Vericiguat en insuficiencia cardíaca: de la evidencia científica a la práctica clínica / Vericiguat in heart failure: from scientific evidence to clinical practice

A pesar de los tratamientos actuales, el riesgo de muerte y hospitalizaciones en pacientes con insuficiencia cardíaca con fracción de eyección reducida (IC-FEr) sigue siendo elevado. La fisiopatología de la IC-FEr incluye activación neurohormonal caracterizada por la estimulación de las vías deletéreas (sistemas simpático y renina-angiotensina-aldosterona) y la supresión de las vías protectoras como las dependientes del óxido nítrico. La inhibición o estimulación de algunas de estas vías, pero no de todas, es insuficiente. En la IC-FEr existe una menor actividad de óxido nítrico, guanilato ciclasa soluble y GMPc que provoca efectos deletéreos a nivel miocárdico, vascular y renal. Vericiguat estimula la actividad de esta vía protectora. El estudio VICTORIA demostró, en pacientes con IC-FEr y descompensación reciente, que la adición de vericiguat al tratamiento médico óptimo reducía de forma significativa la incidencia del objetivo primario compuesto de muerte cardiovascular u hospitalización por IC, con un número de 24 pacientes que es necesario tratar, y una excelente tolerabilidad (AU)

Despite currently available treatments, risk of death and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF) remains high. The pathophysiology of HFrEF includes neurohormonal activation characterized by stimulation of deleterious pathways (i.e., sympathetic nervous and renin-angiotensin-aldosterone systems) and suppression of protective pathways such as nitric oxide-dependent pathways. Inhibition or stimulation of some, but not all, of these pathways is insufficient. In HFrEF, there is reduced nitric oxide, soluble guanylate cyclase, and cGMP activity, leading to deleterious effects in the myocardial, vascular, and renal systems. Vericiguat is able to stimulate the activity of this protective pathway. The VICTORIA study demonstrated that the addition of vericiguat to optimal medical treatment in patients with HFrEF and recent decompensation significantly reduced the incidence of the primary endpoint, a composite of cardiovascular death or HF hospitalization, with a number needed to treat of 24 patients and excellent tolerability (AU)

Enfermedad cardiovascular progresiva en paciente bajo tratamiento con nilotinib / Progressive cardiovascular disease in a patient under treatment with nilotinib

No disponible

Controversia en neoadyuvancia y cáncer de recto / The controversy of neoadjuvant therapy in rectal cáncer

No disponible

Toxicidad de la gemcitabina intravesical en el tratamiento del cáncer de vejiga superficial / Toxicity of intravesical gemcitabine in superficial bladder cancer treatment

No disponible

Mecanismo de acción y farmacocinética de rilpivirina / Mechanism of action and pharmacokinetics of rilpivirine

Rilpivirina es un potente inhibidor no nucleósido de la transcriptasa inversa que ha mostrado gran eficacia en el tratamiento de la infección por el virus de la inmunodeficiencia humana 1 (VIH-1) en pacientes naïve. Rilpivirina es un fármaco activo, tanto frente a cepas salvajes de VIH-1 como frente a una extensa variedad de cepas virales resistentes a los inhibidores no nucleósidos de la transcriptasa inversa de primera generación. Posee un perfil farmacocinético muy favorable, aunque al ser su absorción dependiente del pH gástrico debe ser administrada con comida para asegurar su correcta absorción. Su metabolismo está mediado a través del citocromo P450 (CYP) 3A, por lo que deben considerarse las potenciales interacciones cuando se administre conjuntamente con inductores o inhibidores de esta vía enzimática. Aunque a dosis más altas puede comportarse como inductor enzimático, no es esperable que rilpivirina a la dosis de 25mg al día pueda alterar las concentraciones de otros fármacos metabolizados por esta vía. Su prolongada vida media permite su administración por vía oral 1 vez al día

