RESUMO
INTRODUCTION: Spontaneous intracerebral haemorrhage associated with oral anticoagulants (ICH-OAC) has a high mortality rate. The emergence of new anticoagulant drugs and reversal protocols increases interest in this entity. OBJECTIVES: The main objective is to determine the mortality rate in patients with ICH-OAC (early, in-hospital, global) in our health area and to analyse the main variables related to it. The secondary objective is to determine the efficacy of anticoagulation reversal therapies (ART) as reflected by radiological expansion of the haematoma and the functional prognosis. PATIENTS AND METHODS: A prospective observational study that introduced a protocol aimed at the management of patients with ICH-OAC. It included general measures and neuromonitoring, individualised administration of ART, cranial tomography and a six-month follow-up. Data on the drugs prescribed in the area during this period, mortality and functional prognosis were collected. A bivariate and logistic regression study was designed to investigate mortality-related variables. RESULTS: Forty-nine patients were included over three years; of these, 71.4% received ART. Mortality was 16.3% (first 24 hours), 53.1% (admission) and 61.2% (180 days). Lower survival was observed among patients with higher baseline scores on the National Institutes of Health Stroke Scale (NIHSS) (p < 0.0001), creatinine value (p = 0.02), International Normalised Index (p = 0.048), bleeding volume (p = 0.008), hydrocephalus (p = 0.015) and acenocoumarol intake (p = 0.030). Patients who did not receive ART had a greater rate of early mortality (p = 0.003). The only variable independently related to overall mortality was the baseline NIHSS score (odds ratio = 1.282; 95% confidence interval: 1.023-1.608; p = 0.031). CONCLUSIONS: ICH-OAC has a high mortality rate, related to the use of acenocoumarol and regardless of the initial clinical situation. A lower rate of early mortality was found among patients who received ART.
TITLE: Mortalidad en pacientes con hemorragia intracerebral asociada a anticoagulación oral. Eficacia de un protocolo de reversión y seguimiento clínico (proyecto HIC-ACO).Introducción. La hemorragia intracerebral espontánea asociada a anticoagulantes orales (HIC-ACO) presenta una elevada mortalidad. La aparición de nuevos fármacos anticoagulantes y protocolos de reversión aumenta el interés por esta entidad. Objetivos. El objetivo principal es determinar la tasa de mortalidad en pacientes con HIC-ACO (precoz, hospitalaria, global) en nuestra área sanitaria y analizar las principales variables relacionadas. El objetivo secundario es determinar la eficacia de las terapias de reversión de la anticoagulación (TRA), reflejada por la expansión radiológica del hematoma y el pronóstico funcional. Pacientes y métodos. Estudio prospectivo observacional que introdujo un protocolo dirigido al manejo de pacientes con HIC-ACO. Incluyó medidas generales y neuromonitorización, administración individualizada de TRA, tomografía craneal y seguimiento durante seis meses. Se recogieron los fármacos prescritos en el área durante este período, mortalidad y pronóstico funcional. Se diseñó un estudio bivariante y regresión logística para investigar variables relacionadas con la mortalidad. Resultados. Se incluyó a 49 pacientes durante tres años; de ellos, un 71,4% recibió TRA. La mortalidad fue del 16,3% (primeras 24 horas), el 53,1% (ingreso) y el 61,2% (180 días). Se observó una menor supervivencia entre pacientes con puntuaciones basales mayores en la National Institutes of Healt Stroke Scale (NIHSS) (p lower than 0,0001), valor de creatinina (p = 0,02), índice internacional normalizado (p = 0,048), volumen hemorrágico (p = 0,008), hidrocefalia (p = 0,015) y toma de acenocumarol (p = 0,030). Los pacientes que no recibieron TRA tuvieron una mayor mortalidad precoz (p = 0,003). La única variable relacionada con la mortalidad global de forma independiente fue la puntuación en la NIHSS basal (odds ratio = 1,282; intervalo de confianza al 95%: 1,023-1,608; p = 0,031). Conclusiones. La HIC-ACO presenta una elevada mortalidad, relacionada con la toma de acenocumarol y de forma independiente con la situación clínica inicial. Se comprobó una menor tasa de mortalidad precoz entre pacientes que recibieron TRA.
