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For domestic cats ovaries, recommended cold-storage limit is 24â¯h in Phosphate Buffered Saline (PBS) or Dulbecco`s PBS (DPBS). Here, we attempted to verify wheatear cat ovaries may benefit from more complex solutions during prolonged cold-storage (>24â¯h). First, the preservation capabilities of extracellular (SP+), intracellular (UW) solutions and DPBS supplemented with glutathione (DPBS+GSH) were compared using ovary fragments from the same ovary (n=10). Intact ovary stored in DPBS served as a control. Ovaries were kept at 4⯰C for 48â¯h, and 72â¯h. In the second experiment, first ovary was stored in DPBS, second in SP+ or UW solution for 48â¯h (nâ¯=â¯12). Ovaries pairs stored in DPBS for 24â¯h served as a control (n=8). Tissue samples were evaluated directly after cold-storage and after following 24â¯h in vitro culture. Ovarian follicle morphology, apoptosis rates (cleaved caspase-3, TUNEL), and follicular growth activation (Ki-67) were assessed. Ovary fragmentation impaired follicular morphology preservation upon cold-storage comparing to intact ovary. However, ovarian fragments stored in UW for 48â¯h and in SP+ for 72â¯h presented better morphology than DPBS+GSH group. Comparison of intact ovaries cold-storage for 48â¯h showed that SP+ provided superior follicular morphology over DPBS, and it was comparable to the outcome of 24-hour storage. No follicular activation after in vitro culture was observed. Nevertheless, tissue culture increased considerably caspase-3 cleavage and TUNEL detection. The ovary fragmentation prior to cold-storage is not recommended in domestic cats. Replacement of DPBS with SP+ solution for whole ovary and UW solution for ovarian tissue fragments improves follicular structure preservation during 48-hour cold-storage.
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Soluciones Preservantes de Órganos , Ovario , Femenino , Animales , Gatos , Ovario/fisiología , Caspasa 3 , Folículo Ovárico/fisiología , Glutatión , Rafinosa , Alopurinol , Insulina , AdenosinaRESUMEN
INTRODUCTION: the prevalence of osteoporosis among candidates for lung transplantation is high and its pathophysiology is multifactorial. OBJECTIVES: to evaluate differences in bone mineral density, risk of fractures and bone remodeling markers in patients with terminal lung disease, at the time they are evaluated for lung transplantation, comparing two types of pathologies. MATERIAL AND METHODS: fifty-nine subjects, proposed to receive a lung transplant due to advanced lung disease, were included in this study. They were divided into two groups according to their respiratory pathology: chronic obstructive pulmonary disease (COPD) and diffuse interstitial pulmonary disease (ILD). Demographic data were collected and bone densitometry, blood analysis with markers of bone remodeling, spirometry, six-minute walk test (6MWT), echocardiography and cardiac catheterization were performed Results: no differences were found between the groups, regarding their age, sex, BMI or exposure to tobacco. A higher prevalence of osteoporosis and a higher FRAX were observed in the group with COPD. Regarding bone remodeling markers, higher parathyroid hormone (PTH) and higher osteocalcin were found in the COPD group. Vitamin D was lower in COPD patients. CONCLUSIONS: two out of three of the patients evaluated for lung transplantation had osteopenia or osteoporosis. The prevalence of osteoporosis and FRAX is higher in COPD patients. Vitamin D supplementation should be considered in certain patients. Differences in bone remodeling markers may be useful for suspected osteoporosis and therapeutic management.
