Rhabdomyolysis After Coadministration of Atorvastatin and Sacubitril/Valsartan (Entresto™) in a 63-Year-Old Woman.

A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient's rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.

Pharmacogenetics and ethnicity: relevance for clinical implementation, clinical trials, pharmacovigilance and drug regulation in Latin America.

Congress of Pharmacogenetics and Personalized Medicine. Ethnicity, clinical implementation and regulatory environment (MESTIFAR 2016 Quito) Quito, Ecuador, 19-21 May 2016. The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) was created in 2006 with the main aim of promoting personalized medicine and collaborative pharmacogenetics research in Spanish- and Portuguese-speaking countries in America and the Iberian Peninsula. The final goal of this initiative was the inclusion of Latin American populations that may benefit from the implementation of personalized medicine in drug therapy. Several initiatives have been promoted including the MESTIFAR project, which aimed to analyze the ethnicity, genotype and/or metabolic phenotype in Ibero-American populations. To date, 6060 healthy volunteers have been analyzed; among them, 2571 were admixed, 1824 were Caucasians, 1395 were Native Americans, 174 were Jews and 96 were Afro-descendants. Due to the large genetic variability within Latin Americans, ethnicity may be a relevant factor for the clinical implementation of personalized medicine. Moreover, the present status of clinical implementation and the future perspectives of pharmacogenetics, pharmacovigilance and clinical trials for drug regulation in Latin America compared with the EMA-Pharmacogenomics Working Party and the US FDA initiatives were analyzed.

Pharmacogenetic research activity in Central America and the Caribbean: a systematic review.

AIM: The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. MATERIALS & METHODS: A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including 'phenotyping probe drugs' for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients). RESULTS: The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine.

Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014).

MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects.

Health, healthcare access, and use of traditional versus modern medicine in remote Peruvian Amazon communities: a descriptive study of knowledge, attitudes, and practices.

There is an urgent need for healthcare research, funding, and infrastructure in the Peruvian Amazon. We performed a descriptive study of health, health knowledge and practice, and healthcare access of 13 remote communities of the Manatí and Amazon Rivers in northeastern Peru. Eighty-five adults attending a medical boat service were interviewed to collect data on socioeconomic position, health, diagnosed illnesses, pain, healthcare access, and traditional versus modern medicine use. In this setting, poverty and gender inequality were prevalent, and healthcare access was limited by long distances to the health post and long waiting times. There was a high burden of reported pain (mainly head and musculoskeletal) and chronic non-communicable diseases, such as hypertension (19%). Nearly all participants felt that they did not completely understand their diagnosed illnesses and wanted to know more. Participants preferred modern over traditional medicine, predominantly because of mistrust or lack of belief in traditional medicine. Our findings provide novel evidence concerning transitional health beliefs, hidden pain, and chronic non-communicable disease prevalence in marginalized communities of the Peruvian Amazon. Healthcare provision was limited by a breach between health education, knowledge, and access. Additional participatory research with similar rural populations is required to inform regional healthcare policy and decision-making.

Pharmacogenetics in Central American healthy volunteers: interethnic variability.

Ethnicity is one of the major factors involved in interindividual variability to drug response. This study aims to describe the frequency of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in Central American healthy volunteers and to determine its interethnic variability. Twenty-six original research articles on allelic, genotypes or metabolic phenotype frequencies were analyzed, in which a total number of 7611 Central American healthy volunteers were included (6118 were analyzed for genotype and 1799 for metabolic phenotype). No reports were available for population from Belize and Honduras. The CYP2D6*4 and *5 frequencies in Amerindian populations from Costa Rica have shown to be among the highest frequencies so far reported in the world. Furthermore, NAT2*5 and *6 presented higher frequencies in admixed populations than in Amerindians, but, inversely, the NAT2*7 was more frequent in Amerindians compared to an admixed population. Likewise, different patterns of distribution have been shown in HLA-A*02, *03 and HLA-B*07 among Native populations from Latin America. Reports on Central American populations were also found for the CYP2C19, LDLR, CYP2E1, MDR1, G6PD, TP53, CYP1A2, CYP3A4 and CYP3A5 biomarkers, but no data were available for the other 91 pharmacogenetic biomarkers revised in Central American populations. Differences in the frequency of some pharmacogenetic biomarkers and metabolic phenotypes were found, showing interethnic variability within Central American and with other Latin American populations.