Rilpivirine is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) with high efficacy in the treatment of HIV infection in treatment-naïve patients. This drug is active against both wild-type HIV-1 and a wide variety of first-generation NNRTI. Rilpivirine has a highly favorable pharmacokinetics profile, but, because its absorption depends on gastric pH, it should be administered with food to ensure correct absorption. Rilpivirine is metabolized by cytochrome P450 (CYP) 3A and consequently potential interactions should be considered when it is administered with P450 (CYP) 3A inducers or inhibitors. Although higher doses can behave as enzyme inducers, at a dose of 25mg/day, rilpivirine is unlikely to alter the concentrations of other drugs metabolized through this pathway. Because of its prolonged half-life, rilpivirine can be administered orally once daily

Perfil de seguridad de rilpivirina: tolerabilidad general y neuropsiquiátrica, seguridad en pacientes coinfectados con virus de la hepatitis B/virus de la hepatitis C, y perfil lipídico / Safety profile of rilpivirine: general and neuropsychiatric tolerability, safety in patients with hepatitis B or C viruses, and lipid profile

Los datos actualmente disponibles de seguridad y tolerabilidad de rilpivirina proceden de la ficha técnica del producto, del ensayo clínico en fase IIb de búsqueda de dosis TMC278-C204, de los ensayos clínicos en fase III ECHO y THRIVE, y de los datos preliminares de los ensayos STaR y SPIRIT, con un total de 1.728 pacientes. Su comparador habitual ha sido efavirenz, y en todos los estudios se ha observado una menor incidencia y severidad de efectos adversos neuropsiquiátricos, un mejor perfil lipídico y un menor número de casos con elevación subclínica de transaminasas en los pacientes tratados con rilpivirina. Sin embargo, el número de pacientes coinfectados por virus B o C es relativamente pequeño para obtener conclusiones definitivas en este tipo de pacientes. Asimismo, la experiencia en pacientes con insuficiencia hepática leve o moderada es limitada, y no se dispone de datos de seguridad en pacientes con insuficiencia hepática avanzada

Currently available data on the safety and tolerability of rilpivirine come from the product information document, a phase IIb, dose-finding clinical trial (TMC278-C204), the phase III ECHO and THRIVE clinical trials, and the preliminary data from the STaR and SPIRIT clinical trials, with a total of 1,728 patients. The comparator has usually been efavirenz. All studies have found a lower incidence and severity of neuropsychiatric adverse effects, a better lipid profile, and a lower number of patients with subclinical transaminase elevation in patients treated with rilpivirine. However, because of the relatively low number of patients coinfected with hepatitis B or C virus, definitive conclusions cannot be drawn. Similarly, experience in patients with mild or moderate liver failure is limited and there are no safety data in patients with advanced liver failure

Interacciones farmacocinéticas / Pharmacokinetic interactions

Rilpivirina (RPV) es un fármaco perteneciente a la familia de los inhibidores no nucleósidos de la transcriptasa inversa (INNTI), con potente actividad antiviral, aprobado para pacientes naïve, con perfil de efectos secundarios diferente a los INNTI de primera generación. Las interacciones farmacológicas producidas por RPV se deben a su efecto sobre el sistema CYP450, es sustrato de CYP3A4 y ligeramente inductor. Además, in vitro es inhibidor de la glucoproteína-P. RPV presenta interacciones farmacológicas clínicamente significativas, entre las que destacan los inhibidores de la proteasa, a excepción de darunavir y lopinavir potenciados, y los INNTI efavirenz y nevirapina. La toma de RPV junto con fármacos que aumentan el pH gástrico, como omeprazol, o los que inducen el CYP3A4, como rifampicina, puede causar reducciones significativas en las concentraciones de RPV y está contraindicada. El uso concomitante de RPV con un inhibidor del CYP3A4, por ejemplo claritromicina, puede provocar aumento de las concentraciones de RPV. Se recomienda la administración de RPV con alimentos para obtener mejor absorción y valores plasmáticos adecuados

