Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

Práctica clínica en prevención de migraña con anticuerpos monoclonales del péptido relacionado con el gen calcitonina: evidencias de casos reales / Clinical practice in prevention of migraine with calcitonin-gene related peptide monoclonal antibodies: real-world evidence

Introducción: Los anticuerpos monoclonales (mAbs) del péptido relacionado con el gen de la calcitonina (CGRP) son un novedoso tratamiento para prevenir la migraña crónica y la episódica de alta frecuencia. Método: Se realizó un estudio observacional, retrospectivo, multicéntrico para analizar la efectividad y seguridad de los mAbs anti-CGRP (erenumab, galcanezumab, fremanezumab). La variable de efectividad fue la reducción en los días de migraña al mes (MMDs). La seguridad se midió con los efectos adversos descritos. Resultados: Los resultados de 127 pacientes muestran efectividad similar entre erenumab y galcanezumab en la reducción de los MMDs. Una proporción importante de pacientes cambió de mAb por pérdida de respuesta o fallo primario tras una media de 7 meses: 15,11% erenumab; 24% galcanezumab. Algunos pacientes se trataron con-comitantemente con toxina botulínica A: 8,13% erenumab; 12% galcanezumab; 6,25% fremanezumab. Más del 60% de pacientes habían sido tratados previamente con toxina botulínica A con falta de respuesta tras varias dosis. Se describieron efectos adversos cardiovasculares (dolor en el pecho, taquicardia) exclusivamente en pacientes con erenumab. Conclusiones: La práctica clínica actual se basa en el intercambio de mABs anti-CGRP en casos de falta de respuesta o migraña refractaria, aunque su evidencia es limitada y se ha demostrado que la efectividad entre los tres fármacos es equivalente. Las Agencias Reguladoras recomiendan un período de 12 semanas para evaluar la efectividad del mAb. La mitad de los pacientes refirieron falta de seguimiento por Neurología. Los farmacéuticos clínicos son nece-sarios en la atención integrada de la migraña. (AU)

Introduction: Calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are novel therapeutic option for prevention of chronic migraine (CM) and high-frequency episodic migraine (HFEM). Method: An observational, retrospective, multicentre, real-world evidence study was developed to analyse the ef-fectiveness and safety of anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab). Effectiveness was measured by monthly migraine days (MMDs) reduction. Adverse events were recorded for safety outcome. Results: Results from 127 patients showed similar effectiveness between erenumab and galcanezumab in MMDs reduction. A notable proportion of patients switched of mAb because of loss of response or primary no-response after seven months: 15.11% erenumab; 24% galcanezumab. Some patients were concomitant treated with Onabot-ulinumtoxin A (Onabot A): 8.13% erenumab; 12% galcanezumab; 6.25% fremanezumab. More than 60% of the total were previously treated with Onabot A with loss of response. Cardiovascular adverse events are exclusively reported by erenumab group (chest pain, tachycardia). Conclusions: Current clinical practice is based on switching of CGRP mAbs after loss of response or refractory mi-graine, even though evidence for this practice is limited and effectiveness between the drugs has been demonstrat-ed to be equivalent. The period of 12 weeks since the first dose of the CGRP mAb, recommended by Regulatory Agencies, should be respected to determine if the mAb selected is being ineffective. At least, half of the patients complained about lack of follow-up by reference neurologist. Clinical pharmacists are important to help these pa-tients manage the burden of migraine. (AU)

Fumarase deficiency: a difficult diagnosis and a challenging treatment approach

Introduction: Fumarase deficiency is a rare autosomal metabolic disease that curse with hypotonia, hyperlacticaemia and seizures. Diagnosis based in laboratory test might be done carefully, as most of metabolic diseases present similar symptomatology: hypotony, convulsions, lactic and pyruvic acidemia. Method: The objective is to analyse the pharmacological and nutritional approach of a neonate who presented symptoms of metabolic congenital disorders.Results:The patient is a three-month girl with heterozygote mutation in fumarase gene, who presented clinical manifestations of the altered enzyme function. She presented hyperlacticaemia, organic aciduria and alterations of amino acid levels. First diagnosis suspected was pyruvate dehydrogenase deficiency, so nutritional treatment with ketogenic diet was initiated. After medical discharge, she was hospitalized in emergency basis with cardiac arrest and metabolic decompensation. Genetic test revealed a heterozygote mutation in fumarase. Clinical symptomatology could have worsened because of the difficult diagnosis. Conclusions: Nutritional and pharmacological treatment of fumarase deficiency is considered essential for the patient’s evolution, but further researchers must be carried out to profoundly understand the mechanism underlying metabolic inborn errors. Multidisciplinary teams would manage the disease from the point of view of diverse clinician experts so the correct diagnosis and treatment would be decided with precision(AU)

