[Effects of pharmaceutical counseling on the effectiveness of anticoagulation in patients with atrial fibrillation]. / Impacto de la atención farmacéutica en la calidad del tratamiento con acenocumarol en pacientes con fibrilación auricular.

BACKGROUND: Vitamin K antagonists such as acenocoumarol and warfarin are usually indicated for the treatment of Atrial Fibrillation (AF). The Therapeutic Range Time (TRT) is a quality of treatment indicator. Values greater than 65% are associated with significantly lower stroke and bleeding rates. Proper pharmaceutical care improves TRT. AIM: To evaluate the impact of pharmaceutical care in patients with AF treated with acenocoumarol. MATERIAL AND METHODS: We studied 41 patients using acenocoumarol for AF aged 71 ± 11 years (43% women). They received pharmaceutical counseling during 12 weeks. TRT was calculated retrospectively for the year before counseling and prospectively during the intervention period. RESULTS: After receiving pharmaceutical counseling TRT improved from 29% at baseline to 46% at the end of the intervention (p < 0.01). After pharmaceutical care, the adherence of patients to drug treatment improved from 27% at baseline to 85% at the end of the study. The user satisfaction survey of the pharmaceutical care received showed a high degree of patient satisfaction. CONCLUSIONS: Pharmaceutical care in patients with oral anticoagulant treatment improves TRT of anticoagulation. It is accepted and positively evaluated by patients.

Impacto de la atención farmacéutica en la calidad del tratamiento con acenocumarol en pacientes con fibrilación auricular / Effects of pharmaceutical counseling on the effectiveness of anticoagulation in patients with atrial fibrillation

Background: Vitamin K antagonists such as acenocoumarol and warfarin are usually indicated for the treatment of Atrial Fibrillation (AF). The Therapeutic Range Time (TRT) is a quality of treatment indicator. Values greater than 65% are associated with significantly lower stroke and bleeding rates. Proper pharmaceutical care improves TRT. Aim: To evaluate the impact of pharmaceutical care in patients with AF treated with acenocoumarol. Material and Methods: We studied 41 patients using acenocoumarol for AF aged 71 ± 11 years (43% women). They received pharmaceutical counseling during 12 weeks. TRT was calculated retrospectively for the year before counseling and prospectively during the intervention period. Results: After receiving pharmaceutical counseling TRT improved from 29% at baseline to 46% at the end of the intervention (p < 0.01). After pharmaceutical care, the adherence of patients to drug treatment improved from 27% at baseline to 85% at the end of the study. The user satisfaction survey of the pharmaceutical care received showed a high degree of patient satisfaction. Conclusions: Pharmaceutical care in patients with oral anticoagulant treatment improves TRT of anticoagulation. It is accepted and positively evaluated by patients.

Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 (rs4244285), CYP1A2*1F (rs762551), GGCx (rs11676382), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP4F2 (rs2108622), VKORC1 (rs9923231), VKORC1 (rs7294), CYP3A4*1B (rs2740574), and ABCB1 (rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study.

BACKGROUND: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. OBJECTIVE: The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients. METHODOLOGY: DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0-3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910). RESULTS: The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability. CONCLUSION: We developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.

Estudio comparativo de equipos INR capilar "point of care" versus INR venoso, en pacientes en tratamiento con antagonistas de vitamina K / Comparison of point of care capillary international normalized ratio (INR) with INR measured in venous samples

Background: INR is used to monitor the treatment with vitamin K antagonists. A strategy to reduce waiting times for sampling is to measure INR in a capillary sample using a portable point of care (POC) type coagulometer. Aim: To evaluate the correlation of CoaguChek Pro II™, Xprecia™ and microINR™ with venous INR measured at the clinical laboratory and their ease of use. Materials and Methods: Patients provided capillary and venous blood samples for parallel tests comparing Xprecia™ Stride with CoaguChek Pro II™ and with venous INR, microINR™ with CoaguChek Pro IITM and with venous INR. The devices' ease of use was assessed surveying the sampling staff. Results: The three tested devices had good correlation coefficients with venous INR: CoaguChek Pro IITM 0.953 and 0.962; Xprecia™ of 0.912 and microINR™ of 0.932. The correlation coefficient of Xprecia™ with CoaguChek Pro IITM was 0.937 and microINR™ with CoaguChek Pro IITM was 0.976. Conclusions: CoaguChek Pro IITM, Xprecia™ and microINR™ results had a good correlation coefficient with INR measured at the laboratory. Our results indicate that, in the hands of trained users, POC-type coagulometers are reliable and acceptable for routine use in anticoagulant treatment control.