Rilpivirine (RPV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been approved for use in treatment-naïve patients and which has potent antiviral activity. Its adverse effects profile differs from that of first-generation NNRTs. The pharmacological interactions produced by RPV are due to its effects on the CYP450 system; RPV is a substrate and mild inducer of CYP3A4. Moreover, in vitro, RPV inhibits glycoprotein-P. RPV has clinically significant pharmacological interactions, especially with protease inhibitors (except boosted darunavir and lopinavir) and the NNRTIs efavirenz and nevirapine. Coadministration of RPV with drugs that increase gastric pH, such as omeprazole, or those inducing CYP3A4, such as rifampicin, can significantly reduce RPV concentrations and is contraindicated. The concomitant use of RPV with a CYP3A4 inhibitor (such as clarithromycin) can increase RPV concentrations. Administration of PRV with food is recommended to obtain better absorption and adequate plasma values

Datos de rilpivirina en pacientes naïve. Lecciones de los estudios ECHO, THRIVE y STaR / Data on rilpivirine in treatment-naïve patients. Lessons from ECHO, THRIVE and STaR

Rilpivirina (RPV) es un nuevo inhibidor de la transcriptasa inversa no análogo de nucleósidos de segunda generación, aprobado recientemente para el tratamiento de pacientes con infección por el virus de la inmunodeficiencia humana a dosis de 25mg, administrado 1 vez al día con alimentos. En pacientes que inician tratamiento, RPV se ha evaluado en 1 estudio fase IIb (TMC278-C204) y en 3 estudios fase III (ECHO, THRIVE y STaR). En todos ellos, RPV se compara con el gold standard (efavirenz [EFV]), incluyendo un considerable número de pacientes tratados con el nuevo fármaco (n=1.349). La eficacia terapéutica ha resultado elevada y similar con ambos tratamientos, demostrándose que RPV es no inferior a EFV a las 48 y 96 semanas. En todos los estudios y en todos los subgrupos analizados, RPV ha mostrado una mejor tolerabilidad que EFV, especialmente en lo referido a efectos adversos del área neuropsiquiátrica, exantema cutáneo y de la esfera lipídica. En el análisis conjunto de los estudios ECHO y THRIVE se observaron diferencias notables en función de la carga viral (CV) basal. Así, la eficacia terapéutica de RPV resultó superior a la de EFV en pacientes con CV basal ≤ 100.000 copias/ml, con similar eficacia virológica y, además, una mejor tolerabilidad de RPV. Por el contrario, en los pacientes con CV basal ≥ 100.000 copias/ml se observó una mayor incidencia de fallos virológicos en el grupo de RPV, especialmente con CV basal ≥ 500.000 copias/ml. La aparición de mutaciones de resistencia en los pacientes con fallo virológico resultó superior a la esperada, especialmente en los pacientes con CV basal elevada. Según estos resultados, las agencias del medicamento europeo (EMA) y americana (FDA) han aprobado el uso de RPV en pacientes naïve con CV basal ≤ 100.000 copias/ml. Algunas guías terapéuticas ya incorporan RPV en sus recomendaciones. Así, las americanas (DHHS e IAS-USA), en espera de datos adicionales, la consideran todavía como un régimen alternativo, mientras que las europeas y la reciente actualización de las Guías de GeSIDA la consideran entre los regímenes preferidos en pacientes con CV ≤ 100.000 copias/ml. Los datos recientes del estudio STaR, en el que se utilizan combinaciones a dosis fijas de los 3 fármacos, muestran no inferioridad de RPV frente a EFV, independientemente de la CV basal, con menos fallos virológicos y una menor selección de resistencias que en los estudios ECHO y THRIVE. En definitiva, los datos de eficacia y seguridad del fármaco indican que los regímenes basados en RPV con 2 inhibidores de la transcriptasa inversa análogos de nucleósidos son eficaces y seguros en el tratamiento antirretroviral de inicio

