Adherence With Oral Anticancer Therapies: Clinical Trial vs Real-world Experiences With a Focus on Prostate Cancer.

PURPOSE: In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence. MATERIALS AND METHODS: Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed. RESULTS: Mean nonadherence rates of 25% to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and health care teams. CONCLUSIONS: Many oral anticancer medications improve survival in men with prostate cancer, and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes.

Adesão à quimioterapia antineoplásica oral, apoio social e bem- estar de pacientes com câncer cerebral: estudo correlacional / Adhesión a la quimioterapia antineoplásica oral, apoyo social y bienestar de pacientes con cáncer cerebral: estudio correlacional / Adherence to oral antineoplastic chemotherapy, social support and well-being of patients with brain cancer: a correlational study

Objetivos: identificar as percepções sobre o bem-estar, apoio social, intensidade dos sintomas e o seu impacto nas atividades diárias de pacientes com cânceres cerebrais e correlacionar os achados com os níveis de adesão aos quimioterápicos antineoplásicos orais. Método: estudo correlacional e transversal, realizado num ambulatório hospitalar universitário de São Paulo, Brasil, entre 2019 e 2020. Utilizou-se instrumento para caracterização da amostra e escalas específicas. Resultados: 26 participantes, mediana de 36,5 anos, 61,5% sexo masculino, 53,9% diagnosticados com glioblastoma; 73,1% apresentaram adesão, rede de apoio social e índice alto de bem-estar. O escore médio de intensidade dos sintomas foi de baixo para médio, com pior pontuação para preocupação no pior estado. A maior adesão relacionou-se ao apoio afetivo, apoio informação, interação social e apoio emocional. Conclusão: a maioria declarou níveis positivos de bem-estar, suporte social e poucos sintomas. A percepção de apoio social e bem-estar influenciaram positivamente na adesão medicamentosa.

Objetivos: identificar las percepciones sobre el bienestar, apoyo social, intensidad de los síntomas y su impacto en las actividades diarias de pacientes con cánceres cerebrales y correlacionar los resultados con los niveles de adhesión a los quimioterápicos antineoplásicos orales. Método: estudio correlacional y transversal, realizado en un ambulatorio hospitalario universitario de São Paulo, Brasil, entre 2019 y 2020. Se utilizó un instrumento para la caracterización de la muestra y escalas específicas. Resultados: 26 participantes, mediana de 36,5 años, 61,5% sexo masculino, 53,9% diagnosticados con glioblastoma; 73,1% presentaron adhesión, red de apoyo social y índice alto de bienestar. El puntaje promedio de intensidad de los síntomas fue de bajo a medio, con peor puntuación para preocupación en el peor estado. La mayor adhesión se relacionó al apoyo afectivo, apoyo información, interacción social y apoyo emocional. Conclusión: la mayoría declaró niveles positivos de bienestar, apoyo social y pocos síntomas. La percepción de apoyo social y bienestar influyó positivamente en la adhesión medicamentosa.

Objectives: to identify perceptions about well-being, social support, intensity of symptoms and their impact on the daily activities of patients with brain cancers and correlate the findings with levels of adherence to oral antineoplastic chemotherapy. Method: correlational and cross-sectional study, conducted in a university hospital outpatient clinic in São Paulo, Brazil, between 2019 and 2020. An instrument was used to characterize the sample, in addition to specific scales. Results: 26 participants, median 36.5 years, 61.5% male, 53.9% diagnosed with glioblastoma; 73.1% showed adherence, social support network and high well-being index. The mean symptom intensity score was low to medium, with a worse score for worry in the worst state. Greater adherence was related to affective support, information support, social interaction and emotional support. Conclusion: most reported positive levels of well-being, social support and few symptoms. The perception of social support and well-being positively influenced drug adherence.

Considerations for clinical evaluation of the effects of bariatric surgery on the pharmacokinetics of orally administered drugs.

Obesity has been a growing worldwide concern, and surgical intervention including bariatric surgery is considered as one of the options for treatment. However, there still is controversy over the change in pharmacokinetics (PKs) of drugs after the surgery. To investigate the potential covariates that can influence the area under the curve (AUC) and maximum plasma concentration (Cmax), the design of previous studies was reviewed based on pre-determined eligibility criteria. Each study calculated the ratios of the AUC and Cmax before and after bariatric surgery. These studies investigated whether the PK parameters were affected by the time after the surgery or by the type of control group. The ratio of the AUC calculated in the early and late follow-up period was similar across Roux-en Y gastric bypass patients. No significant difference in the PK parameters was found between the pre-surgical patients and matched healthy subjects. However, certain control groups could be preferable depending on the purpose of the clinical trial. Although Cmax was inconsistent compared to the AUC, insufficient sampling of the time points may have caused such an inconsistency. This is the first article exploring the appropriate methodology in designing clinical studies for changes in the PK characteristics of orally administered drugs in patients with bariatric surgery.

