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1.
Orphanet J Rare Dis ; 14(1): 98, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053156

RESUMO

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP. METHODS: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed. RESULTS: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52). CONCLUSIONS: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients. TRIAL REGISTRATION: This study ( NCT02322255 ) was first posted on 23 December, 2014.


Assuntos
Miosite Ossificante/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ossificação Heterotópica/patologia , Inquéritos e Questionários , Adulto Jovem
2.
Orphanet J Rare Dis ; 14(1): 113, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122250

RESUMO

The original version of this article [1] unfortunately included an error to an author's name. Author Maja Di Rocco was erroneously presented as Maja DiRocco.The correct author name has been included in the author list of this Correction article and is already updated in the original article.

3.
Muscle Nerve ; 55(3): 323-332, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27422379

RESUMO

INTRODUCTION: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. RESULTS: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. CONCLUSIONS: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/terapia , Qualidade de Vida , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Neuropatias Amiloides Familiares/psicologia , Análise de Variância , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Estatísticas não Paramétricas , Adulto Jovem
4.
Circ Heart Fail ; 8(3): 519-26, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25872787

RESUMO

BACKGROUND: Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid. METHODS AND RESULTS: This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I-II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea. CONCLUSIONS: Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Miocárdio/metabolismo , Pré-Albumina/metabolismo , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Benzoxazóis/efeitos adversos , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Mutação , Pré-Albumina/química , Pré-Albumina/genética , Dobramento de Proteína , Multimerização Proteica , Estabilidade Proteica , Estrutura Quaternária de Proteína , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
5.
J Peripher Nerv Syst ; 19(2): 104-14, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24738700

RESUMO

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.


Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina/genética , Qualidade de Vida , Inquéritos e Questionários , Atividades Cotidianas , Adulto , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/psicologia , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/fisiologia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Estatística como Assunto
6.
JACC Heart Fail ; 2(2): 113-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24720917

RESUMO

OBJECTIVES: This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. METHODS: Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. RESULTS: The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size-adjusted heart weight (p = 0.04). CONCLUSIONS: Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.


Assuntos
Amiloidose/patologia , Cardiomiopatias/patologia , Insuficiência Cardíaca/patologia , Idoso , Amiloide/metabolismo , Amiloidose/metabolismo , Amiloidose/fisiopatologia , Autopsia , Biomarcadores/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Espectrometria de Massas , Pré-Albumina/metabolismo , Volume Sistólico/fisiologia
7.
J Cardiovasc Transl Res ; 6(6): 1011-20, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24101373

RESUMO

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Amiloide/genética , Benzoxazóis/uso terapêutico , Mutação , Pré-Albumina/genética , Adulto , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Benzoxazóis/efeitos adversos , Progressão da Doença , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
8.
J Neurol ; 260(11): 2802-14, 2013 11.
Artigo em Inglês | MEDLINE | ID: mdl-23974642

RESUMO

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/uso terapêutico , Pré-Albumina/metabolismo , Adulto , Idoso , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/psicologia , Progressão da Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Cooperação Internacional , Masculino , Metionina/genética , Pessoa de Meia-Idade , Mutação/genética , Pré-Albumina/genética , Qualidade de Vida , Fatores de Tempo , Valina/genética , Adulto Jovem
9.
Curr Med Res Opin ; 29(1): 77-84, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23193943

