a possible set of significant genetic and clinical biomarkers for better understanding pathophysiology, early diagnosis and management of dementia.
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BACKGROUND: The identification of variants in genes involved in nicotine metabolism may have implications for the pharmacological therapy of smoking. In the scenario of precision medicine, the aim of this study was to evaluate a possible association of cytochrome P450 2A6 and 2B6 polymorphisms with varenicline pharmacotherapy. METHODS: The present study included 167 patients treated with varenicline in monotherapy who were from a cohort study of 1049 patients (treated with smoking cessation drugs: nicotine replacement therapy, bupropion, varenicline, or combinations of same). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. The CYP2A6 rs1801272 and rs28399433 and CYP2B6 rs8109525 polymorphisms were genotyped by real-time PCR using the TaqMan® platform. RESULTS: Patients with AG or GG genotypes for CYP2B6 rs8109525 had a higher success rate of smoking cessation with varenicline (51.2%) compared with carriers of the AA genotypes (33.3%, P = 0.03, n = 167). The AG or GG genotypes were also associated with a higher odds ratio of success, even in a multivariate analysis adjusting for potential confounders (OR = 2.01; 95%CI = 1.01 to 4.00; P = 0.047). CONCLUSION: CYP2B6 rs8109525 was associated with a higher success rate of smoking cessation with varenicline treatment. This finding may be useful in pharmacogenomic strategies for smoking cessation therapy.
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Citocromo P-450 CYP2B6/genética , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Abandono do Hábito de Fumar/estatística & dados numéricos , Fumar/tratamento farmacológico , Vareniclina/uso terapêutico , Adulto , Citocromo P-450 CYP2A6/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fumar/genética , Resultado do TratamentoRESUMO
Thromboembolic 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.
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Abstract Introduction The need for surgery can be a decisive factor for long-term smoking cessation. On the other hand, situations that precipitate stress could precipitate smoking relapse. The authors decided to study the impact of a surgery on the patient's effort to cease smoking for, at least, 24 h before hospital admission and possible relapse on the last 24 h before hospital admission for ex-smokers. Methods Smoker, ex-smokers and non-smokers adults, either from pre-anesthetic clinic or recently hospital admitted for scheduled elective surgeries that were, at most, 6 h inside the hospital buildings were included in the study. The patients answered a questionnaire at the ward or at the entrance of the operating room (Admitted group) or at the beginning of the first pre-anesthetic consultation (Clinic group) and performed CO measurements. Results 241 patients were included, being 52 ex-smokers and 109 never smokers and 80 non-smokers. Smokers had higher levels of expired carbon monoxide than non-smokers and ex-smokers (9.97 ± 6.50 vs. 2.26 ± 1.65 vs. 2.98 ± 2.69; p = 0.02). Among the smokers, the Clinic group had CO levels not statistically different of those on the Admitted group (10.93 ± 7.5 vs. 8.65 ± 4.56; p = 0.21). The ex-smokers presented with no significant differences for the carbon monoxide levels between the Clinic and Admitted groups (2.9 ± 2.3 vs. 2.82 ± 2.15; p = 0.45). Conclusion A medical condition, such as a surgery, without proper assistance is unlikely to be enough for a patient to stop smoking for, at least, 24 h prior to admission. The proximity of a surgery was not associated with smoking relapse 24 h before the procedure.