Uso de anticoagulantes orales directos en pacientes con fibrilación auricular post implante de TAVI: resultados de una encuesta internacional / Use of anticoagulants in patients with atrial fibrillation undergoing transcatheter aortic valve implantation

BACKGROUND: Transcatheter Aortic Valve Implantation (TAVI) is beneficial in patients with symptomatic severe Aortic Stenosis (AS). There is no consensus about the best anticoagulation strategy for patients with a recent TAVI and with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) are effective to prevent embolic events with a significant lower incidence of bleeding. There is scarce evidence about the use of these drugs in patients undergoing TAVI. AIM: To assess the management of anticoagulation at the moment of discharge of patients with AF and TAVI. Material and Methods: A four question survey was sent to cardiologists involved in TAVI programs in different international centers. Results: The survey was answered by 72 interventional cardiologists. Even with the lack of randomized evidence, in most of the scenarios DOACs are prescribed at discharge in patients with indication for anticoagulation. Also, in patients with high bleeding risk, most cardiologists would perform a left atrial appendage closure. In patients with concomitant coronary artery disease, if a stent was recently implanted, prescription of the combination of a DOAC and one antiplatelet drug was the most common answer. In patients with a former coronary angioplasty, DOAC or Warfarin was the therapy of choice. CONCLUSIONS: In the absence of randomized data, interventional cardiologists prescribe DOACs at discharge to patients with AF and TAVI, without following current guidelines in most cases.

Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial.

BACKGROUND: Oropharyngeal administration of colostrum (OAC) may provide immunoprotective and anti-inflammatory effects that potentially reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis and improve short-term outcomes. Our objective was to evaluate the role of OAC in the early prevention of NEC and late-onset sepsis in preterm infants with gestational age (GA) ≤ 32 weeks. METHODS: A pilot, single-center, 1:1 parallel randomized controlled trial was conducted in a 40-bed tertiary neonatal intensive care unit (NICU) in China from 1 January 2019 to 30 September 2020. Preterm infants were randomly divided into two groups with GA ≤ 32 weeks. The OAC group included preterm infants who received 0.4 ml of maternal colostrum via the oropharyngeal route every 3 h for 10 days beginning within the first 48 h after birth, and the control group included preterm infants who received normal saline instead. Data from the two groups were collected and compared. RESULTS: A total of 127 infants in the OAC group and 125 infants in the control group were enrolled. The incidence of NEC (Bell stage 2 or 3) and late-onset sepsis were lower in the OAC group [2.36% vs. 10.40%, relative risk (RR) 0.23 (95% confidence interval (CI) 0.07, 0.78), adjusted RR 0.23 (95% CI 0.06, 0.84); 4.72% vs. 13.60%, RR 0.35 (95% CI 0.14, 0.85), adjusted RR 0.36 (95% CI 0.14, 0.95)]. In addition, the incidence of proven sepsis and intraventricular hemorrhage (IVH) (stage 3 or 4) were lower in the OAC group [2.36% vs. 8.80%, RR 0.27 (95% CI 0.08, 0.94); 1.57% vs. 7.20%, RR 0.22 (95% CI 0.05, 0.99)], and the time to achieve full enteral feeding was shorter (23.13 ± 9.45 days vs. 28.50 ± 14.80 days). No adverse reactions were observed in either group. CONCLUSIONS: Oropharyngeal administration of colostrum is a safe and simple NICU procedure that may yield a potential effect in decreasing the incidences of NEC, late-onset sepsis, and severe IVH and shorten the time to achieve full enteral feeding in preterm infants with GA ≤ 32 weeks. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900023697 , Registered 8 June 2019, retrospectively registered.

Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.

Pharmaceutical consultation to detect drug interactions in patients treated with oral chemotherapies: A descriptive cross-sectional study.