Rilpivirine (RPV) is a new, second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been recently approved for use in the initial antiretroviral therapy (ART) of treatment-naïve HIV-infected patients, combined with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). The approved dose is 25mg once daily with food. RPV has been assessed in a phase IIb study (TMC278-C204) and in three phase III trials (ECHO, THRIVE and STaR). In all of them, RPV was compared with the gold standard, efavirenz (EFV); these studies enrolled a large number of patients (n=1,349 on RPV). RPV was non-inferior to EFV at 48 and 96 weeks. In all the studies and study arms, the tolerability of RPV was better than that of EFV, especially for neuropsychiatric adverse effects, rash, and lipid profile. An analysis of the combined data from the ECHO and THRIVE trials showed marked differences, depending on baseline viral load. The therapeutic efficacy of RPV was superior to that of EFV in patients with a baseline viral load ≤100,000 copies/mL, due to a similar virological efficacy and a better tolerability profile. However, in patients with a baseline viral load ≥100,000 copies/mL, virological failure was more frequent in the RPV arm, especially in patients with a viral load ≥500,000 copies/mL. Emerging resistance mutations to RPV were commonly detected in patients with virological failure, especially in those with a higher baseline viral load. In view of these results, the European Medications Agency and the US Food and Drug Administration have approved the use of RPV in treatment-naïve patients with a baseline viral load ≤100,000 copies/mL. Some treatment guidelines have already included RPV among their recommendations. The guidelines of the US Department of Health and Human Services (DHSS) and the International Antiviral Society-USA ((IAS-USA), while awaiting additional data, consider RPV-based regimens as an alternative regimen. The Gesida guidelines consider RPV to be among the preferred regimens in patients with a viral load ≤100,000 copies/mL. Recent data from the STaR trial, which used fixed drug combinations, have shown the non-inferiority of RPV with respect to EFV, less virological failure and less emergence of resistance mutations with RPV use, irrespective of baseline viral load. In summary, efficacy and safety data suggest that RPV plus 2 NRTI is an effective and safe initial antiretroviral regime

Potencial papel de rilpivirina en el escenario de simplificación / Potential role of rilpivirine in simplification regimens

La simplificación del tratamiento antirretroviral es una estrategia útil para mejorar la adherencia, la calidad de vida, y prevenir o revertir efectos secundarios en los pacientes con infección por el virus de la inmunodeficiencia humana. La disponibilidad de nuevos fármacos con alta eficacia y mejor tolerados, en presentaciones 1 vez al día o en combinación a dosis fija, puede ofrecer una mejor opción para un tratamiento prolongado. Rilpivirina, un nuevo no análogo de nucleósido, ha demostrado alta eficacia antiviral en ensayos clínicos en pacientes naïve, con menor incidencia de efectos adversos y buena tolerancia del paciente. Su uso en simplificación ha sido evaluado tras el cambio desde efavirenz, demostrando que no precisa ajuste de dosis, y en un amplio estudio aleatorizado en pacientes que recibían inhibidores de la proteasa, con mantenimiento de la eficacia virológica, menor incidencia de efectos adversos, y mejoría en los parámetros lipídicos y en el cálculo de riesgo cardiovascular. Dada la comodidad de uso y la tolerancia, recientes comunicaciones a congresos demuestran la rápida aplicabilidad de los resultados de estudios en la clínica diaria en este escenario

Antiretroviral simplification is a useful strategy to improve adherence and quality of life and prevent or reverse adverse effects in patients with HIV infection. The availability of new drugs with high efficacy and better tolerability in once-daily formulations or in fixed-dose combinations may be a better option for prolonged treatment. Rilpivirine, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), has shown high antiviral efficacy in clinical trials with treatment-naïve patients, with a lower incidence of adverse effects and good tolerability. Its use in simplification regimens has been evaluated after the switch from efavirenz, demonstrating that dose adjustment is not required. In a large randomized study in patients who were receiving protease inhibitors, virological efficacy was maintained, with a lower incidence of adverse effects and improved lipid parameters and cardiovascular risk score. Given the ease of administration and good tolerability of this drug, recent communications at congresses have shown the rapid applicability of the results of studies in daily clinical practice in this scenario