The role of phase I and II genetic polymorphisms, smoking, alcohol and cancer family history, in the risk of developing testicular cancer.

BACKGROUND: Testicular cancer (TCa) is a malignant tumor with highest incidence and mortality rates in Chile. The genes coding for cytochrome P450, glutathione-S-transferases (GSTs), and UDP glucuronyl transferases (UGT) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes have been associated with a high incidence of various types of cancer and an increased risk of presenting adverse reactions to drugs. OBJECTIVE: The aim of this study was to relate the presence of genetic polymorphisms in cytochrome P450 1A1 (CYP1A1), CYP3A4, GSTM1, GSTP1, GSTT1, and UGT1A1 genes and nongenetic factors with the risk of developing TCa. METHODS: A total of 276 volunteers from the Chilean general population and 251 Chilean TCa patients were recruited for the study. Genotypic analyses were performed using qPCR and PCR-RFLP. RESULTS: Variant alleles found to increase the risk of developing TCa were CYP1A1*2C (rs1048943), GSTP1 (rs1695), and GSTT1null, especially when in conjunction with a cancer family history and/or a smoking habit. The results of the multivariate analysis showed that the presence of variant alleles of GSTP1 (rs1695) together with a smoking habit and a family history of cancer accounted for a 15.9% risk of developing TCa in the Chilean population. CYP1A1*2C, GSTM1null, GSTT1null, and GSTP1 (rs1695) are statistically related to the risk of appearance of TCa, alone or associated with nongenetic factors. CONCLUSION: Therefore, phase I and II variant alleles might be useful in evaluating susceptibility to TCa in the studied population.

Anticoagulation Management With Coumarinic Drugs in Chilean Patients.

Warfarin and acenocoumarol are used in various cardiovascular disorders to improve the prognosis of patients with thromboembolic disease. However, there is a lack of substantial efficacy and safety data on antithrombotic prophylaxis in several countries, particularly in Latin America. The aim of this study was to provide information about the efficacy of anticoagulants in Chilean patients. Data were collected from databases of the Western Metropolitan Health Service, Santiago, Chile. We identified 6280 records of patients receiving anticoagulant treatment. The three most common diagnoses were rhythm disorder (43.7%), venous thrombosis (22%), and valvular prosthesis (10.7%). The majority of patients (98.5%) received acenocoumarol while 1.5% of patients received warfarin, at weekly therapeutic doses of 13.6 mg and 30.4 mg, respectively. For total diagnoses, the median time in the therapeutic range was 50%. However, better results, 66.7%, were observed when a telemedicine strategy was used only in Santiago Province. Our findings emphasize that in Chile, where the number of patients receiving anticoagulant treatment increases every year, telemedicine, by committed teams, improves the use of oral anticoagulants and is able to increase quality indicators of anticoagulant treatment care.

Association Study Among Candidate Genetic Polymorphisms and Chemotherapy-Related Severe Toxicity in Testicular Cancer Patients.

Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan ®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III-IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III-IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy.

[Comparison of point of care capillary international normalized ratio (INR) with INR measured in venous samples]. / Estudio comparativo de equipos INR capilar "point of care" versus INR venoso, en pacientes en tratamiento con antagonistas de vitamina K.

BACKGROUND: INR is used to monitor the treatment with vitamin K antagonists. A strategy to reduce waiting times for sampling is to measure INR in a capillary sample using a portable point of care (POC) type coagulometer. AIM: To evaluate the correlation of CoaguChek Pro II™, Xprecia™ and microINR™ with venous INR measured at the clinical laboratory and their ease of use. MATERIALS AND METHODS: Patients provided capillary and venous blood samples for parallel tests comparing Xprecia™ Stride with CoaguChek Pro II™ and with venous INR, microINR™ with CoaguChek Pro IITM and with venous INR. The devices' ease of use was assessed surveying the sampling staff. RESULTS: The three tested devices had good correlation coefficients with venous INR: CoaguChek Pro IITM 0.953 and 0.962; Xprecia™ of 0.912 and microINR™ of 0.932. The correlation coefficient of Xprecia™ with CoaguChek Pro IITM was 0.937 and microINR™ with CoaguChek Pro IITM was 0.976. CONCLUSIONS: CoaguChek Pro IITM, Xprecia™ and microINR™ results had a good correlation coefficient with INR measured at the laboratory. Our results indicate that, in the hands of trained users, POC-type coagulometers are reliable and acceptable for routine use in anticoagulant treatment control.