OBJECTIVE: The development of oral chemotherapy (OC) has led to the recent establishment of multidisciplinary programmes involving pharmacists. We evaluated the utility of our local programme for detecting potential interactions with OCs, particularly drug-drug interactions (DDIs) and herbal-drug interactions (HDIs). METHODS: We performed a single-centre retrospective descriptive study of patients on OC attending a pharmaceutical consultation (PC) during a seven-month period. These consultations included the use of various complementary tools/databases to search for interactions. RESULTS: We analysed 308 treatments taken by 42 consecutive patients. Fifty-four potential interactions with OCs were detected in 26% (n = 79) of the treatments taken by patients: 46 DDIs (32 minor, 12 major, 2 contraindicated) and eight HDIs. Five interventions associated with interactions were suggested by pharmacists during the consultations (4 were taken into account by oncologists). The total mean time spent on each PC for an individual patient was 80 minutes (36 minutes of preparation, 44 minutes with the patient). CONCLUSION: This pilot study highlights the importance of studying interactions in such patients, and of the expertise of pharmacists for detecting interactions, which were found in more than one in four treatment lines. The further development of such activities, which already take up considerable amounts of time, is therefore warranted.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

Oral Antineoplastics: Treatment Adherence and Medication Beliefs / Antineoplásicos Orais: Adesão ao Tratamento e Crenças sobre os Medicamentos / Agentes Antineoplásicos Orales: Adherencia al Tratamiento y Creencias sobre los Medicamentos

Introduction: Adherence to oral antineoplastics (OA) is an important indicator of therapeutic response related to personal, social, and structural factors. Objective: To determine rates of adherence to OA, investigating possible risk factors for nonadherence and to assess patient beliefs about medication, identifying opportunities for pharmaceutical intervention. Method: An analytical study was conducted with cancer patients using OA in 2015. Adherence to Refills and Medication Scale (ARMS) and Beliefs about Medicines Questionnaire (BMQ) were applied to assess adherence and beliefs about medication and treatment. Mann-Whitney, Chi-square, and Fisher's Exact tests were used for data analysis. Results: A total of 222 patients were interviewed, with a 92.8% adherence rate according to ARMS and 84.7% according to BMQ, in which the necessity-beliefs exceeded the concerns with the treatment and use of OA. Family income, treatment interruption, number and causes of interruptions, depression, and medication possession ratio were the risk factors identified. Comparison of BMQ domains showed that, in the adherent group, patient beliefs in the necessity of the medication exceeded their concerns about it. Conclusion: Understanding the patient's beliefs is a decisive factor in comprehending the risks related to nonadherence as well as in defining strategies to deal with it.

Introdução: A adesão aos antineoplásicos orais (AO) é um importante indicador de resposta terapêutica relacionada a fatores pessoais, sociais e estruturais. Objetivo: Determinar as taxas de adesão aos AO, investigando possíveis fatores de risco para a não adesão, e avaliar as crenças dos pacientes sobre medicamentos, identificando oportunidades de intervenção farmacêutica. Método: Estudo analítico realizado com pacientes com câncer em uso de AO em 2015. Escala de Adesão e Recarga dos Medicamentos (ARMS) e Questionário de Crenças sobre Medicamentos (BMQ) foram aplicados para avaliar a adesão e crenças sobre medicamentos e tratamento. Os testes de Mann-Whitney, qui-quadrado e exato de Fisher foram usados para análise de dados. Resultados: Foram entrevistados 222 pacientes, com taxa de adesão de 92,8%, segundo o ARMS e 84,7%, segundo o BMQ, no qual as crenças de necessidade excederam as preocupações com o tratamento e o uso de AO. Renda familiar, interrupção do tratamento, número e causas das interrupções, depressão e razão de posse de medicamentos foram os fatores de risco identificados. A comparação dos domínios do BMQ demostrou que, no grupo aderente, as crenças dos pacientes sobre a necessidade do medicamento excederam suas preocupações quanto a isso. Conclusão: Considerar as crenças do paciente é um fator decisivo para compreender os riscos relacionados à não adesão, bem como para definir estratégias para lidar com ela.