Assuntos
Anticoagulantes/efeitos adversos , Reversão da Anticoagulação , Antídotos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/mortalidade , Protocolos Clínicos , Inibidores do Fator Xa/efeitos adversos , Feminino , Seguimentos , Mortalidade Hospitalar , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neuroimagem , Estudos Prospectivos , Índice de Gravidade de Doença , Centros de Atenção Terciária/estatística & dados numéricos , Tromboembolia/epidemiologia , Tromboembolia/prevenção & controle , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vitamina K/antagonistas & inibidoresRESUMO
This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 µg, 200 µg, 400 µg (via Genuair®*), formoterol 12 µg (via Aerolizer®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0-12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12-24, FEV1 normalised AUC0-24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0-12 vs placebo (p<0.0001). FEV1 normalised AUC12-24, FEV1 normalised AUC0-24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p<0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 µg vs 100 µg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 µg and 400 µg as suitable doses for further investigation in Phase III trials.
Assuntos
Broncodilatadores/uso terapêutico , Etanolaminas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Administração por Inalação , Idoso , Área Sob a Curva , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etanolaminas/administração & dosagem , Etanolaminas/efeitos adversos , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Resultado do Tratamento , Tropanos/administração & dosagem , Tropanos/efeitos adversosRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 µg, 400 µg, 800 µg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 µg; 5, aclidinium 800 µg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t(½) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 µg and 800 µg, similar to the terminal t(½) observed on Day 1 (4.5-5.9 h). Exposure for aclidinium and both metabolites increased with increasing dose, with the increase in exposure being less than dose proportional between the 400 µg and 800 µg doses. Overall, all doses of aclidinium were safe and well tolerated throughout the study. Pharmacokinetic steady state was reached for aclidinium and both metabolites within the 7-day treatment period for all doses tested. Aclidinium bromide exhibited time-independent PK following dosing to steady state, indicating that similar concentration versus time profiles will occur after repeated administration at the same dose and frequency.
Assuntos
Antagonistas Muscarínicos/administração & dosagem , Tropanos/administração & dosagem , Adolescente , Adulto , Cromatografia Líquida , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Método Simples-Cego , Espectrometria de Massas em Tandem , Fatores de Tempo , Tropanos/efeitos adversos , Tropanos/farmacocinética , Adulto JovemRESUMO
5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKα by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Autofagia , Fluoruracila/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD. METHODS: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV(1)] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900microg and placebo with a washout period between doses. The primary outcome was area under the FEV(1) curve over the 0-24h time interval. RESULTS: Seventeen patients with COPD were studied. Mean FEV(1) over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900microg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV(1) were detected 15min post-dose for aclidinium bromide 300 and 900microg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation. CONCLUSION: Aclidinium bromide 100-900microg produced sustained bronchodilation over 24h in patients with COPD.
Assuntos
Broncodilatadores/farmacocinética , Volume Expiratório Forçado/efeitos dos fármacos , Antagonistas Muscarínicos/farmacocinética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Métodos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tropanos/administração & dosagem , Tropanos/efeitos adversosRESUMO
Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400microg), placebo, or open-label tiotropium (18microg) for 4 weeks. Spirometric measurements were performed at 22-24h after the first dose and then at weekly intervals, and from 0.5 to 6h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200microg and 400microg significantly increased trough FEV(1) on day 29 versus baseline. During the first 6h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV(1) was 3h for aclidinium 100-400microg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24h and was well tolerated during this short-term study. Based on these data, aclidinium 200microg was selected as the investigational dose for future clinical trials in COPD.