Introducción: El déficit de fumarasa es una enfermedad rara del metabolismo, autosómica, que cursa con hipotonía, hiperlactacidemia y convulsiones. El diagnóstico basado en pruebas de laboratorio debe realizarse con precaución ya que la mayoría de enfermedades relacionadas con el metabolismo presentan la misma sintomatología: hipotonía, convulsiones y acidemia láctica y pirúvica. Método: Analizar retrospectivamente el manejo farmacológico y nutricional de un neonato con síntomas relacionados con errores del metabolismo congénitos.Resultados:La paciente de 3 meses de vida presentaba una mutación heterocigota en el gen de la fumarasa y síntomas relacionados con la alteración de la función enzima. La paciente presentaba hiperlactacidemia, aciduria orgánica y alteraciones analíticas de los aminoácidos. El primer diagnóstico supuesto fue un déficit de piruvato deshidrogenasa, por lo que se inició tratamiento nutricional con dieta cetogénica. Tras el alta de la paciente, volvió a ingresar por urgencias sufriendo una parada cardíaca y descompensación metabólica. El test genético reveló la presencia de una mutación heterocigota en el gen de la fumarasa. La sintomatología clínica pudo haber empeorado debido al difícil diagnóstico. Conclusiones: El tratamiento farmacológico y nutricional del déficit de fumarasa es esencial para la buena evolución del paciente, pero es necesario que se realicen más estudios para entender con profundidad el mecanismo de los errores congénitos del metabolismo Los equipos multidisciplinares permiten manejar la enfermedad desde distintos puntos de vista clínicos para un diagnóstico correcto y poder decidir el tratamiento adecuado con precisión(AU)

Pharmacogenetic polymorphisms affecting bisoprolol response.

ß-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to ß-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other ß-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

Cerebral toxoplasmosis associated with treatment with rituximab, azathioprine and prednisone for dermatomyositis.

We observed a severe case of cerebral toxoplasmosis in a 22-year-old woman diagnosed with dermatomyositis in 2016 in Venezuela, and treated with rituximab and azathioprine. The patient met clinical and microbiological criteria. Treatment with pyrimethamine and sulfadiazine was initiated, and the patient was discharged. She was rehospitalized with signs and symptoms of a manic episode. During hospitalization, the patient developed acute kidney injury related to sulfadiazine crystalluria. Finally, acute kidney injury was resolved and the patient was successfully discharged.

Activos antioxidantes en la formulación de productos cosméticos antienvejecimiento / Antioxidant actives in the formulation of anti-aging cosmetic products

Objetivos: El conocimiento acerca de los mecanismos subyacentes al envejecimiento de la piel es, en la actualidad, una estrategia clave en la prevención de sus manifestaciones cutáneas. A través del estudio de la principal vía responsable de la senescencia celular, el estrés oxidativo, se revisan activos cosméticos capaces de neutralizar su efecto y la relevancia del mismo. Métodos: Se utilizó la base de datos PubMed para la revisión de artículos científicos, así como diversos textos de Cosmética y Dermofarmacia. Resultados: En el transcurso del envejecimiento cutáneo se solapan dos procesos, uno intrínseco, con alteración del propio sistema redox antioxidante, y otro extrínseco derivado de factores externos, en concreto la radiación solar. El resultado es un grave daño celular a través de especies reactivas de oxígeno y otros mecanismos de oxidación. La revisión de activos cosméticos antioxidantes revela la eficacia de dichas sustancias en el curso de la senescencia celular, gracias a su capacidad de neutralizar los productos dañinos que son generados. Destaca la acción conjunta de ácido ascórbico y vitamina E. Otros, como los derivados del retinol, carotenoides, vitamina B3 y flavonoides han demostrado tener un efecto beneficioso. Conclusiones: En el objetivo de tratar y prevenir el envejecimiento cutáneo es esencial la aplicación de activos antioxidantes. La importancia de su inclusión en productos cosméticos antienvejecimiento o anti-age, en la actualidad, ha alcanzado su auge con el planteamiento de aprovechar su acción antioxidante para reducir al mínimo el efecto del estrés oxidativo y retrasar la muerte celular que se oculta tras el proceso de envejecimiento de la piel

Objectives: Knowledge about skin aging underlying process, nowadays, is the key strategy in prevention of its main cutaneous expression. Through the study of the major mechanism responsible of cellular senescence, oxidative stress, it is reviewed the relevance of various cosmetic actives with the potential to neutralise the oxidative damaging effect. Methods: To carry out the review of related scientific articles we used the databases PubMed, as well as various texts about Cosmetic and Dermopharmacy. Results: During the course of skin aging two mechanisms overlap, an intrinsic process with disorder of the natural anti-oxidative redox system, and an extrinsic process resulting of external factors, specifically solar radiation. A serious cellular damage is the result of reactive oxygen species (ROS) and other oxidative mechanisms. The review of several antioxidant cosmetic actives reveals the efficacy of these substances in the cellular senescence development, because of its action neutralizing harmful products generated. Therefore, combination of ascorbic acid and vitamin E stands out. Others, as retinoids, carotenoids, vitamin B3 or flavonoids have beneficial effects demonstrated. Conclusions: In order to treat and prevent effectively skin aging, we conclude it results essential the use of antioxidant actives. The relevance of including them in anti-aging cosmetic products has reach a new height, approaching their antioxidant property to reduce to a minimum stress oxidative effect and slow down cellular death disguised by skin aging