Introducción: La adherencia a antineoplásicos orales (AO) es un indicador importante de la respuesta terapéutica relacionada con factores personales, sociales y estructurales. Objetivo: Determinar tasas de adherencia a AO, investigar posibles factores de riesgo de incumplimiento y evaluar creencias de los pacientes sobre la medicación, identificando oportunidades para intervención farmacéutica. Método: Estudio analítico con pacientes con cáncer que usaban AO en 2015. Se aplicó Adherencia a la Recogida y Administración de la Medicación (ARMS) y Cuestionario de Creencias sobre Medicación (BMQ) para evaluar el cumplimiento y las creencias sobre medicación y tratamiento. Las pruebas de Mann-Whitney, Chi-cuadrado y Exacto de Fisher se utilizaron para análisis de datos. Resultados: Se entrevistó un total de 222 pacientes, con una tasa de adherencia de 92,8% según ARMS y 84,7% según BMQ, en la cual las creencias de necesidad excedieron preocupaciones con el tratamiento y uso de AO. Ingreso familiar, interrupción del tratamiento, número y causas de interrupciones, depresión y proporción de posesión de medicamentos fueron los factores de riesgo identificados. La comparación de los dominios de BMQ mostró que, en el grupo adherente, las creencias sobre necesidad de la medicación excedieron preocupaciones. Conclusión: La consideración de las creencias del paciente es un factor decisivo para comprender los riesgos relacionados con la no adherencia, así como para definir estrategias para afrontarla.

Práticas educativas junto às famílias de crianças e adolescentes em quimioterapia antineoplásica oral: revisão integrativa / Prácticas educativas con familias de niños y adolescentes en quimioterapia antineoplástica oral: revisión integrativa / Educative practices with families of children and teenagers under oral antineoplastic chemotherapy: an integrative review

Objetivo: Analisar, nas produções científicas, as práticas educativas empregadas para orientação dos familiares e cuidadores de crianças e adolescentes com câncer quanto ao tratamento quimioterápico antineoplásicos orais. Método: Revisão integrativa da literatura disponível nas bases de dados LILACS via BVS, SCIELO, CINAHL, PUBMED e EMBASE, realizada no mês de setembro de 2020. Foram incluídos artigos originais que abordassem a temática. Excluíram-se aqueles que focavam práticas educativas direcionadas a profissionais, pacientes adultos e outros tipos de quimioterapia. Resultados: A amostra foi constituída de cinco artigos internacionais. As evidências foram agrupadas de acordo com o tipo de prática educativa: consulta clínica, orientações em grupo com dinâmicas, programa de manutenção domiciliar e produção de materiais educativos impressos. Considerações Finais: A educação em saúde é essencial no preparo de familiares de crianças e adolescentes em quimioterapia antineoplásica oral e a equipe de enfermagem deve desenvolver treinamentos e orientações que promovam um cuidado integral, seguro e resolutivo(AU)

Objective: This study aims to analyze the educative practices applied to the orientation of families and caregivers of children and teenagers with cancer under oral antineoplastic chemotherapy treatment. Method: In this study an integrative review of the available literature was performed through the utilization of databases such as LILACS by BVS, SCIELO, CINAHL, PUBMAD and EMBASE on September of 2020. Original articles that approached this subject were selected. Articles that focused on educative practices directed to professionals, adult patients and other types of chemotherapy were excluded. Results: A sample of five international articles was taken. The evidences were grouped according to the type of educative practice: clinical appointment, group orientations with dynamics, homecare program and production of printed educative material. Final considerations: Health education is essential in the preparation of families of children and teenagers that have cancer and are under oral antineoplastic chemotherapy treatment. The nursing team should develop training sessions and orientation that promote comprehensive, safe and resolving care.(AU)

Objetivo: Analizar, en las producciones científicas, las prácticas educativas empleadas en la orientación de las familias y de los cuidadores de niños y adolescentes con respecto al tratamiento con quimioterapia antineoplásica oral. Método: Revisión integradora de la literatura disponible en las bases de datos LILACS vía BVS, SCIELO, CINAHL, PUBMED y EMBASE logadas en el mes de septiembre de 2020. Fueran inclusos artículos originales que abordaron el tema. Se excluyeron los que eran centrados en prácticas educativas dirigidas a profesionales, pacientes adultos y otros tipos de quimioterapia. Resultados: La muestra se constituyó de cinco artículos internacionales. Las evidencias fueran agrupadas de acordo con el tipo de práctica educativa: citas clínicas, orientaciones grupales con dinámica, programa de atención domiciliaria y producción de materiales educativos impresos. Consideraciones finales: La educación en salud es esencial en el preparo de las familias de niños y adolescentes en tratamiento con quimioterapia antineoplásica oral y el equipo de enfermería debe desarrollar capacitaciones y pautas que promuevan una atención integral, segura y resolutiva(AU)

Route and duration of antibiotic therapy in acute cellulitis: A systematic review and meta-analysis of the effectiveness and harms of antibiotic treatment.