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Mammalian zinc metallothionein-3 (Zn7MT3) plays an important role in protecting against copper toxicity by scavenging free Cu(II) ions or removing Cu(II) bound to ß-amyloid and α-synuclein. While previous studies reported that Zn7MT3 reacts with Cu(II) ions to form Cu(I)4Zn(II)4MT3ox containing two disulfides (ox), the precise localization of the metal ions and disulfides remained unclear. Here, we undertook comprehensive structural characterization of the metal-protein complexes formed by the reaction between Zn7MT3 and Cu(II) ions using native ion mobility mass spectrometry (IM-MS). The complex formation mechanism was found to involve the disassembly of Zn3S9 and Zn4S11 clusters from Zn7MT3 and reassembly into Cu(I)xZn(II)yMT3ox complexes rather than simply Zn(II)-to-Cu(I) exchange. At neutral pH, the ß-domain was shown to be capable of binding up to six Cu(I) ions to form Cu(I)6Zn(II)4MT3ox, although the most predominant species was the Cu(I)4Zn(II)4MT3ox complex. Under acidic conditions, four Zn(II) ions dissociate, but the Cu(I)4-thiolate cluster remains stable, highlighting the MT3 role as a Cu(II) scavenger even at lower than the cytosolic pH. IM-derived collision cross sections (CCS) reveal that Cu(I)-to-Zn(II) swap in Zn7MT3 with concomitant disulfide formation induces structural compaction and a decrease in conformational heterogeneity. Collision-induced unfolding (CIU) experiments estimated that the native-like folded Cu(I)4Zn(II)4MT3ox conformation is more stable than Zn7MT3. Native top-down MS demonstrated that the Cu(I) ions are exclusively bound to the ß-domain in the Cu(I)4Zn(II)4MT3ox complex as well as the two disulfides, serving as a steric constraint for the Cu(I)4-thiolate cluster. In conclusion, this study enhances our comprehension of the structure, stability, and dynamics of Cu(I)xZn(II)yMT3ox complexes.
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Complejos de Coordinación , Metalotioneína 3 , Animales , Cobre/química , Metalotioneína/química , Espectrometría de Masas , Zinc/química , Complejos de Coordinación/química , Disulfuros , Mamíferos/metabolismoRESUMEN
Ion mobility-mass spectrometry (IM-MS) unraveled different conformational stability in Zn4-7-metallothionein-2. We introduced a new molecular dynamics simulation approach that permitted the exploration of all of the conformational space confirming the experimental data, and revealed that not only the Zn-S bonds but also the α-ß domain interactions modulate protein unfolding.
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Simulación de Dinámica Molecular , Zinc , Zinc/química , Metalotioneína/química , Metalotioneína/metabolismo , Conformación Proteica , Espectrometría de MasasRESUMEN
INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin ProgresiónRESUMEN
A multicentre case series of patients with chronic migraine (CM) treated with monoclonal antibodies directed against calcitonin gene-related peptide (CGRP-mAbs) switching were developed. The effectiveness and safety of CGRP-mAbs switching as a preventive treatment for CM in clinical practice were recorded. Effectiveness was measured by ≥50% reduction of monthly migraine days in respect to baseline and reduction in pain intensity. Safety was analysed through adverse events (AEs) and treatment discontinuations. Seven patients were included. The reason for switching was non-response in all cases. Two patients presented a response to the first CGRP-mAb, but the effect was lost after 3 months. The remaining five patients were non-responders. Response to the second CGRP-mAb was observed in three patients, one of them for >3 months. Less than half of the patients previously treated with a CGRP-mAb responded to switching with a second CGRP-mAb. AEs were rare, with no treatment discontinuations.
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Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Humanos , Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & controlRESUMEN
Belantamab mafodotin (BLMF) is an interesting therapeutic alternative for multiple myeloma (MM) patients pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Scientific evidence on BLMF provides immature data about progression-free survival and overall survival by short follow-up of patients with poor prognoses. Cases with long follow-ups could provide additional information about BLMF. This case reports a patient with MM treated with BLMF who had received nine previous lines of therapy with a follow-up of 11 months. No complete response was obtained. However, no disease progression was observed and the patient was still alive at the end of this work. BLMF showed manageable adverse effects. Our patient presented advanced disease, good functional status at the beginning of BLMF treatment, and elevated levels of lactate dehydrogenase during BLMF therapy. The influence of these last two factors was not evaluated in clinical trials. This relationship should be assessed more deeply in future studies.