Conclusiones. Posicionamiento de rilpivirina en el manejo de la infección por el virus de la inmunodeficiencia humana / No disponible

No disponible

Tratamiento de las alopecias de patrón masculino y femenino. Eficacia clínica del aminexil y SP94 en dos series de 180 pacientes, hombres y mujeres / Treatment of alopecias of male and female patterns. Clinical efficacy of aminexil and SP94 in two surveys of 180 patients, men and women

El efecto del aminexil combinado con SP.94 fue evaluado como positivo en un grupo de pacientes de ambos sexos. Para poder confirmar estos positivos efectos se ha realizado un estudio en 180 pacientes de cada sexo en las Unidades de Tricología de dos Hospitales. Los pacientes se aplicaron sobre cuero cabelludo y cabellos húmedos 6 ml. de la loción todas las noches. A los pacientes se les realizó controles al comienzo del tratamiento y a los 45,90 y 180 días. Se efectuó en todos tipificación de la alopecia según las escalas de Ebling y Ludwig, y se les preguntó por su edad separándolos en grupos de menores de 17 años, entre 18 y 34 años, entre 35 y 49 años, y 50 o más años. También se interrogó por enfermedades y medicación concomitantes, presencia de dermatitis seborreica, cantidad de cabellos caídos en un lavado de 48 horas antes, deficiencias nutricionales o errores congénitos. A las mujeres con signos clínicos de síndrome SAHA se les realizó una analítica hormonal. La exploración del paciente en cada visita incluyó la realización de un tricograma con estudio del diámetro de los cabellos, signo de arrancamiento, sebometrías, corneometría, control iconográfico, graduación de la alopecia, y una valoración de la evolución de la dermatitis seborreica según una escala cuantitativa. En las visitas también se les pidió a los pacientes una valoración de la cosmeticidad y eficacia del producto, que de (..) (AU)

Effect of aminexil combined with SP94 was evaluated as positive in a group of patients of both genders. To confirm these positive effects a survey in 180patients of each gender has been performed in two Trichology Units of two Hospitals. Patients applied 6 ml. of the lotion in humid scalp all the nights. Controls to the start of treatment and at 45, 90, and 180 days was realized. Graduation of alopecia in accordance with the Ebling’s and Ludwig’s scales, and differentiation on four group of age (less than 17 year, between 18 and 34 years, between 35 and 49 years, and more than 50 year) was performed. All the patients were asked about their clinical background or treatments realized, seborrhoeic dermatitis, number of hairs shedding in a wash 48 hour before, nutritional deficiencies or congenital errors. Women with clinical signs of SAHA syndrome an hormonal analysis was performed Exploration of patients at each visit included trichogram and study of the hair diameter, pull sign, sebometry, corneometry, photographic control, graduation of alopecia, and a valoration of seborrhoeic dermatitis evolution in a quantitative scale. In each visit was also asked to patients for a evaluation about cosmeticity and efficacy of the lotion, by which of a subjecitive manner was divided in worst, similar, acceptable-better, and excellent, that was contrasted with the opinion of two physicians that had their evaluation based on the signs and photograph of each visit. Patient’s compliment was study with the Morisky-Green’s questionnaire. Patients that do not follow the protocol of application or that did not attend to some visit were substituted. Results permit to assure aminexil associated with SP.94 stop or delay loss of hair and favored its wide, although regroth of new hair lost in the evolutive process of androgenetic alopecia was not demonstrated, neither its actuation in seborrhorea and soborrhoeic dermatitis (AU)