OBJECTIVES: Compared with guideline recommendations, antibiotic overuse is common in treating cellulitis. We conducted a systematic review and meta-analyses on antibiotic route and duration of treatment for cellulitis in adults and children. METHODS: We searched MEDLINE, EMBASE and trial registries from inception to Dec 11, 2019 for interventional and observational studies of antibiotic treatment for cellulitis. Exclusions included case series/reports, pre-septal/orbital cellulitis and non-English language articles. Random-effects meta-analyses were used to produce summary relative risk (RR) estimates for our primary outcome of clinical response. PROSPERO: CRD42018100602. RESULTS: We included 47/8423 articles, incorporating data from eleven trials (1855 patients) in two meta-analyses. The overall risk of bias was moderate. Only two trials compared the same antibiotic agent in each group. We found no evidence of difference in clinical response rates for antibiotic route or duration (RR(oral:IV)=1.12, 95%CI 0.98-1.27, I2=32% and RR(shorter:longer)=0.99, 95%CI 0•96-1.03, I2 = 0%, respectively). Findings were consistent in observational studies. Follow-up data beyond 30 days were sparse. CONCLUSIONS: The evidence base for antibiotic treatment decisions in cellulitis is flawed by biased comparisons, short follow-up and lack of data around harms of antibiotic overuse. Future research should focus on developing patient-tailored antibiotic prescribing for cellulitis to reduce unnecessary antibiotic use.

Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12).

OBJECTIVES: To compare the effectiveness of oral versus intramuscular (IM) vitamin B12 (VB12) in patients aged ≥65 years with VB12 deficiency. DESIGN: Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain). PARTICIPANTS: 283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm. INTERVENTIONS: The IM arm received 1 mg VB12 on alternate days in weeks 1-2, 1 mg/week in weeks 3-8 and 1 mg/month in weeks 9-52. The oral arm received 1 mg/day in weeks 1-8 and 1 mg/week in weeks 9-52. MAIN OUTCOMES: Serum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction. RESULTS: The follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B12 levels was well above 90%; the differences in this percentage between the oral and IM arm were -0.7% (133 out of 135 vs 129 out of 130; 95% CI: -3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: -1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B12 levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were -6.3% (103 out of 112 vs 115 out of 117; 95% CI: -11.9 to -0.1; p=0.025) and -6.8% (103 out of 140 vs 115 out of 143; 95% CI: -16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>-10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route. CONCLUSIONS: Oral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low. TRIAL REGISTRATION NUMBERS: NCT01476007; EUDRACT (2010-024129-20).

Prevención del stroke en fibrilación auricular. Hallazgos del registro GLORIA-AF / Stroke Prevention In Atrial Fibrillation. Findings From The Gloria-Af Registry

RESUMEN Introducción: El GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) es un registro internacional, prospectivo, en tres fases, para determinar la seguridad y eficacia del dabigatrán en pacientes con fibrilación auricular no valvular recientemente diagnosticada, en riesgo de stroke. La fase II empezó cuando el dabigatrán, el primer anticoagulante oral no antagonista de la vitamina K (NOAC) estuvo disponible. Objetivos: Describir los datos clínicos basales de la fase II en la población general y el seguimiento a 2 años de aquellos que recibieron dabigatrán. Material y Métodos: Se reclutaron un total de 15 644 pacientes, de los cuales 15 308 fueron elegibles y 4873 recibieron dabigatrán. Se analizaron las características de la fibrilación auricular, los hallazgos en el seguimiento y las enfermedades concomitantes. Los datos fueron analizados usando estadísticas descriptivas. Resultados: Del total de pacientes elegibles, el 45,5% eran mujeres, con una edad promedio de 71 (rango intercuartilo: 64-78) años. Los pacientes eran de Europa (47,9%), América del Norte (22,2%), Asia (20,1%), América Latina (6,0%) y Medio Oriente/ África (3,9%). La mayoría se encontraba en alto riesgo de stroke (CHA2DS2-VASc score >2; 86,1%); un 13,9% tuvieron riesgo moderado (CHA2DS2-VASc score >1). El 80,3% recibieron anticoagulantes orales; de ellos, el 47,9% recibieron NOAC y el 32,4%, antagonistas de la vitamina K (VKA); 12,0% recibieron agentes antiagregantes plaquetarios y el 7,6% no recibieron tratamiento antitrombótico. A 2 años de seguimiento, el 70,5% permanecieron en dabigatrán. Conclusiones: Los datos de la fase II del registro GLORIA-AF demostraron que, en FA no valvular, los NOAC han sido ampliamente adoptados en la práctica clínica y fueron más frecuentemente prescriptos que los VKA. No obstante, una gran proporción de pacientes en todo el mundo permanecieron sin tratamiento.