Assuntos
Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tropanos/efeitos adversos , Capacidade Vital/efeitos dos fármacosRESUMO
The Genuair inhaler is a new multidose dry powder inhaler for the delivery of aclidinium bromide - a novel, long-acting, muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to assess the inspiratory flow characteristics through Genuair in patients with moderate or severe COPD. Using a three-period cross-over design, 48 patients were randomised to inhale placebo powder through Genuair, HandiHaler A (slow, deep inhalation as per manufacturer's instructions) or HandiHaler B (fast, forceful inhalation). Three measurements of peak inspiratory flow (PIF), 10min apart, were recorded for each method of administration. The highest and average PIFs for the three attempts (mean+/-standard deviation) generated through the Genuair inhaler were 97.7+/-15.7 and 92.0+/-15.4L/min, respectively. Furthermore, 97% of inhalations with the Genuair inhaler were successful (activation of trigger threshold mechanism) and optimal (PIF> or =45L/min). The highest and average PIFs generated through HandiHaler A and B were significantly lower than with the Genuair inhaler. In conclusion, patients with moderate or severe COPD were able to generate sufficient inspiratory airflow through the Genuair inhaler to reliably inhale the full dose and reset the inhaler.
Assuntos
Inaladores Dosimetrados , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Doença Aguda , Administração por Inalação , Idoso , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pós/administração & dosagemRESUMO
OBJECTIVE: Aclidinium bromide is a novel antimuscarinic being developed for the treatment of chronic obstructive pulmonary disease. The objective of this Phase I study was to determine the maximum tolerated dose (MTD) as well as the tolerability, safety and pharmacokinetics of aclidinium in healthy subjects. MATERIALS AND METHODS: 16 healthy subjects were randomized to receive 5 single ascending doses of aclidinium 600 - 6,000 microg or placebo inhaled via dry powder inhaler, with 7 day washouts. Safety measurements included adverse events (AEs), physical examination, vital signs, pupillometry examination, clinical laboratory tests, and 12-lead electrocardiogram. Pharmacokinetic parameters of aclidinium and its metabolites were assessed. RESULTS: The incidence of AEs was comparable between aclidinium and placebo at all doses. Most AEs were mild to moderate with no dose-related or anticholinergic/cardiac AEs. At doses >or= 2,400 microg, only 13 AEs were considered treatment related. Aclidinium (600 - 6,000 microg) did not produce function-limiting or severe AEs in >or= 50% of subjects; hence, the prospectively-defined MTD was not established. Aclidinium was rapidly converted in plasma into alcohol and carboxylic acid metabolites, and was no longer detectable after 3 hours post-dose for all doses. At lower doses, aclidinium was quantifiable only up to 1 hour post-dose in the majority of subjects. Maximum plasma concentrations for aclidinium were reached within 5 - 7 minutes (all doses) and declined rapidly. Mean elimination half-lives of aclidinium > 2,400 microg were approximately 1 hour. AUC and Cmax increased proportionately up to 4,800 microg. CONCLUSIONS: Aclidinium appears to be safe and well tolerated in single doses of 600 - 6,000 microg.
Assuntos
Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Tropanos/efeitos adversos , Tropanos/farmacocinética , Administração por Inalação , Adulto , Idoso , Área Sob a Curva , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Método Simples-Cego , Tropanos/administração & dosagemRESUMO
AIM: The aim of this study was to correlate the morphologic and microbiologic findings of the post mortem biopsies of a series of pediatric patients. MATERIAL AND METHODS: A complete morphologic study of all the organs of the patients included in the study was performed. In the pulmonary samples provided by the pathologist, the presence of aerobic and anaerobic microorganisms and fungi were determined. RESULTS: Ninety-three pulmonary biopsies corresponding to 77 dead patients (47 infants and 30 fetuses) were undertaken. Forty-five patients showed pulmonary histology of infectious processes. The concordance between the morphology and the microbiologic culture was of 66.2%. The microorganisms most frequently isolated were gram positive cocci (46.4%) followed by gram negative bacillus (30.4%). CONCLUSIONS: Although post mortem pulmonary tissue cultures should be interpreted with caution without first relating these with the morphologic findings and the clinical characteristics of the patient, a statistically significant agreement was observed between the anatomo-pathological study and the microbiologic findings.