RESUMO

UNLABELLED: Abstract Background: Transthyretin (TTR) amyloidosis - the most common type of hereditary amyloidosis - also has an acquired form and is observed in geographically dispersed populations. TTR amyloidosis is marked by considerable clinical heterogeneity, and the main phenotypes are neurologic and cardiovascular. METHODS: THAOS is an international, noninterventional, longitudinal, observational registry designed to evaluate overall survival in patients, better understand genotype-phenotype relationships and the natural history of TTR amyloidosis, and evaluate the effects of liver transplantation and other treatments on disease progression in TTR amyloidosis. All individuals with a confirmed TTR mutation with or without a diagnosis of TTR amyloidosis and patients with wild-type TTR amyloidosis are eligible to be enrolled in the registry. PURPOSE: To describe the design and methodology of the recently established registry. Procedures for data collection are outlined and a minimum set of assessments for the standard evaluation of all subjects with TTR amyloidosis is described. Demographic information, TTR genotype, medical history, family history of the disease, and transplant history are assessed at baseline. On return visits, signs and symptoms of the disease are evaluated, general examinations are conducted, and laboratory data, measures of neurologic and cardiovascular function, and quality of life are assessed according to the standard of care for patients. Visits on at least a biannual basis are recommended. The registry will remain open for a period of at least 10 years. RESULTS: The initial experience suggests that the registry is characterized by a comprehensive set of data elements which can be completed by providers from the various clinical backgrounds who administer care to individuals with TTR amyloidosis. CONCLUSION: As of September 2011, 30 centers in 15 of the 19 countries participating in the THAOS registry have enrolled 975 patients. Such data provide a representative sample of the global TTR amyloidosis patient population, including asymptomatic TTR variant carriers, which can inform the natural history of the disease and offer the potential to evaluate novel therapeutic modalities in diverse patient subpopulations.


Assuntos
Neuropatias Amiloides Familiares , Coleta de Dados , Sistema de Registros , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino
10.
Neurology ; 79(8): 785-92, 2012 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-22843282

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. RESULTS: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. CONCLUSIONS: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Pré-Albumina/genética , Adolescente , Adulto , Idoso , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Benzoxazóis/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Polimorfismo de Nucleotídeo Único , Pré-Albumina/metabolismo , Qualidade de Vida , Índice de Gravidade de Doença
11.
Medicine (Baltimore) ; 87(6): 319-28, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19011503

RESUMO

Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias. The effect of inhaled long-acting beta2-agonists (LABAs) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease (COPD) in 2 double-blind randomized clinical trials. The pretreatment arrhythmia occurrence frequency in these patients was also described. In this analysis, 24-hour Holter monitoring data were pooled from 2 identically designed Phase III trials. Patients were randomized to LABA treatment or placebo for 12 weeks: a) nebulized arformoterol 15 microg BID, b) 25 microg BID, or c) 50 microg QD; d) salmeterol metered dose inhaler 42 microg BID; or e) placebo. The 24-hour Holter monitoring was performed pretreatment and at Weeks 0 (first day of dosing), 6, and 12. We assessed the proportion of patients with each of 4 arrhythmias: atrial tachycardia, atrial fibrillation/flutter, and "nonsustained"; (4-10 beats) and "sustained"; (>10 beats) ventricular tachycardia. There were 5226 Holter recordings in 1429 treated patients. At baseline, there was a low frequency of occurrence of atrial fibrillation/flutter (0.1%), nonsustained ventricular tachycardia (3.1%), and >10 beat ventricular tachycardia (0.3%). Atrial tachycardia occurred frequently (41.8%). The proportion of patients with treatment-emergent atrial tachycardia ranged from 27% to 32% and was non-significantly higher, by approximately 2%-5% (p = 0.70), in the LABA groups compared with the placebo group. The rates of the other more serious arrhythmias did not increase with LABA treatment and were similar to placebo. All treatment groups (LABA and placebo) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate. In conclusion, in this large cohort of COPD patients with no or stable cardiac comorbidities, a high proportion ( approximately 40%) of patients were observed to have atrial tachycardia before treatment, which increased by 2%-5% with LABA treatment. More serious arrhythmias were infrequent and did not increase with inhaled LABA therapy. LABA administration did not increase mean heart rate.


Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/análogos & derivados , Arritmias Cardíacas/induzido quimicamente , Etanolaminas/efeitos adversos , Etanolaminas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/efeitos adversos , Idoso , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Albuterol/uso terapêutico , Arritmias Cardíacas/complicações , Arritmias Cardíacas/fisiopatologia , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etanolaminas/administração & dosagem , Feminino , Fumarato de Formoterol , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Xinafoato de Salmeterol , Taquicardia/induzido quimicamente , Taquicardia/epidemiologia , Taquicardia/fisiopatologia , Resultado do Tratamento
12.
Am Heart J ; 151(3): 689.e1-689.e10, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16504633

RESUMO

BACKGROUND: Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI. METHODS: In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times. RESULTS: Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor. CONCLUSIONS: This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Angioplastia Coronária com Balão , Anticorpos Monoclonais/uso terapêutico , Doença das Coronárias/terapia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Abciximab , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem
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