ABSTRACT Background: GLORIA-AF is a prospective, global, 3-phase registry program to determine the safety and effectiveness of dabigatran in patients with newly diagnosed non-valvular atrial fibrillation at risk of stroke. Phase II began when dabigatran, the first non-vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives: To describe phase II baseline clinical data in the general population and 2-year follow-up of those patients treated with dabigatran. Methods: A total of 15,644 patients were enrolled, 15,308 of whom were eligible and 4,873 received dabigatran. Atrial fibrillation disease characteristics, follow-up findings and concomitant diseases were collected. Data were analyzed using descriptive statistics. Results: Of the total eligible patients, 45.5% were female; median age was 71.0 (interquartile range: 64, 78) years. Patients were from Europe (47.9%), North America (22.2%), Asia (20.1%), Latin America (6.0%), and the Middle East/Africa (3.9%). Most had high stroke risk (CHA2DS2-VASc score ≥2; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc =1). Overall, 80.3% received oral anticoagulants, of whom 47.9% received NOACs and 32.4% vitamin K antagonists (VKA); 12.0% received anti-platelet agents; and 7.6% received no antithrombotic treatment. At 2-year follow-up, 70.5% remained on dabigatran. Conclusions: Data from GLORIA-AF phase II showed that in non-valvular AF, NOACs have been highly adopted in clinical practice, becoming more frequently prescribed than VKAs. Worldwide, however, a large proportion of patients remain undertreated.

Oral Misoprostol for Induction of Labour in Term PROM: A Systematic Review.

OBJECTIVE: To assess the efficacy of oral misoprostol for induction of labour (IOL) in the context of term pre-labour rupture of membranes (TPROM), and to assess pregnancy outcomes following the administration of oral misoprostol. DATA SOURCES: A systematic literature search was performed using Ovid Medline, Embase, PubMed, and the Cochrane Database of Systematic Reviews. STUDY SELECTION: Eligible studies were quasi-experimental trials or randomized controlled trials involving the use of oral misoprostol in singleton cephalic term pregnancies with confirmed rupture of membranes and no spontaneous labour at the time of membranes rupture, in mothers with no contraindications to vaginal delivery. Studies were excluded if they utilized vaginal misoprostol, excluded primigravid participants, or if the full text of the article was not accessible in English. DATA EXTRACTION: Data were extracted by two reviewers using a standardized data extraction form. Study quality was assessed using the modified Jadad score. DATA SYNTHESIS: Twelve randomized controlled trials that included 1489 singleton pregnancies were included. Doses of oral misoprostol ranged from 20 to 200 µg. The incidence of vaginal birth ranged from 73.0%-95.0% in the oral misoprostol group compared with 52.4%-94% in the control group. Hyperstimulation was infrequent, ranging from 0% to 13.8% in the oral misoprostol group compared with 0%-24% in the control group. Two trials, involving a total of 144 women that compared 50 µg of oral misoprostol every 4 hours versus expectant management followed by PGE2 gel showed a higher incidence of vaginal birth with misoprostol (pooled risk ratio 1.33, 95% confidence interval 1.10-1.61). CONCLUSION: Oral misoprostol appears to be a safe and effective for IOL in TPROM. However, the varying administration, dose, and frequency reported in the literature highlights the need to develop a standardized protocol for use in Canadian obstetrical practice.

European Paediatric Formulation Initiative workshop report: Improving the administration of oral liquid medicines in paediatrics using dosing syringes and enteral accessories.

Accurate dosing of the right medicine to the right patient is a key element of safe and efficacious pharmacotherapy, yet prone to technical challenges and human error when dosing involves the administration of small volumes of liquid medicines. For this reason, the topic has gained increased attention over the last decade from multiple stakeholder parties e.g. academia, hospital pharmacy, the medical device and pharmaceutical industry, and regulatory agencies. It is now well acknowledged that spoons and cups are not suitable for the measurement of small volumes of oral liquid medicines and that syringes are a better alternative, but syringes for parenteral use should not be used for oral dosing in order to avoid accidental parenteral delivery of oral products. However, dosing accuracy of very small volumes of liquid medicines to young children, and especially pre-term neonates, is still not sufficiently ensured. A workshop was organised in 2018 by the European Paediatric Formulation Initiative to reflect on current status and challenges (first part) and possible strategies to improve the present situation (second part). A voting system (n = 24) was used to consider the most favourable solutions. The harmonisation and/or standardisation of the technical design of oral syringes (including e.g. female/male connection) was considered a key priority.