CYP2D6 -1584C>G promoter polymorphism and debrisoquine ultrarapid hydroxylation in healthy volunteers.

BACKGROUND & AIM: The CYP2D6 -1584C>G polymorphism (rs1080985) has been identified as a major factor for CYP2D6 expression and function, with the mutant -1584G promoter type being consistently associated with significantly greater expression than -1584C. It may therefore be associated with ultrarapid metabolism. The objective of the present study was to explore the relationship between the CYP2D6 -1584C>G polymorphism and the debrisoquine metabolic ratio in healthy volunteers in order to evaluate its potential impact on the ultrarapid CYP2D6 hydroxylation capacity. MATERIALS & METHODS: The CYP2D6 -1584C>G polymorphism was analyzed in 320 unrelated healthy individuals who were previously phenotyped for debrisoquine hydroxylation. RESULTS: The metabolic ratio (log10 mean ± standard deviation) of individuals with the -1584G allele was lower than that of individuals with the -1584C allele for carriers of one active CYP2D6 gene (-0.13 ± 0.33 and 0.17 ± 0.52, respectively; p < 0.05) or two active CYP2D6 genes (-0.32 ± 0.39 and -0.20 ± 0.44, respectively; p < 0.05). CONCLUSION: The presence of the -1584G allele in the promoter region of the CYP2D6 gene was related to a high CYP2D6 hydroxylation capacity.

Restricción del crecimiento intrauterino en preeclámpticas con síndrome metabólico / Intrauterine growth restriction in preeclamptic patients with metabolic syndrome

Objetivos: Identificar la tasa de restricción del crecimiento intrauterino en preeclámpticas con síndrome metabólico en el Hospital Nacional Docente Madre Niño San Bartolomé durante el período comprendido entre Enero a Diciembre del 2012. Material y métodos: Se realizó un estudio observacional, analítico, de casos y controles. Se revisaron 266 historias clínicas de pacientes gestantes preeclámpticas con síndrome metabólico con recién nacido con restricción del crecimiento intrauterino (casos) y de gestantes preeclámpticas sin síndrome metabólico con recién nacido sin restricción del crecimiento intrauterino en el Hospital Nacional Docente Madre Niño San Bartolomé en el periodo que comprende el estudio. Resultados: las pacientes preeclámpticas con síndrome metabólico y restricción del crecimiento intrauterino se caracterizaron por: Ser convivientes (76.6 por ciento), multigestas (62.5 por ciento), con preeclampsia leve (60.9 por ciento), que tuvieron parto cesárea (54.7 por ciento), con HELLP (17.2 por ciento), eclampsia (21.9 por ciento), con desprendimiento prematuro de placenta (28.1 por ciento), con coagulación intravascular diseminada (18.8 por ciento), que requirieron transfusión (26.6 por ciento), que presentaron falla renal (17.2 por ciento), con edema puImonar (20.3 por ciento), hematoma subcapsular (26.6 por ciento), ruptura capsular (26.6 por ciento), hemorragia post parto (28.1 por ciento), sufrimiento fetal (53.1 por ciento), asfixia perinatal (50 por ciento), síndrome de distrés respiratorio (48.4 por ciento), muerte fetal (23.4 por ciento), muerte neonatal (17.2 por ciento). Conclusiones: Existe una asociación estadísticamente significativa de restricción del crecimiento intrauterino en las pacientes preeclámpticas con síndrome metabólico (P<0.05), La prevalencia de restricción del crecimiento intrauterino en preeclámpticas con síndrome metabólico fue del 48.1 por ciento. La mayoría de las gestantes fueron convivientes, multigestas, que...