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Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , InmunoterapiaRESUMEN
Patient empowerment is one of the main pillars of humanisation. Therefore, consideration of patients' preferences and expectations should be taken into account during the practice of any healthcare professional. Improving overall survival and quality of life are the main wishes of patients. Indeed, the recent emergence of Patient Reported Outcomes has become an important focus for healthcare providers. The hospital pharmacist specialised in drug evaluation is a professional who evaluates the efficacy, safety, appropriateness and efficiency of treatments prescribed by physicians, and decision-making must be based on both technical factors and the four principles of bioethics. The correct application of evidence-based clinical practice allows to provide patients with increases in survival and/or quality of life, adapting the convenience and costs to the current situation. With this in mind, it could be said that the evaluation of medicines involves a strong commitment to humanisation. On the other hand, rganisations that promote the rigorous evaluation and selection of medicines stand as allies of patients, as they have a direct impact on them and an indirect impact on society. Regulatory agencies in charge of approving and financing medicines in healthcare systems play a key role in the process of humanising clinical decision-making and empowering patients. If these agencies approve the use of new medicines based on data that do not measure quality of life or survival of patients when there are already other therapeutic alternatives for these pathologies, they are indirectly failing to meet patients' expectations and are infringing bioethical principles. This can have a considerable influence on the benefit-risk ratio of drugs, and patients may be treated with regimens that do not provide benefit, or may even harm them. Therefore, where should the process of humanisation be oriented? It seems reasonable that the benefit of the patient should be the fundamental objective of the process of humanisation of healthcare, evidently.
El empoderamiento del paciente supone uno de los principales pilares de la humanización. Por ello, la consideración de las preferencias y expectativas de los pacientes debería ser tenida en cuenta durante el ejercicio de cualquiera de los profesionales de la salud. Mejorar la supervivencia global y la calidad de vida son los deseos principales de los pacientes. De hecho, la reciente aparición de los llamados Patient Reported Outcomes ha supuesto un importante foco para los agentes involucrados en la asistencia sanitaria. El farmacéutico hospitalario especializado en la evaluación de medicamentos es un profesional que evalúa la eficacia, seguridad, adecuación y eficiencia de los tratamientos prescritos por facultativos, y debe basar la toma de decisiones tanto en factores técnicos como en los cuatro principios bioéticos. La correcta aplicación de la práctica clínica basada en la evidencia permite proveer a los pacientes de incrementos de supervivencia y/o calidad de vida, adecuando la conveniencia y costes a la situación actual. Teniendo en cuenta esto, podría decirse que la evaluación de medicamentos supone un fuerte compromiso con la humanización. Por otra parte, las organizaciones que promueven la evaluación y selección de medicamentos rigurosamente se erigen como aliados de los pacientes, ya que repercuten de forma directa en éstos y de forma indirecta en la sociedad. Las agencias reguladoras encargadas de la aprobación y financiación de medicamentos en los sistemas sanitarios protagonizan un papel fundamental en el proceso de humanización de la toma de decisiones clínicas y empoderamiento de pacientes, ya que si aprueban el uso de nuevos medicamentos según datos que no miden la calidad de vida o supervivencia de los pacientes cuando ya existen otras alternativas terapéuticas para estas patologías, indirectamente no estarán dando respuesta a las expectativas de los pacientes y conculcarán los principios bioéticos. Esto puede tener una considerable influencia en la relación beneficio-riesgo de los fármacos, pudiendo tratar a pacientes con esquemas que no aportan beneficio, o incluso podrían perjudicarles. Por tanto, ¿hacia dónde debiera ir orientado el proceso de humanización? Parece razonable que el beneficio del paciente sea el objetivo fundamental del proceso de humanización de la asistencia sanitaria, evidentemente.
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Motivación , Calidad de Vida , Humanos , Objetivos , Pacientes , Personal de SaludRESUMEN
Classical zinc fingers domains (ZFs) bind Zn(II) ion by a pair of cysteine and histidine residues to adopt a characteristic and stable ßßα fold containing a small hydrophobic core. As a component of transcription factors, they recognize specific DNA sequences to transcript particular genes. The loss of Zn(II) disrupts the unique structure and function of the whole protein. It has been shown that the saturation of ZFs under cellular conditions is strictly related to their affinity for Zn(II). High affinity warrants their constant saturation, while medium affinity results in their transient structurization depending on cellular zinc availability. Therefore, there must be factors hidden in the sequence and structure of ZFs that impact Zn(II)-to-protein affinities to control their function. Using molecular dynamics simulations and experimental spectroscopic and calorimetric approaches, we showed that particular non-conserved residues derived from ZF sequences impact hydrogen bond formation. Our in silico and in vitro studies show that non-conserved residues can alter metal-coupled folding mechanisms and overall ZF stability. Furthermore, we show that Zn(II) binding to ZFs can also be entropically driven. This preference does not correlate either with Zn(II) binding site or with the extent of the secondary structure but is strictly related to a reservoir of interactions within the second coordination shell, which may loosen or tighten up the structure. Our findings shed new light on how the functionality of ZFs is modulated by non-coordinating residues diversity under cellular conditions. Moreover, they can be helpful for systematic backbone alteration of native ZF ßßα scaffold to create artificial foldamers and proteins with improved stability.