Efficacy and safety of beta carotones in treatment of oral leukoplakia: systematic review and meta-analysis / Eficacia y seguridad de las betacarotonas en el tratamiento de la leucoplasia oral: revisión sistemática y metanálisis

Objectives: A systematic review was conducted to evaluate effectiveness and safety of beta carotenes for the treatment of oral leukoplakia regarding clinical resolution and prevention of malignant transformation. Material and Methods: The systematic search was conducted in three electronic databases and the study's selection was performed according to pre-set eligibility criteria. Four studies evaluating the efficacy of beta carotenes in oral leukoplakia compared to placebo were included in the review; three of which were assigned for quantitative analysis. Data were extracted, tabulated, quality assessed and statistically analyzed. Results: The meta-analysis revealed that when comparing clinical resolution the beta carotene group favored was favored compared to placebo, with statistically significant difference. However, a meta-analysis comparing beta carotene and placebo groups regarding malignant transformation as a primary outcome failed to show any significant benefit. Furthermore, results showed evidence of beta carotene safety. Conclusion: the overall quality of evidence about efficacy of beta carotene in oral leukoplakia treatment was not high. However, given the obvious safety of this agent, data suggests it could have a promising effect in clinical improvement of oral leukoplakia lesions. However, no evidence supporting its benefits in reducing risk of malignant transformation in these lesions was found. Therefore, further long term, well designed randomized clinical trials are highly recommended.

Objetivos: Se realizó una revisión sistemática para evaluar la efectividad y la seguridad de los betacarotenos para el tratamiento de la leucoplasia oral en relación con la resolución clínica y la prevención de la transformación maligna. Material y Métodos: la búsqueda sistemática se realizó en tres bases de datos electrónicas y la selección del estudio se realizó de acuerdo con los criterios de elegibilidad preestablecidos. En la revisión se incluyeron cuatro estudios que evaluaban la eficacia de los betacarotenos en la leucoplasia oral en comparación con el placebo; tres de los cuales fueron asignados para el análisis cuantitativo. Los datos fueron extraídos, tabulados, su calidad evaluada y analizados estadísticamente. Resultados: El metanálisis reveló que al comparar la resolución clínica, el grupo de betacaroteno fue favorecido en comparación con el placebo, con una diferencia estadísticamente significativa. Sin embargo, un metaanálisis que comparó los grupos de betacaroteno y placebo con respecto a la transformación maligna como resultado primario no mostró ningún beneficio significativo. Además, los resultados mostraron evidencia de seguridad de betacaroteno. Conclusión: La calidad general de la evidencia sobre la eficacia del betacaroteno en el tratamiento de la leucoplasia oral no es alta. Sin embargo, dada la obvia seguridad de este agente, los datos sugieren que podría tener un efecto prometedor en la mejora clínica de las lesiones de leucoplasia oral. Sin embargo, no se encontraron pruebas que respalden sus beneficios en la reducción del riesgo de transformación maligna en estas lesiones. Por lo tanto, se recomiendan ensayos clínicos aleatorios bien diseñados a largo plazo.

A pharmacokinetic-pharmacodynamic assessment of oral antibiotics for pyelonephritis.

Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs ≥ 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC ≤ 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC ≤ 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs ≥ 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed.

Ischemic stroke in patients previously anticoagulated for non-valvular atrial fibrillation: Why does it happen? / Acidente vascular cerebral isquémico em doentes previamente anticoagulados por fibrilhação auricular não valvular: por que acontece?

