RESUMEN
BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.
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Aminopiridinas/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Antagonistas del Receptor de Estrógeno/administración & dosificación , Fulvestrant/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Trastuzumab/administración & dosificación , Anciano , Aminopiridinas/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Argentina , Australia , Bencimidazoles/efectos adversos , Brasil , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Antagonistas del Receptor de Estrógeno/efectos adversos , Europa (Continente) , Femenino , Fulvestrant/efectos adversos , Humanos , Persona de Mediana Edad , América del Norte , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , República de Corea , Transducción de Señal , Factores de Tiempo , Trastuzumab/efectos adversosRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of shortened 8-week regimen of ledipasvir/sofosbuvir (LED/SOF) combination therapy in treatment-naïve children without cirrhosis aged 4-10 years of age with chronic hepatitis C virus (HCV) infection. STUDY DESIGN: This observational single arm prospective study included 30 treatment-naïve children (20 males) with proved chronic HCV fulfilling inclusion criteria. Their body weights ranged from 17 to 26 kg. Four patients were excluded from the study. All the included children received a single oral dose of LED/SOF 45/200 mg for 8 weeks. Body weight, HCV-RNA, complete blood count, and liver function tests were monitored at 0, 2, 4, and 8 weeks and sustained virologic response was evaluated after 12 weeks after treatment (SVR12). The emergence of any side effects was also monitored. RESULTS: The most common risk factor (53.3%) was an parent or sibling with HCV infection. Twenty-nine patients (96.7%) were negative for HCV-RNA by week 2 of treatment and 1 patient became negative by week 4. The end of treatment response and SVR12 were 100%. Transaminases levels declined and returned to normal levels by week 2. Major side effects were fatigue in 90% (27/30) and headache in 76.7% (23/30). Side effects were minimal, tolerable, and did not interfere with daily activity or necessitate treatment discontinuation. CONCLUSIONS: A shortened 8-week regimen of LED/SOF (45/200 mg) is safe and effective with 100% SVR12 in treatment-naïve children with cirrhosis aged 4-10 years with chronic HCV infection genotype 4.
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Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Niño , Preescolar , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/virología , Humanos , Masculino , Estudios Prospectivos , Sofosbuvir , Factores de Tiempo , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/efectos adversosRESUMEN
INTRODUCTION AND OBJECTIVES: Four regimens are recommended for treating hepatitis C (HCV) genotype 1 infection. Study aims were to (1) compare frequencies of contraindicated drug interactions (XDDIs) when each HCV regimen is added to medication profiles of HCV-monoinfected patients, (2) quantify the proportion of patients with XDDIs to all four regimens and (3) determine covariates independently associated with having a XDDI to all four regimens. MATERIALS AND METHODS: A cross-sectional study was performed within Upstate New York Veterans Healthcare Administration. INCLUSION CRITERIA: (1) age ≥18 years, (2) HCV monoinfection and (3) available medication list. Data extracted were: demographics, comorbidities, and medication list. Primary outcome was XDDIs involving patient's home medications and each HCV regimen. University of Liverpool drug interaction website was used to define XDDIs. Two-way comparisons of regimens were performed using McNemar's test where p<0.0083 was considered statistically significant. Multivariate regression analyses were performed to determine predictors. RESULTS: Of the 4047 subjects, mean±standard deviation age was 59.8±7.6. Median (interquartile range) number of medications used was 7 [4-11]. Frequencies of XDDIs after the addition of each regimen ranged from 2.8% to 17.8% and were mostly statistically different from one another. There were 95 (2.3%) patients with XDDIs to all four regimens. Predictors of having XDDIs to all four regimens were ≥6 medications and HCV infection ≥10 years. CONCLUSION: The frequencies of XDDIs varied between HCV regimens. Number of medications and duration of HCV infection were predictors of having XDDIs to all four regimens.