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Aminoácidos , Dedos de Zinc , Secuencia de Aminoácidos , Termodinámica , Sitios de Unión , Zinc/metabolismoRESUMEN
El empoderamiento del paciente supone uno de los principales pilares dela humanización. Por ello, la consideración de las preferencias y expectativas de los pacientes debería ser tenida en cuenta durante el ejerciciode cualquiera de los profesionales de la salud. Mejorar la supervivenciaglobal y la calidad de vida son los deseos principales de los pacientes. Dehecho, la reciente aparición de los llamados Patient Reported Outcomes hasupuesto un importante foco para los agentes involucrados en la asistenciasanitaria. El farmacéutico hospitalario especializado en la evaluación demedicamentos es un profesional que evalúa la eficacia, seguridad, adecuación y eficiencia de los tratamientos prescritos por facultativos, y debebasar la toma de decisiones tanto en factores técnicos como en los cuatroprincipios bioéticos. La correcta aplicación de la práctica clínica basadaen la evidencia permite proveer a los pacientes de incrementos de supervivencia y/o calidad de vida, adecuando la conveniencia y costes a lasituación actual. Teniendo en cuenta esto, podría decirse que la evaluaciónde medicamentos supone un fuerte compromiso con la humanización. Porotra parte, las organizaciones que promueven la evaluación y selecciónde medicamentos rigurosamente se erigen como aliados de los pacientes,ya que repercuten de forma directa en éstos y de forma indirecta en lasociedad. Las agencias reguladoras encargadas de la aprobación y financiación de medicamentos en los sistemas sanitarios protagonizan un papelfundamental en el proceso de humanización de la toma de decisiones clínicas y empoderamiento de pacientes, ya que si aprueban el uso de nuevos medicamentos según datos que no miden la calidad de vida o supervivencia de los pacientes cuando ya existen otras alternativas terapéuticaspara estas patologías, indirectamente no estarán dando respuesta a lasexpectativas de los pacientes y conculcarán los principios bioéticos. (AU)
Patient empowerment is one of the main pillars of humanisation. Therefore,consideration of patients preferences and expectations should be takeninto account during the practice of any healthcare professional. Improvingoverall survival and quality of life are the main wishes of patients. Indeed,the recent emergence of Patient Reported Outcomes has become animportant focus for healthcare providers. The hospital pharmacist specialised in drug evaluation is a professional who evaluates the efficacy, safety,appropriateness and efficiency of treatments prescribed by physicians,and decision-making must be based on both technical factors and thefour principles of bioethics. The correct application of evidence-based clinical practice allows to provide patients with increases in survival and/orquality of life, adapting the convenience and costs to the current situation.With this in mind, it could be said that the evaluation of medicines involvesa strong commitment to humanisation. On the other hand, organisationsthat promote the rigorous evaluation and selection of medicines standas allies of patients, as they have a direct impact on them and an indirect impact on society. Regulatory agencies in charge of approving andfinancing medicines in healthcare systems play a key role in the processof humanising clinical decision-making and empowering patients. If theseagencies approve the use of new medicines based on data that do notmeasure quality of life or survival of patients when there are already othertherapeutic alternatives for these pathologies, they are indirectly failing tomeet patients expectations and are infringing bioethical principles. (AU)
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Humanos , Farmacia , Atención Dirigida al Paciente , Bioética , Medicina Basada en la Evidencia , Evaluación de Medicamentos , Poder PsicológicoRESUMEN