INTRODUCTION: Oral anticoagulants have proved to be highly effective in preventing atrial fibrillation (AF)-related strokes. The occurrence of stroke despite oral anticoagulation is unexpected and little is known about the mechanisms responsible. The aim of this study was to assess possible mechanisms for stroke occurrence, such as poor treatment adherence and inappropriate dosage, in patients chronically anticoagulated for AF. METHODS: We performed a prospective observational study of 60 consecutive patients with non-valvular AF, chronically medicated with an oral anticoagulant and admitted due to ischemic stroke. Treatment adherence was assessed through the Brief Medication Questionnaire (BMQ) and the Medição da Adesão ao Tratamento (MAT) scales. Patient characteristics, stroke etiology, and appropriacy of anticoagulant dosage were also assessed. RESULTS: Patients' mean age was 78.6±8.0 years, and 51.7% were male. Overall, the proportion of patients with good adherence to anticoagulants was 63.3%. Adherent patients were more frequently illiterate (26.3% vs. 4.5%, p=0.012). The proportion of patients under vitamin K antagonists (VKAs) with good treatment adherence was significantly higher than that of patients under novel oral anticoagulants (NOACs) (83.3% vs. 54.8%, respectively, for BMQ, p=0.035). However, 91.7% of patients under VKAs presented an admission INR <2. Subtherapeutic prescriptions were found in 43% of patients under NOACs. CONCLUSION: In the majority of patients, stroke occurrence despite chronic anticoagulation appears to be explained by subtherapeutic dosage, poor treatment adherence or non-cardioembolic etiology, and not by inefficacy of the anticoagulants.

Determination of Mirabegron in rat plasma by UPLC-MS/MS after oral and intravenous administration

SUMMARY Mirabegron is a kind of β3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3→379.6, m/z 326.4→121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.

RESUMO Mirabegron é um tipo de agonista do receptor adrenérgico beta 3 que demonstra eficácia no tratamento de bexiga hiperativa. Nesta pesquisa, o método UPLC-MS/MS é desenvolvido e validado para o estudo da farmacocinética mirabegron em ratos. Um método de precipitação de proteínas é aplicado para a preparação de amostras com acetonitrilo. 397.3 → 379.6 M / Z, M / Z 326.4 → 121.0 para mirabegron, tolterodina (IS), respectivamente, para o íon positivo foi realizado para quantificação. O método é fiável e reprodutível em nosso estudo (precisão intradia ≤ 11,06%; precisão entredia ≤ 11.43%), com curvas de concentração linear de 5 a 2 ng/ml (R2 > 0,999). Estudos de estabilidade demonstraram que mirabegron permanece estável sob uma variedade de condições de armazenamento. Este método foi aplicado com sucesso para a determinação de mirabegron em ratos após administração oral e intravenosa.

Clinical study on treatment of radiation proctitis with Bupi-Qingchang recipe combined with Chinese herbal enema / 国际中医中药杂志

Objective To evaluate the efficacy of Bupi-Qingchang recipe combined with traditional Chinese medicine enema on the patients with radiation proctitis.Methods Eighty patients with radioactive proctitis who met the inclusion criteria were randomly divided into two groups,40 in each group.The control group was treated with western medicine combined with enema,and the observation group was treated with oral spleen and clearing spleen combined with traditional Chinese medicine enema.Symptoms were scored before and after treatment from abnormal sensation of bowel movement,blood in stool,stool traits and frequency,abdominal pain;TNF-α,IL-8,IL-6,IL-10 levels were detected by ELISA.The intestinal mucosal healing and recurrence were observed by microscopy.Results After treatment,the serum TNF-α (1.18 ± 0.61 ng/ml vs.1.78 ± 0.66 ng/ml,t=4.860),IL-6 (2.52 ± 0.75 ng/ml vs.3.02 ± 0.81 ng/ml,t=3.297),IL-8 (2.51 ± 0.68 ng/ml vs.3.01 ± 0.82 ng/ml,t=3.417),IL-10 (0.56 ± 0.25 ng/ml vs.0.89 ± 0.29 ng/ml,t=6.275) in the observation group were significantly lower than those in the control group (P＜0.01).The total scores of abdominal pain,blood in the stool,stool characteristics and frequency,abnormal feeling of defecation and symptoms were significantly lower in the observation group than in the control group (t values were 8.108,2.085,4.965,7.865,9.586,P＜0.01 or P＜0.05).The total effective rate was 92.5％ (37/40) in the observation group and 67.5％ (27/40) in the control group.The difference between the two groups was statistically significant (x2=7.813,P＜0.01).The intestinal mucosa of the observation group was treated.The healing rate was significantly better than that of the control group (x2=15.535,P＜0.01),and the recurrence rate was significantly lower than that of the control group (x2=10.912,P＜0.01).Conclusions The Bupi-Qingchang recipe combined with traditional Chinese medicine enema can improve the clinical symptoms of patients with radiation proctitis,reduce inflammation,reduce recurrence and improve curative effect.