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Antivirales/efectos adversos , Contraindicaciones de los Medicamentos , Interacciones Farmacológicas , Hepatitis C Crónica/tratamiento farmacológico , Anciano , Ansiolíticos/efectos adversos , Antiasmáticos/efectos adversos , Anticoagulantes/efectos adversos , Anticonvulsivantes/efectos adversos , Antidepresivos/efectos adversos , Antieméticos/efectos adversos , Antihipertensivos/efectos adversos , Antipsicóticos/efectos adversos , Bencimidazoles/efectos adversos , Benzofuranos/efectos adversos , Carbamatos/efectos adversos , Estudios Transversales , Suplementos Dietéticos/efectos adversos , Combinación de Medicamentos , Femenino , Fluorenos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Polifarmacia , Pirrolidinas/efectos adversos , Quinoxalinas/efectos adversos , Sofosbuvir/efectos adversos , Sulfonamidas/efectos adversos , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/análogos & derivados , Veteranos , Vitaminas/efectos adversosRESUMEN
We report for the first time the efficiency and safety of a 49-month compassionate use of the microsomal transfer protein inhibitor lomitapide in a child with homozygous familial hypercholesterolemia. On average, 20 mg of lomitapide caused a 37% reduction in low-density lipoprotein cholesterol levels on top of ezetimibe and atorvastatin. The drug was well tolerated with no changes in liver enzymes and occurrence of steatosis on hepatic ultrasound. The patient presented adequate growth and sexual maturation. Nonetheless, there was progression in either subclinical atherosclerotic carotid or aortic valve diseases. Further studies are necessary to test the impact and safety of lomitapide in children with homozygous familial hypercholesterolemia.
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Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Homocigoto , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Seguridad , Niño , Preescolar , Femenino , Humanos , Hiperlipoproteinemia Tipo II/genética , Resultado del TratamientoRESUMEN
INTRODUCTION: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelminthic action. A very limited number of drugs are available for the treatment of some zoonotic helminth infections, such as neurocysticercosis and echinococcosis. More recent work has expanded oxfendazole's nonclinical safety profile and demonstrated its safety and bioavailability in healthy human volunteers, thus advancing the possibility of a new and greatly needed option for antiparasitic treatment of geohelminths and tissue parasites. Areas covered: The present article reviews evidence supporting the safety and efficacy of oxfendazole against both gut and tissue dwelling helminths in animals, as well as more recent safety and pharmacokinetic data supporting its potential for use in human parasitoses. Expert commentary: The pharmacokinetics, safety, and wide spectrum of efficacy of oxfendazole are consistently demonstrated in intestinal helminth infections of animals as well as in tissue dwelling larval cestode and trematode infections in diverse animal species. Now supported by first-in-human safety and pharmacokinetic data, oxfendazole becomes a promising alternative to the limited portfolio of antiparasitic drugs available to treat helminthic diseases of humans.
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Antihelmínticos/uso terapéutico , Bencimidazoles/uso terapéutico , Helmintiasis/tratamiento farmacológico , Animales , Antihelmínticos/efectos adversos , Antihelmínticos/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Semivida , Helmintiasis/parasitología , Helmintiasis Animal/tratamiento farmacológico , Helmintiasis Animal/parasitología , Humanos , Zoonosis/tratamiento farmacológico , Zoonosis/parasitologíaRESUMEN
INTRODUCTION AND AIM: Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited. OBJECTIVE: Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF. MATERIAL AND METHODS: Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed. RESULTS: Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred. CONCLUSIONS: Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Ribavirina/uso terapéutico , Simeprevir/uso terapéutico , Sofosbuvir/uso terapéutico , Uridina Monofosfato/análogos & derivados , Anciano , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Ribavirina/efectos adversos , Simeprevir/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/uso terapéutico , Carga ViralRESUMEN
Arterial hypertension is a highly manageable disorder due to a variety of drugs available for its treatment. Since the late 1990s, angiotensin II receptor blockers have been widely prescribed, achieving appropriate control in patients' blood pressure. Few cases of serious adverse effects have been reported to date. Here, we present a case of acute hepatocellular injury secondary to candesartan administration. Further studies should be performed in patients who present with this adverse effect, in order to prevent more serious outcomes.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Antihipertensivos/uso terapéutico , Bencimidazoles/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Hipertensión/tratamiento farmacológico , Tetrazoles/efectos adversos , Adulto , Amlodipino/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bencimidazoles/administración & dosificación , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Relación Dosis-Respuesta a Droga , Humanos , Hipertensión/sangre , Pruebas de Función Hepática , Masculino , Tetrazoles/administración & dosificaciónRESUMEN
This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514-523).