[Pharmacogenetics, tobacco, alcohol and its effect on the risk development cancer]. / Farmacogenética, tabaco, alcohol y su efecto sobre el riesgo de desarrollar cáncer.

Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

Farmacogenética, tabaco, alcohol y su efecto sobre el riesgo de desarrollar cáncer / Pharmacogenetics, tobacco, alcohol and its effect on the risk development cancer

El cáncer es la segunda causa de muerte en el mundo, según datos de la Organización Mundial de la Salud (OMS) en el año 2015 ocasionó 8,8 millones de muertes. Dentro de los factores de riesgo para el desarrollo de cáncer se encuentran el tabaquismo y el consumo de alcohol. En Chile el 33,6% de la población fuma y un 21,2 % de los jóvenes. El consumo de alcohol en la población chilena es de 74,5 % y en los jóvenes de un 12,2 %. Entre los factores fisiológicos que influyen en el desarrollo de cáncer, el factor genético juega un rol relevante, habiéndose demostrado que la presencia de polimorfismos genéticos alteran la capacidad del organismo de eliminar contaminantes y aumentan el riesgo de desarrollar cáncer. Lo mismo ocurre con polimorfismos que impiden la reparación de ADN debido a daños producidos por efecto de contaminantes ambientales como el humo de cigarrillo. El objetivo de esta revisión es analizar el estado del arte de la relación entre farmacogenética, tabaco y alcohol como factores de riesgo para el desarrollo de cáncer. Los resultados sugieren que la presencia de po limorfismos que alteran la función de enzimas de biotransformación fase I (CYP1A1, CYP1E1) y fase II (GST), además de polimorfismos en enzimas de reparación del ADN (ERCC1/ERCC2) aumentan el riesgo de cáncer inducido por el hábito tabáquico y alcohólico. Esta asociación es importante, si consideramos que en la población chilena el hábito de fumar y beber alcohol es altamente prevalente.

Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

Clinical applications of pharmacogenomics.

Pharmacogenomics is an emergent field aimed at tailoring pharmacological therapy. Genetic polymorphisms can modify the expression and function of enzymes and proteins involved in drug metabolism, affecting absorption, distribution, biotransformation and excretion as well as the drug-target interaction. Therefore, the presence of allelic variants will classify people as poor, extensive or rapid/ultra rapid metabolizers, modifying drug efficacy and safety. In this work, the state of art in relation to this discipline is presented and the genetic variants of enzymes that are involved in drug pharmacokinetics or pharmacodynamics are described. The effects of these variants on the therapeutic response to drugs used in our country are also discussed.

Farmacogenómica como herramienta fundamental para la medicina personalizada: aplicaciones en la práctica clínica / Clinical applications of pharmacogenomics

Pharmacogenomics is an emergent field aimed at tailoring pharmacological therapy. Genetic polymorphisms can modify the expression and function of enzymes and proteins involved in drug metabolism, affecting absorption, distribution, biotransformation and excretion as well as the drug-target interaction. Therefore, the presence of allelic variants will classify people as poor, extensive or rapid/ultra rapid metabolizers, modifying drug efficacy and safety. In this work, the state of art in relation to this discipline is presented and the genetic variants of enzymes that are involved in drug pharmacokinetics or pharmacodynamics are described. The effects of these variants on the therapeutic response to drugs used in our country are also discussed.

Impacto de Ia telemedicina en Ia calidad del control de tratamiento anticoagulante oral / Impact of tele-medicine for control of oral anticoagulant treatment

Antecedentes: En el año 2014 se inició Telemedicina desde el Policlinico de Tratamiento Anticoagulante oral del Hospital San Juan de Dios y el Hospital de Curacaví, evitando así el traslado de pacientes a Santiago para el control con el médico especialista. Métodos: Se utilizó licencia de video conferencia en el Hospital San Juan de Dios, dispositivo móvil, equipo de INR capilar y stock de Acenocumarol en el Hospital de Curacaví. Resultados: En total se han realizado 2.174 consultas vía Telemedicina (junio 2014 a diciembre 2015). Esta estrategia ha sido bien evaluada por los pacientes. La mejora en la calidad del tratamiento ha sido evidente: 58,3% de los pacientes del Hospital de Curacaví se encuentran en rango terapéutico, superior al 50,8% de los pacientes del Hospital San Juan de Dios (p < 0,05). En cuanto al Tiempo en Rango Terapéutico (TTR) 50,6% de los pacientes del Hospital de Curacaví se encuentran en rango versus 46,2% de los pacientes del Hospital San Juan de Dios (p< 0,05). Conclusiones: La Telemedicina utilizada por equipos comprometidos es capaz de mantener indicadores de calidad de la atención que la validan como herramienta de atención clínica a distancia. La Telemedicina, en cuanto es una herramienta que acerca el especialista a comunidades alejadas de centros hospitalarios complejos, es valorada y muy bien calificada por los usuarios.