Resumo Introdução A necessidade de cirurgia pode ser um fator decisivo para a cessação do tabagismo em longo prazo. Por outro lado, situações que precipitam o estresse podem precipitar a recaída do tabagismo. Decidimos avaliar o impacto de uma cirurgia no esforço do paciente para deixar de fumar durante pelo menos 24 horas antes da internação hospitalar e a possível recaída nas últimas 24 horas anteriores à internação em ex-fumantes. Métodos Fumantes, ex-fumantes e não fumantes adultos, quer de clínica pré-anestésica ou recentemente internados para cirurgias eletivas programadas que ficariam, no máximo, seis horas dentro das unidades hospitalares, foram incluídos no estudo. Os pacientes responderam um questionário na enfermaria ou na entrada da sala de operação (Grupo Internação) ou no início da primeira consulta pré-anestesia (Grupo Clínico) e fizeram mensurações dos níveis de CO. Resultados No total, 241 pacientes foram incluídos: 52 ex-fumantes, 109 que nunca fumaram e 80 não fumantes. Os fumantes apresentaram níveis mais elevados de monóxido de carbono expirado que os não fumantes e ex-fumantes (9,97 ± 6,50 vs. 2,26 ± 1,65 vs. 2,98 ± 2,69;p = 0,02). Entre os fumantes, o Grupo Clínico apresentou níveis de CO não estatisticamente diferentes daqueles do Grupo Internação (10,93 ± 7,5 vs. 8,65 ± 4,56; p = 0,21). Os ex-fumantes não apresentaram diferenças significativas entre os grupos Clínico e Internação para os níveis de monóxido de carbono (2,9 ± 2,3 vs. 2,82 ± 2,15; p = 0,45). Conclusão É improvável que uma condição médica, como uma cirurgia, sem assistência adequada seja suficiente para que um paciente pare de fumar, pelo menos, 24 horas antes da internação. A proximidade de uma cirurgia não foi associada à recaída do tabagismo nas 24 horas anteriores ao procedimento.
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Humanos , Monóxido de Carbono , Fumar , Procedimentos Cirúrgicos Eletivos , Interpretação Estatística de Dados , Abandono do Hábito de FumarRESUMO
PURPOSE: Interpatient 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. METHODS: Two 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® 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. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) 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%). CONCLUSION: Although 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.
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Algoritmos , Anticoagulantes/administração & dosagem , Família 4 do Citocromo P450/genética , Farmacogenética , Polimorfismo Genético/genética , Varfarina/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Anticoagulantes/farmacocinética , Brasil , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Varfarina/farmacocinéticaRESUMO
INTRODUCTION: The need for surgery can be a decisive factor for long-term smoking cessation. On the other hand, situations that precipitate stress could precipitate smoking relapse. The authors decided to study the impact of a surgery on the patient's effort to cease smoking for, at least, 24h before hospital admission and possible relapse on the last 24h before hospital admission for ex-smokers. METHODS: Smoker, ex-smokers and non-smokers adults, either from pre-anesthetic clinic or recently hospital admitted for scheduled elective surgeries that were, at most, 6h inside the hospital buildings were included in the study. The patients answered a questionnaire at the ward or at the entrance of the operating room (Admitted group) or at the beginning of the first pre-anesthetic consultation (Clinic group) and performed CO measurements. RESULTS: 241 patients were included, being 52 ex-smokers and 109 never smokers and 80 non-smokers. Smokers had higher levels of expired carbon monoxide than non-smokers and ex-smokers (9.97±6.50 vs. 2.26±1.65 vs. 2.98±2.69; p=0.02). Among the smokers, the Clinic group had CO levels not statistically different of those on the Admitted group (10.93±7.5 vs. 8.65±4.56; p=0.21). The ex-smokers presented with no significant differences for the carbon monoxide levels between the Clinic and Admitted groups (2.9±2.3 vs. 2.82±2.15; p=0.45). CONCLUSION: A medical condition, such as a surgery, without proper assistance is unlikely to be enough for a patient to stop smoking for, at least, 24h prior to admission. The proximity of a surgery was not associated with smoking relapse 24h before the procedure.
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BACKGROUND: The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS: This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS: Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION: CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.