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Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/etiología , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Alanina Transaminasa/sangre , Ácidos Aminoisobutíricos , Bencimidazoles/efectos adversos , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/sangre , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efectos adversos , Sulfonamidas/efectos adversos , Respuesta Virológica SostenidaRESUMEN
INTRODUCTION: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival. MATERIALS AND METHODS: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant. RESULTS: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock. CONCLUSION: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Cirrosis Hepática/cirugía , Trasplante de Hígado , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida , Anciano , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/mortalidad , Hepatitis C/virología , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/virología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
ABSTRACT Background and aim. The combination of Sofosbuvir (SOF) and Ledipasvir (LDV) has been lead to considerable enhancement of treatment of hepatitis C virus (HCV) genotype 1 infection. A meta-analysis of the currently available studies was undertaken with the aim to evaluate the antiviral efficacy of SOF/LDV therapy for 12 or 24 weeks with or without Ribavirin (RBV) in patients with HCV genotype 1 infection. Material and methods. In this meta-analysis, we searched databases including PubMed, Scopus, Science Direct and Web of Science using appropriate keywords. All papers which evaluated the efficacy of combination therapy of SOF/LDV with or without RBV for 12 or 24 weeks among patients with HCV genotype 1 infection were included. Results. The 20 published articles were assessed for eligibility and finally 10 articles pooling 2248 participants were included in this meta-analysis. Pooled SVR12 for four SOF/LDV regimens were 95% (95%CI = 93%-97%) for 12 weeks of treatment with SOF/LDV, 97% (95%CI = 95%-98%) for 24 weeks of treatment with SOF/LDV, 96% (95%CI = 94%-97%) for 12 weeks of treatment with SOF/ LDV/RBV and 98% (95%CI = 97%-99%) for 24 weeks of treatment with SOF/LDV/RBV. Only in treatment regimen of SOF/LDV for 12 weeks, cirrhosis had a significant effect on the SVR12 (OR = 0.21, 95%CI = 0.07-0.66). Furthermore, NS5A resistance-associated substitutions at baseline were associated with decrease in the rate of SVR (OR = 0.31, 95%CI = 0.2-0.5). Conclusions. The Interferon-free regimen of SOF/LDV for 12 or 24 weeks with or without RBV is highly effective for treatment of patients with HCV genotype 1 infection.
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Humanos , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Hepatitis C/tratamiento farmacológico , Hepacivirus/efectos de los fármacos , Fluorenos/uso terapéutico , Sofosbuvir/uso terapéutico , Antivirales/efectos adversos , Ribavirina/uso terapéutico , Factores de Tiempo , Bencimidazoles/efectos adversos , Distribución de Chi-Cuadrado , Oportunidad Relativa , Resultado del Tratamiento , Hepatitis C/diagnóstico , Hepatitis C/virología , Hepacivirus/genética , Quimioterapia Combinada , Fluorenos/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , GenotipoAsunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Distribución de Chi-Cuadrado , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Ribavirina/uso terapéutico , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND AIM: Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1. METHODS: We performed a systematic review followed by a pairwise meta-analysis including randomized controlled trials that reported efficacy (rapid virological response, sustained virological response at 4 and 12 weeks post-treatment (SVR4 and 12), and viral relapse) and safety outcomes (any AE, serious AE, discontinuation owing to AE, anemia, and rash). It was performed a subgroup analysis evaluating the SVR12 including only cirrhotic patients. Results were reported as risk ratios (RR) and with 95% confidence intervals (95% CI). RESULTS: Seven randomized controlled trials were analyzed. LED/SOF with RBV showed a worse safety profile when compared with LED/SOF without RBV for the following outcomes: any AE (RR 0.56 [95% CI 0.46-0.69]), anemia (RR 0.08 [95% CI 0.04-0.17]), and rash (RR 0.35 [95% CI 0.19-0.65]). No significant differences were observed regarding serious AE, rapid virological response, SVR4, SVR12, or viral relapse. The subgroup analysis did not show significant differences between either treatment groups. CONCLUSION: Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.