OBJECTIVE: The European Medicines Agency's marketing authorisation criteria for drugs are reflected in the European Public Assessment Reports. The objective is to describe the expectations and preferences of our oncohematological outpatients with respect to their oral treatments, and to evaluate the concordance with the results of European Public Assessment Reports. METHOD: A survey of onco-hematological patients' expectations and preferences about overall survival and quality of life was developed, with three items: expectations on treatment, preferences of benefit and willingness to receive novel treatments with non-definitive results. European Public Assessment Reports of the indicated drugs were reviewed. Kappa index (κ) was used to assess the agreement between patients' expectations and preferences respect to the benefit in overall survival and quality of life described in the corresponding European Public Assessment Report. Concordance between willingness of patients to receive novel treatments and European Public Assessment Reports results was evaluated by absolute agreement (Ao). RESULTS: There were 29 participants, and 19 different European Public Assessment Reports were consulted. Patients' expectations about their treatment: 82.1% expected improvement in overall survival and quality of life; the κ value between expectations and results of European Public Assessment Reports was 0.091 (confidence interval 95%: -0.025 to 0.207). Patients' preferences about benefit of their treatment: 92.6% preferred quality of life; the κ value was 0.016 (confidence interval 95%: - 0.127 to 0.160). Willingness to receive novel treatments: 82.1% participants demanded benefit in overall survival or quality of life; exigences were met in Ao = 53.6% of patients. CONCLUSIONS: Little agreement was observed between expectations and preferences of our onco-hematological patients and European Public Assessment Reports, according to overall survival and quality of life. Most patients preferred an improvement in quality of life, but also expected an increase in overall survival with their treatment. Almost half of patients would not meet their requirements to receive their drug when it was authorized.
OBJETIVO: Los criterios de autorización de comercialización de medicamentos de la Agencia Europea del Medicamento se reflejan en los European Public Assessment Reports. El objetivo es describir las expectativas y preferencias de nuestros pacientes externos oncohematológicos con respecto a sus tratamientos orales, y evaluar la concordancia con los resultados de los European Public Assessment Reports. Método: Se elaboró una encuesta sobre las expectativas y preferencias de los pacientes oncohematológicos respecto a la supervivencia global y calidad de vida, con tres ítems: expectativas sobre el tratamiento, preferencias de beneficio y disposición a recibir tratamientos novedosos con resultados inmaduros. Se revisaron los European Public Assessment Reports de los fármacos indicados. Se utilizó el índice kappa (κ) para evaluar la concordancia entre las expectativas y preferencias de los pacientes respecto al beneficio en supervivencia global y calidad de vida descrito en el European Public Assessment Report correspondiente. La concordancia entre la disposición de los pacientes a recibir nuevos tratamientos y los resultados de los European Public Assessment Reports se evaluó mediante la concordancia absoluta (Ao). RESULTADOS: Se incluyeron 29 participantes y se consultaron 19 European Public Assessment Reports diferentes. Expectativas de los pacientes sobre su tratamiento: el 82,1% esperaba una mejora de la supervivencia global y calidad de vida; el valor κ entre las expectativas y los resultados de los European Public Assessment Reports fue de 0,091 (intervalo de confianza 95%: 0,025 a 0,207). Preferencias de los pacientes sobre el beneficio de su tratamiento: el 92,6% prefirió la calidad de vida; el valor κ fue de 0,016 (intervalo de confianza 95%: 0,127 a 0,160). Disposición a recibir tratamientos novedosos: el 82,1% de los participantes exigió un beneficio en la supervivencia global o en la calidad de vida; las exigencias se cumplieron en Ao = 53,6% de los pacientes. CONCLUSIONES: Se observó poca concordancia entre las expectativas y preferencias de nuestros pacientes oncohematológicos y los European Public Assessment Reports, según la supervivencia global y la calidad de vida. La mayoría de los pacientes preferían una mejora de la calidad de vida, pero también esperaban un aumento de la supervivencia global con su tratamiento. Casi la mitad de los pacientes no cumpliría con sus requisitos para recibir su medicación cuando ésta fuera autorizada.