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Proteínas do Tecido Nervoso/genética , Variantes Farmacogenômicos , Receptores Nicotínicos/genética , Abandono do Hábito de Fumar , Fumar/terapia , Adulto , Idoso , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Fumar/genética , TabagismoRESUMO
BACKGROUND: Hereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient's quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload. In the present study, our aim was to evaluate whether domains of QL are different according to genotypic groups in patients suspected of HH. METHODS: Seventy-nine patients with primary iron overload were included and two genotypic groups were formed (group 1: homozygous genotype for the HFE p.Cys282Tyr mutation; group 2: other genotypes). RESULTS: Group 1 had higher means of plasma transferrin saturation (86 ± 19%) and serum ferritin (1669 ± 1209 ng/mL) compared to group 2 (71 ± 12%, 1252 ± 750 ng/mL, respectively; p = 0.001). Four domains were significantly different among groups 1 and 2: physical functioning (p = 0.03), bodily pain (p = 0.03), vitality (p = 0.02) and social functioning (p = 0.01). CONCLUSIONS: Our main finding was that patients with p.Cys282Tyr homozygosity had a worse QL scenario assessed by SF-36, compared with patients with iron overload without the same genotype. Being aware of this relationship between genotypes and QL might be helpful in the overall management of patients suspected of hereditary hemochromatosis.
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Predisposição Genética para Doença , Hemocromatose/diagnóstico , Hemocromatose/genética , Qualidade de Vida , Adulto , Feminino , Ferritinas/sangue , Testes Genéticos , Genótipo , Homozigoto , Humanos , Ferro/sangue , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fatores Socioeconômicos , Inquéritos e Questionários , Transferrina/metabolismoRESUMO
A novel analytical method was developed to determine 5 antihypertensive drugs of different pharmacological classes (angiotensin-converting enzyme inhibitors, calcium channel blockers, α-2 adrenergic receptor agonists, angiotensin II receptor blockers, and aldosterone receptor antagonists) and some of their metabolites in human serum. The untreated samples were directly analyzed in a column switching system using an extraction column packed with restricted access carbon nanotubes (RACNTs) in an ultra-high performance liquid chromatography coupled to a mass spectrometer (UHPLC-MS/MS). The RACNTs column was able to exclude approximately 100% of proteins from the samples in 2.0min, maintaining the same performance for about 300 analytical cycles. The method was validated in accordance with Food and Drug Administration (FDA) guidelines, being linear for all the determined analytes in their respective analytical ranges (coefficients of determination higher than 0.99) with limits of detection (LODs) and quantification (LOQs) ranging from 0.09 to 10.85µgL-1 and from 0.30 to 36.17µgL-1, respectively. High recovery values (88-112%) were obtained as well as suitable results for inter and intra-assay accuracy and precision. The method provided an analytical frequency of 5 samples per hour, including the sample preparation and separation/detection steps. The validated method was successfully used to analyze human serum samples of patients undergoing treatment with antihypertensive drugs, being useful for pharmacometabolomic, pharmacogenomic, and pharmacokinetic studies.
Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/isolamento & purificação , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/instrumentação , Nanotubos de Carbono/química , Análise Química do Sangue/instrumentação , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
As doenças cardiovasculares (DCV) são a principal causa de morte e representam uma percentagem significativa das internações. No cenário de minimização dos custos ao sistema de saúde, métodos que identifiquem DCV subclínica seriam importantes. Algumas diretrizes incluem a medida da rigidez aórtica e da espessura íntima-média da artéria carótida como métodos para identificação de DCV subclínica em hipertensos. A velocidade de onda de pulso (VOP) é considerada padrão-ouro para avaliar a rigidez arterial. Nesta revisão, abordamos a fisiopatologia e os determinantes da rigidez arterial e justificamos sua inclusão na avaliação do paciente hipertenso dada a associação direta com o risco cardiovascular, como estabelecido na I Diretriz Brasileira de Prevenção Cardiovascular. Apresentamos ainda os principais estudos genéticos deste fenótipo que, dada sua complexidade, pode ser modulado por dezenas de genes. No entanto, um melhor entendimento da relação genética-rigidez arterial, e até mesmo uma intervenção baseada em genótipos, devem ser investigadas em estudos futuros
Assuntos
Humanos , Masculino , Feminino , Fenótipo , Polimorfismo Genético/genética , Rigidez Vascular , Envelhecimento , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Artérias Carótidas/fisiopatologia , Diabetes Mellitus , Fatores de RiscoRESUMO
BACKGROUND: Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital. METHODS/DESIGN: This study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient's INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School. DISCUSSION: This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592980 . Registered on 29 October 2015.