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Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Bases de Datos Bibliográficas , Quimioterapia Combinada , Fluorenos/efectos adversos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Resultado del TratamientoRESUMEN
En los últimos años han surgido algunas investigaciones y guías de práctica clínica relacionadas con el diagnóstico y tratamiento de las dislipidemias, que aportaron nuevos conocimientos (y controversias) sobre dicha problemática. En este resumen se describen, en primer lugar, las características de las "nuevas guías" norteamericanas para el manejo del colesterol publicadas a fines de 2013 y se comparan con las recomendaciones tradicionales. En segundo lugar, se analizan los últimos estudios que evaluaron el impacto cardiovascular de otros fármacos hipolipemiantes (ezetimibe y ácido nicotínico) en pacientes en prevención secundaria tratados con estatinas. Finalmente, se mencionan las nuevas drogas hipolipemiantes desarrolladas en los últimos años, como el lomitapide, el mipomersen y los inhibidores de la PCSK9, y se comentan el mecanismo de acción, su eficacia, sus efectos colaterales y los escenarios clínicos en donde podrían utilizarse. (AU)
In recent years, some research and clinical practice guidelines related to the diagnosis and treatment of dyslipidemia, which provided new knowledge (and controversy) about this problem have emerged. In this review, the characteristics of the American "new guidelines" for cholesterol management published by the end of 2013 are described, and they are compared with the traditional recommendations. In addition, recent studies assessing the cardiovascular impact of other lipid-lowering drugs (ezetimibe and nicotinic acid) in patients in secondary prevention treated with statins are analyzed. Finally, new hypolipidemic drugs developed in recent years are mentioned (lomitapide, mipomersen and PCSK9 inhibitors), discussing the mechanism of action, efficacy, side effects and clinical settings where they could be used. (AU)
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Humanos , Bencimidazoles/uso terapéutico , Dislipidemias/tratamiento farmacológico , Ezetimiba/uso terapéutico , Inhibidores de PCSK9/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Niacina/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Colesterol/sangre , Guías de Práctica Clínica como Asunto , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Interacciones Farmacológicas , Dislipidemias/diagnóstico , Ezetimiba/efectos adversos , Ezetimiba/farmacología , Inhibidores de PCSK9/efectos adversos , Inhibidores de PCSK9/farmacología , Hipercolesterolemia/diagnóstico , Hipolipemiantes/efectos adversos , Hipolipemiantes/farmacología , Niacina/efectos adversos , Niacina/farmacologíaRESUMEN
INTRODUCTION: The therapeutic scheme of triclabendazole (TCBZ), the recommended anthelmintic against Fasciola hepatica , involves 10mg/kg of body weight administered in a single dose; however, clinical trials in children are scarce. We evaluated the efficacy and tolerability of 2 schemes of TCBZ. METHODS: Eighty-four Peruvian children with F. hepatica eggs in their stools were allocated into 2 groups: 44 received 2 dosages of 7.5mg/kg each with a 12-h interval (Group I), and 40 received a single 10-mg/kg dose (Group II). Evaluation of efficacy was based on the presence of eggs in stools, and tolerability was based on the presence of symptoms and signs post-treatment. RESULTS: A parasitological cure was obtained in 100% of individuals from Group I and 95% of individuals from Group II. The most common adverse event was biliary colic. CONCLUSIONS: The tested scheme was efficacious and tolerable, and it might be an optimal scheme in the region. To the best of our knowledge, this represents the largest series of children treated with TCBZ in a non-hospital setting.
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Antihelmínticos/administración & dosificación , Bencimidazoles/administración & dosificación , Fascioliasis/tratamiento farmacológico , Adolescente , Animales , Antihelmínticos/efectos adversos , Bencimidazoles/efectos adversos , Niño , Preescolar , Protocolos Clínicos , Esquema de Medicación , Fasciola hepatica , Heces/parasitología , Femenino , Humanos , Masculino , Recuento de Huevos de Parásitos , Perú , Índice de Severidad de la Enfermedad , TriclabendazolRESUMEN
The therapeutic scheme of triclabendazole (TCBZ), the recommended anthelmintic against
: Eighty-four Peruvian children with
: A parasitological cure was obtained in 100% of individuals from Group I and 95% of individuals from Group II. The most common adverse event was biliary colic.
: The tested scheme was efficacious and tolerable, and it might be an optimal scheme in the region. To the best of our knowledge, this represents the largest series of children treated with TCBZ in a non-hospital setting.
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Adolescente , Animales , Niño , Preescolar , Femenino , Humanos , Masculino , Antihelmínticos/administración & dosificación , Bencimidazoles/administración & dosificación , Fascioliasis/tratamiento farmacológico , Antihelmínticos/efectos adversos , Bencimidazoles/efectos adversos , Protocolos Clínicos , Esquema de Medicación , Fasciola hepatica , Heces/parasitología , Recuento de Huevos de Parásitos , Perú , Índice de Severidad de la EnfermedadRESUMEN
UNLABELLED: Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. CONCLUSIONS: This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks.
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Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Fluorenos/efectos adversos , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/efectos adversos , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Sofosbuvir , Resultado del Tratamiento , Uridina Monofosfato/efectos adversos , Adulto JovenRESUMEN
We report the case of a 49-year-old woman with homozygous familial hypercholesterolemia and a complicated cardiovascular history, treated for 5 years with a microsomal triglyceride transfer protein inhibitor in addition to her other lipid-lowering therapy.