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Motivación , Calidad de Vida , HumanosRESUMEN
OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only dexamethasone has clearly shown a reduction in mortality for COVID-19 hospitalized patients. For interleukin-6 inhibitors, results are variable and nclear. The objective was to review and analyze the effect of tocilizumab and sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A systematic search in Medline, Embase and medRxiv was conducted to identify randomized controlled trials with tocilizumab or sarilumab in hospitalized patients with COVID-19. Mortality data from non-critical and critical patients were extracted. A random-effects (DerSimonian-Laird) meta-analysis was performed for both subgroups and the whole population using MAVIS software v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase, respectively, five were trials with tocilizumab and/or sarilumab; two more were identified at medRxiv. Seven randomized clinical trials fulfilled the inclusion criteria. Another trial was pre-published and included post-hoc. The meta-analysis, with eight randomized clinical trials and 6,340 patients, showed a benefit on mortality for interleukin-6 heterogeneity (I2 = 7%), but a low similarity among studies. The results showed no differences among critical and non-critical patients. A sensitivity analysis excluding non-similar or heterogeneous studies showed different results, without benefit and with low precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but with important differences among the scenarios analyzed in the clinical trials. Positive results are mainly caused by two randomized clinical trials which are similar in concomitant use of steroids and veryhigh mortality in critical patents. Sarilumab was poorly represented in the meta-analysis. Nevertheless, an association between the benefit and the critical/non-critical condition was not found. More randomized clinical trials, mainly focused in atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis.
OBJETIVO: Un año después de la declaración de la pandemia por SARSCoV-2, solo dexametasona había mostrado claramente una reducción de la mortalidad en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de interleucina 6 son diversos y poco claros. El objetivo de este trabajo es revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab; se identificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizados cumplieron los criterios de inclusión. Posteriormente, se prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95% 0,74-0,99), con baja heterogeneidad (I2 = 7%), pero reducida similitud entre los estudios. Los resultados no mostraron diferencias entre pacientes críticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no similares mostró resultados diferentes, sin beneficio y con baja precisión del resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se eben principalmente a dos ensayos que son similares en el uso concomitante de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los inhibidores de interleucina-6 en COVID-19.
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Tratamiento Farmacológico de COVID-19 , Dexametasona/uso terapéutico , Humanos , Interleucina-6 , Pandemias , SARS-CoV-2Asunto(s)
Hipersensibilidad a las Drogas , Omalizumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Desensibilización Inmunológica/métodos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/terapia , Humanos , Omalizumab/uso terapéutico , Trastuzumab/efectos adversosRESUMEN
Objetivo: Los criterios de autorización de comercialización de medicamentosde la Agencia Europea del Medicamento se reflejan en losEuropean Public Assessment Reports. El objetivo es describir las expectativasy preferencias de nuestros pacientes externos oncohematológicoscon respecto a sus tratamientos orales, y evaluar la concordancia con losresultados de los European Public Assessment Reports.Método: Se elaboró una encuesta sobre las expectativas y preferenciasde los pacientes oncohematológicos respecto a la supervivencia globaly calidad de vida, con tres ítems: expectativas sobre el tratamiento, preferenciasde beneficio y disposición a recibir tratamientos novedosos conresultados inmaduros. Se revisaron los European Public Assessment Reportsde los fármacos indicados. Se utilizó el índice kappa (κ) para evaluar laconcordancia entre las expectativas y preferencias de los pacientes respectoal beneficio en supervivencia global y calidad de vida descrito enel European Public Assessment Report correspondiente. La concordanciaentre la disposición de los pacientes a recibir nuevos tratamientos y losresultados de los European Public Assessment Reports se evaluó mediantela concordancia absoluta (Ao). Resultados: Se incluyeron 29 participantes y se consultaron 19 EuropeanPublic Assessment Reports diferentes.