Background: Starting in 2014 telemedicine has been used to control oral anticoagulant treatment (OAT) in patients attending a peripheral hospital (Curacaví), in connection with Hospital San Juan de Dios, based in Santiago. Methods: A license for video conference was available to communicate both hospitals. Capillary INR and medications were available at Curacaví Hospital. Results: Between June 2014 and December 2015, 2174 indications for OAT have been made through tele-medicine. Different estimates of quality of care and user satisfaction have been rated > 6.7 (1-7 scale). Percent of INR measurements in therapeutic range was 58.3% in Curacavi and 50.8% at Hospital San Juan de Dios (p<0.05) and time in therapeutic range was 50.6% vs 42.6%, respectively (p<0.05) Conclusion: Tele-medicine allowed a close relationship between remote medical facilities and a complex medical center and was fully validated as a means of controlling OAT with a high degree of acceptance by patients.

Prevalence of seven cardiovascular-related genetic polymorphisms in a Chilean mestizo healthy population.

OBJECTIVE: Among the genetic factors associated with cardiovascular disease (CVD), determining polymorphic genotypes could help to understand the appearance of the illness. Ethnic differences in these polymorphisms could explain population variability in susceptibility to CVD. The main goal of this research is to study the presence of more relevant genetic variants of ApoE, CETP, ACE, PAI-1, MTHFR, FII and FVL of the coagulation cascade, to describe the presence of cardiovascular-related variants in a mestizo group of the Chilean people. METHODS AND RESULTS: The studied population comprised 146 unrelated subjects from the general population, diagnosed as healthy, who were genotyped through conventional and/or real-time PCR. The allele frequencies for the Chilean population were: Apo E, ε2: 0.036, ε3: 0.875 and ε4: 0.089; CETP, B1: 0.51 and B2: 0.49; MTHFR, C: 0.52 and T: 0.48; ACE, I: 0.603 and D: 0.397; PAI-1, 4G: 0.381 and 5G: 0.619; FII, G: 0.97 and A: 0.03, and FV Leiden, G: 0.97 and A: 0.03. CONCLUSIONS: This study contributes to establish a first picture in the Chilean mestizo population about the frequencies of these variants, which could act as single or complementary risk factors to trigger CVD. The obtained allele frequencies show great differences in relation to other South American populations.

Calidad de las tromboplastinas utilizadas en el laboratorio clínico y en los equipos POCT y su impacto en la dosificación de acenocumarol en pacientes con terapia anticoagulante oral / Types of thromplastin used for INR determination in patients under chronic oral anticoagulant treatment: discrepancies that may affect the dose of coumarin derivatives needed for treatment safety

Antecedentes: El monitoreo del tratamiento con anticoagulantes cumarínicos se realiza a través del INR (International Normalized Ratio) que es el parámetro estandarizado del Tiempo de Protrombina. Las recomendaciones de la OMS indican que la precisión en el cálculo del INR puede ser mejorada usando reactivo de tromboplastina con Indice de Sensibilidad Internacional (ISI) bajo, considerándose como ISI de referencia internacional el valor 1,0. Debido a incongruencias observadas en los INR de pacientes controlados en el Servicio de Salud Metropolitano Occidente, comparando valores de muestra venosa con resultados de INR capilar obtenidos en el mismo paciente el mismo día y hora (con reactivos Tromboplastina de distinto ISI), se efectuó un ensayo clínico cruzado entre los distintos métodos. Materiales y métodos: En 100 pacientes se comparó INR venoso con dos tromboplastinas de diferente ISI (1,3 y 1,0) vs aquel efectuado con muestra capilar (ISI 1,0). Resultados: Los resultados del estudio muestran que a partir de valores de INR 3,0 las determinaciones obtenidas usando Tromboplastina de cerebro de conejo ISI=1,3 subestiman el valor de INR para un mismo paciente y una misma muestra. Conclusiones: El uso de Tromboplastina recombinante humana ISI 1,0 permite evitar la subestimación del INR en pacientes con mayor riesgo tromboembóli-co (indicación de INR objetivo más alto). Por ello, este método se adoptó en el control del TACO en pacientes controlados en el Servicio de Salud Occidente.