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Anticolesterolemiantes/uso terapéutico , Bencimidazoles/uso terapéutico , Proteínas Portadoras/antagonistas & inhibidores , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Alanina Transaminasa/sangre , Anticolesterolemiantes/efectos adversos , Anticoagulantes/uso terapéutico , Aspartato Aminotransferasas/sangre , Bencimidazoles/efectos adversos , Eliminación de Componentes Sanguíneos , Proteínas Portadoras/metabolismo , Colesterol/sangre , Femenino , Hematoma/diagnóstico por imagen , Hematoma/tratamiento farmacológico , Hematoma/etiología , Humanos , Pruebas de Función Hepática , Imagen por Resonancia Magnética , Persona de Mediana Edad , RadiografíaRESUMEN
Oral mucositis (OM) is a common complication of treatments for head and neck cancer, particularly radiotherapy with or without chemotherapy. OM is characterised by oral erythema, ulceration, and pain. The aim of this study was to evaluate the effect of azilsartan (AZT), an angiotensin II receptor antagonist, on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in Syrian hamsters. OM was induced by the intraperitoneal administration of 5-FU on experimental days 1 (60 mg/Kg) and 2 (40 mg/Kg). Animals were pretreated with oral AZT (1, 5, or 10 mg/kg) or vehicle 30 min before 5-FU injection and daily until day 10. Experimental treatment protocols were approved by the Animal Ethics Committee Use/CEUA (Number 28/2012) of the UFRN. Macroscopic analysis and cheek pouch samples were removed for histopathologic analysis. Myeloperoxidase (MPO), Malonyldialdehyde (MDA), interleukin-1 beta (IL-1ß), interleukin-10 (IL-10), and tumour necrosis factor-alpha (TNF-α) were analysed by Enzyme Linked Immuno Sorbent Assay (ELISA). Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), and transforming growth factor (TGF)-α were measured by immunohistochemistry. Analysis of variance followed by Bonferroni's test was used to calculate the means of intergroup differences (p ≤ 0.05). Treatment with 1 mg/kg AZT reduced levels MPO (p<0.01), MDA (p<0.5) and histological inflammatory cell infiltration, and increased the presence of granulation tissue. AZT treatment at 1 mg/kg reduced the TNF-α (p<0.05) and IL-1ß (p<0.05) levels, increased the cheek pouch levels of IL-10 (p<0.01), and upregulated VEGF, FGF, KGF, and TGF-α. Administration of AZT at higher doses (5 and 10 mg/kg) did not significantly reverse the OM. AZT at a dose of 1 mg/kg prevented the mucosal damage and inflammation associated with 5-FU-induced OM, increasing granulation and tissue repair.
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Citocinas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Estomatitis/metabolismo , Animales , Bacteriemia/metabolismo , Bencimidazoles/efectos adversos , Cricetinae , Modelos Animales de Enfermedad , Factor 7 de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Leucocitos/metabolismo , Masculino , Oxadiazoles/efectos adversos , Peroxidasa/metabolismo , Estomatitis/inducido químicamente , Estomatitis/patología , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥ 2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Administración Oral , Anticoagulantes/efectos adversos , Anticoagulantes/economía , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Química Farmacéutica/normas , Química Farmacéutica/tendencias , Dabigatrán , Humanos , Morfolinas/efectos adversos , Morfolinas/uso terapéutico , Rivaroxabán , Tiofenos/efectos adversos , Tiofenos/uso terapéutico , beta-Alanina/efectos adversos , beta-Alanina/análogos & derivados , beta-Alanina/uso terapéuticoRESUMEN
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism resulting in extremely elevated serum levels of LDL-C and premature atherosclerotic cardiovascular disease. Treatment typically involves multiple pharmacologic agents, as well as mechanical filtration using weekly or biweekly LDL apheresis. Despite combination lipid-lowering therapy, LDL-C levels and cardiovascular morbidity and mortality remain unacceptably high in HoFH patients. The European Commission and the US Food and Drug Administration approved the use of lomitapide, a novel medication designed to address this significant unmet need. Lomitapide is an orally administered inhibitor of microsomal triglyceride transfer protein that is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available for the reduction of LDL-C, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol in adult patients with HoFH. The risks of transaminase elevations, hepatic steatosis, and gastrointestinal side effects, and the potential for drug interactions, require vigilant examination of the clinical and laboratory data and patient counseling prior to initiation of lomitapide, as well as regular monitoring during follow-up care. This article highlights important practical considerations for the use of lomitapide in the context of the evaluation and management of a HoFH patient case.