Effect of some pyrimidine compounds on rat brain monoamine oxidase-B in vitro

The effects of some pyrimidine compounds (PCs) including barbituric acid (BA) 5,5-diethyl barbituric acid (DEBA), 2-thiobarbituric acid (TBA), violuric acid (VA), 2-thiouracil (TU), and 6-amino-2-thiouracil (ATU) on the activity of rat brain monoamine oxidase-B (MAO-B) were investigated. The results revealed that MAO-B was activated by BA, DEBA, TBA, TU, and ATU, and the activation was structural, concentration, and time dependent. However, MAO-B was inhibited by VA in a noncompetitive and irreversible manner with an enzyme-inhibitor dissociation constant (K i value) of 32 nM and IC50 equals to 19 nM. All the studied PCs changed both the optimum pH and temperature of MAO-B (AU)

Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome

BACKGROUND: The identification of activating mutations in either c-KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha (PDGFRA) has lead the way for the development of novel agents that selectively inhibit key molecular events in gastrointestinal stromal tumour (GIST) pathogenesis. The aim of this study was to investigate the role of c-KIT and PDGFRA gene mutations in primary resectable, imatinib naïve GISTs located in the stomach and small intestine. METHODS: All adult patients with GIST located in either stomach or small intestine who underwent surgical resection without prior imatinib (Glivec) treatment were included. DNA extraction and mutational analysis were performed. Mutational analyses were performed for c-KIT (exons 9, 11, 13, and 17) and the PDGFRA genes (exons 12, 14 and 18). Clinical and pathological parameters were analyzed in relation to the mutations in c-KIT and PDGFRA. RESULTS: A total of 38 patients who underwent surgery for GIST located in either the stomach (n = 24) or in the small intestines (n = 14) were included. Mutations were found in 31 of 38 (81.6 %) patients, with 24 (63.2 %) located in c-KIT and 7 (18.4 %) in the PDGRFA exons, respectively. Seven patients (18.4 %) were wildtype (WT). The most common mutation was in c-KIT exon 11. Incidentally found GISTs were significantly smaller (size >5 cm in 15 % for incidental vs. 71 % for symptomatic; OR of 13.4, 95 % CI 2.3-76.5; P = 0.001) and had lower mitotic rate (0 % for incidental vs. 44 % of the symptomatic; OR 0.52, 95 % CI 0.36-0.75; P = 0.005). Accordingly, the Fletcher grade was significantly better for incidental cases, with most having very low or low risk (85 %) in contrast to 19 of 25 (76 %) symptomatic cases showing moderate to high-risk features (OR 17.4, 95 % CI 2.98-101.7; P < 0.001). However, the distribution of c-KIT, PDGFRA and WT was not differently distributed between incidental and symptomatic GISTs. Long-term survival up to 25 years (median: 8 years) was best determined by Fletcher risk-score in the multivariate model (HR 14.1, 95 % CI 1.7-114.5; p = 0.013). CONCLUSIONS: Long-term survival in resected GISTs of the stomach and small intestine is best determined by Fletcher risk-score. Mitotic activity appears related to tumour size and young age at onset. Mutational status did not influence the clinical or tumour-specific features in this cohort (AU)

Clinical implications of KIT and PDGFRA genotyping in GIST

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs are characterised by the expression of KIT, a type III tyrosine kinase receptor, and the presence of mutations in KIT or PDGFRA in about 80-85% of cases. The primary treatment for GIST is surgery, which cures most patients with low- or intermediate-risk tumours. The introduction of the kinase inhibitor imatinib mesylate, and sunitinib in second line, against KIT and PDGFRA has provided the first evidence of directed therapy in GIST. The aim of this review is to highlight the growing evidence that KIT and PDGFRA genotyping provides valuable information for the clinical management of GIST patients. We show that KIT and PDGFRA genotyping has emerged as one of the principal factors in the evaluation of GISTs, particularly in those tumours that are clearly malignant or have a high risk of recurrence. In addition to helping establish the diagnosis of GIST in unusual cases, genotyping can be very useful to physicians and patients in deciding on imatinib dose, in estimating the likelihood and duration of benefit, and potentially in selecting second-line therapies (AU)