Objective: The European Medicines Agencys marketing authorisationcriteria for drugs are reflected in the European Public Assessment Reports.The objective is to describe the expectations and preferences of our oncohematologicaloutpatients with respect to their oral treatments, and toevaluate the concordance with the results of European Public AssessmentReports.Method: A survey of onco-hematological patients expectations andpreferences about overall survival and quality of life was developed, withthree items: expectations on treatment, preferences of benefit and willingnessto receive novel treatments with non-definitive results. European PublicAssessment Reports of the indicated drugs were reviewed. Kappa index(κ) was used to assess the agreement between patients expectations andpreferences respect to the benefit in overall survival and quality of lifedescribed in the corresponding European Public Assessment Report. Concordancebetween willingness of patients to receive novel treatments andEuropean Public Assessment Reports results was evaluated by absoluteagreement (Ao). Results: There were 29 participants, and 19 different European PublicAssessment Reports were consulted. Patients expectations about theirtreatment: 82.1% expected improvement in overall survival and qualityof life; the κ value between expectations and results of European PublicAssessment Reports was 0.091 (confidence interval 95%: 0.025 to0.207). Patients preferences about benefit of their treatment: 92.6% preferredquality of life; the κ value was 0.016 (confidence interval 95%:0.127 to 0.160). Willingness to receive novel treatments: 82.1% participantsdemanded benefit in overall survival or quality of life; exigenceswere met in Ao = 53.6% of patients.
Asunto(s)
Humanos , Masculino , Femenino , Motivación , Prioridad del Paciente , Quimioterapia , Medicina Basada en la Evidencia , Hematología , Oncología Médica , Calidad de la Atención de Salud , Servicio de Farmacia en Hospital , Encuestas y CuestionariosRESUMEN
Objetivo: Un año después de la declaración de la pandemia porSARS‑CoV-2, solo dexametasona había mostrado claramente una reducciónde la mortalidad en pacientes hospitalizados por COVID-19. Losresultados de los inhibidores de interleucina 6 son diversos y poco claros.El objetivo de este trabajo es revisar y analizar el efecto de tocilizumaby sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA.Se realizó una búsqueda sistemática en Medline, Embase y medRxiv paraidentificar ensayos controlados aleatorizados con tocilizumab o sarilumaben pacientes hospitalizados con COVID-19. Se recopilaron los datosde mortalidad de pacientes críticos y no críticos y se llevó a cabo unmetaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgruposy para toda la población, usando el software MAVIS v. 1.1.3. Lasimilitud y homogeneidad entre los ensayos fue evaluada.Resultados: Se identificaron 25 y 23 artículos en Medline y Embase,respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab; seidentificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizadoscumplieron los criterios de inclusión. Posteriormente, se prepublicóotro ensayo que cumplía los criterios de inclusión y se incorporó absoalanálisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidoresde interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95%0,74-0,99), con baja heterogeneidad (I2 = 7%), pero reducida similitudentre los estudios. Los resultados no mostraron diferencias entre pacientescríticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneoso no similares mostró resultados diferentes, sin beneficio y conbaja precisión del resultado en pacientes no críticos.
Objective: One year after the declaration of the SARS-CoV-2 pandemic,only dexamethasone has clearly shown a reduction in mortality forCOVID-19 hospitalized patients. For interleukin-6 inhibitors, results arevariable and unclear. The objective was to review and analyze the effectof tocilizumab and sarilumab on survival in this setting.Method: The PRISMA statements were fulfilled for the systematic review.A systematic search in Medline, Embase and medRxiv was conductedto identify randomized controlled trials with tocilizumab or sarilumab inhospitalized patients with COVID-19. Mortality data from non-critical andcritical patients were extracted. A random-effects (DerSimonian-Laird)meta-analysis was performed for both subgroups and the whole populationusing MAVIS software v. 1.1.3. Similarity and homogeneity amongtrials were assessed.Results: Twenty-five and 23 articles were identified in Medline andEmbase, respectively, five were trials with tocilizumab and/or sarilumab;two more were identified at medRxiv. Seven randomized clinical trialsfulfilled the inclusion criteria. Another trial was pre-published and includedpost-hoc. The meta-analysis, with eight randomized clinical trialsand 6,340 patients, showed a benefit on mortality for interleukin-6 inhibitor (hazard ratio 0.85; confidence interval 95% 0.74-0.99), lowheterogeneity (I2 = 7%), but a low similarity among studies. The resultsshowed no differences among critical and non-critical patients. A sensitivityanalysis excluding non-similar or heterogeneous studies showeddifferent results, without benefit and with low precision of the result innon-critical patients.