Background: INR (International Normalized Ratio) is the standard Prothrombin Time parameter for monitoring anticoagulant treatment with coumarin derivatives Recommendations of WHO indicate that precision in the calculation of the INR can be improved using thromboplastins with a low Index of International Sensibility (ISI=1,0). Discrepancies in INR obtained using either this technique or conventional rabbit brain derived reagents in the same sample in patients attending the Servicio de Salud Metropolitano Occidente (West Metropolitan Health Service) were observed. Our objective was to evaluate these discrepancies in a systematic way. Materials and methods: A comparative study was conducted using two thromboplastins of different ISI (1.0 and 1.3) for the calculation of venous INR in comparison with capillary INR in 100 patients. Results: The study showed that INR values may differ significantly according to the method used. In particular, rabbit brain thromboplastin ISI = 1.3 underestimates the value of INR in the range of INR ≥3.0. Conclusions: The use of human recombinant thromboplastin ISI= 1.0. for determination of INR may significantly decrease the risk of hemorrhagic complications in patients requiring higher levels of anticoagulation.

Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility.

Impact of CYP1A1, GSTM1, and GSTT1 polymorphisms in overall and specific prostate cancer survival.

OBJECTIVE: Prognostic biomarkers that distinguish between patients with good or poor outcome can be used to guide decisions of whom to treat and how aggressively. In this sense, several groups have proposed genetic polymorphisms as potential susceptibility and prognostic biomarkers; however, their validity has not been proven. Thus, the main goal of the present work was to investigate the potential role of single and combined CYP1A1, GSTM1, and GSTT1 genotypes as modifiers of cancer survival in Chilean patients with prostate cancer. METHODS AND MATERIALS: A total of 260 histologically confirmed patients were recruited from a voluntary screening, and genomic DNA was obtained from their blood samples for genotyping analyses to detect the CYP1A1*2A polymorphism and GSTM1 and GSTT1 deletions. The progression of illness and mortality were estimated with a median follow-up of 8.82 years. Adjusted estimated genotype risks were evaluated by hazard ratio and 95% CI using the Cox proportional model. In addition, the Kaplan-Meier survival method and log-rank test were used to evaluate patient survival with regard to genotype. RESULTS: The 9-year overall and specific survival rates were 67.6% and 36.6% in the GSTT1null group, 67.6% and 58.7% in the GSTM1non-null group, 69.0% and 51.6% in the *1A/*2A group, 63.9% and 61.5% in the *2A/*2A group vs. 76.2% and 62.3% in the GSTT1non-null group, 82.3% and 50% in the GSTM1null group, and 83.7% and 56.3% in the *1A/*1A group, respectively. The hazard ratios and the Kaplan-Meier curve results demonstrate that the GSTM1non-null, GSTT1null, and CYP1A1*2A genotypes are significantly associated with mortality. Our study has two main limitations: a relatively small sample size and a low global mortality percentage (25.4%); thus, we need to continue the follow-up to confirm these findings. CONCLUSIONS: Our results suggest that the GSTM1non-null, GSTT1null, and CYP1A1*2A genotypes may be good prognosis markers, particularly in patients with high-risk tumors.

Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America.

Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome.

Mutations in the microtubule-associated protein tau gene (MAPT) can cause frontotemporal dementia with Parkinsonism linked to the chromosome 17, and are associated with the risk for progressive supranuclear palsy, Parkinson's disease, corticobasal degeneration, and multiple system atrophy. We tried to establish, whether MAPT H1 discriminating haplotype single nucleotide polymorphisms (SNP) (rs1052553) is associated with the risk for restless legs syndrome (RLS). We studied the allelic and genotype frequencies of the SNP rs1052553 in 205 patients with RLS and 324 healthy controls using TaqMan genotyping. rs1052553 genotype and allelic frequencies did not differ significantly between patients with RLS and controls, and were unrelated with the age at onset of RLS, gender, family history of RLS, and severity of RLS. The results of the present study suggest that the SNP rs1052553 is not related with the risk for RLS.