RESUMO
BACKGROUND: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-ß, and the PRRs: Toll-like receptor 3, melanoma differentiation-associated gene 5, and retinoic acid-inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. RESULTS: We observed IFN-α/ß deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/ß expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/ß in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection-increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/ß expression and numbers of subepithelial IFN-α/ß-expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/ß expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity.
Assuntos
Asma/imunologia , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica/imunologia , Helicase IFIH1 Induzida por Interferon/biossíntese , Interferon-alfa/imunologia , Interferon beta/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Receptor 3 Toll-Like/imunologia , Adulto , Asma/metabolismo , Asma/patologia , Biópsia , Brônquios/imunologia , Brônquios/metabolismo , Brônquios/patologia , Proteína DEAD-box 58/biossíntese , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon/imunologia , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Masculino , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/patologia , Receptores Imunológicos , Rhinovirus/metabolismo , Índice de Gravidade de Doença , Receptor 3 Toll-Like/biossínteseRESUMO
PURPOSE: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. METHODS: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. RESULTS: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. CONCLUSIONS: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.
Assuntos
Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Glicosaminoglicanos/líquido cefalorraquidiano , Humanos , Iduronato Sulfatase/efeitos adversos , Iduronato Sulfatase/líquido cefalorraquidiano , Iduronato Sulfatase/farmacocinética , Injeções Espinhais , Masculino , Mucopolissacaridose II/sangue , Mucopolissacaridose II/líquido cefalorraquidiano , Mucopolissacaridose II/metabolismoRESUMO
The concept of monoclonal antibodies (mAbs) as pharmacotherapeutics was validated in the mid-1980s with the successful clinical development of the fully murine mAb muromonab-CD3 for prevention of acute organ rejection. However, clinical applications of fully murine mAbs are restricted, owing to the high incidence of serious immune-mediated side effects, particularly upon repeated exposure. The rate and severity of immune-mediated toxicities of these agents were significantly attenuated by the development of mouse/human chimeric, fully human, and humanized mAbs. These refinements in molecular structure allowed repeated, long-term administration, where therapeutically warranted, which, in turn, broadened the scope of indications for this class of therapy. Presently, numerous mAbs are approved or are undergoing clinical evaluation for treatment of oncologic and chronic inflammatory diseases. The current experimental development landscape spans respiratory, metabolic, and central nervous system disorders as well as infectious disease. A consequence of the expanding numbers of mAb indications is concomitant administration of these agents with established small molecule pharmacotherapies, which necessitates a comprehensive understanding of mAb-small molecule drug interactions as well as mAb-mAb interactions. Current knowledge indicates that mAbs do not elicit a direct effect on the metabolic/clearance pathways for small molecular therapeutics. However, the immunomodulatory properties of mAbs can indirectly alter clearance of certain small molecule entities through the attenuation of noncatabolic enzymatic pathways.
Assuntos
Anticorpos Monoclonais/farmacologia , Interações Medicamentosas , Preparações Farmacêuticas/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/imunologia , Anticorpos Monoclonais Murinos/farmacologia , Esquema de Medicação , Humanos , Preparações Farmacêuticas/administração & dosagem , Fatores de TempoRESUMO
The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6 months or older to less than 18 years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18 years, 6 months or older to less than 12 years, and 6 months or older to less than 6 years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6 months or older.
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BACKGROUND: Ustekinumab, a fully human immunoglobulin (Ig) G1K monoclonal antibody directed against the p40 subunit of interleukin (IL)-12/23, has demonstrated efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: To evaluate the effect of IL-12/23 inhibition on immunocompetency by antigen-recall response in a preclinical multiple-dose toxicology study and three single-dose, phase 1 studies. METHODS: Cynomolgus monkeys (Mauritius; n = 32) treated with subcutaneous (s.c.) placebo or ustekinumab 22.5 or 45 mg/kg twice weekly for 26 weeks were assessed for antibody responsiveness to keyhole limpet hemocyanin (KLH). Patients with psoriasis or multiple sclerosis who received a single-dose of placebo (n = 8) or ustekinumab (n = 46) 0.09-4.5 mg/kg intravenous (i.v.) or 0.27-2.7 mg/kg s.c. were assessed by pneumococcal and tetanus antigen challenge. Primary T-cell response was not assessed in humans. RESULTS: Anti-KLH antibody responses in ustekinumab-treated cynomolgus monkeys were comparable to those observed in placebo-treated animals. A normal antibody response (> or = two-fold increase from baseline) to pneumococcal antigen was seen in 34/46 (73.9%) ustekinumab-treated versus 4/8 (50%) placebo-treated patients. A normal antigen-recall response (> or = four-fold increase from baseline) was seen in 12/20 (60%) ustekinumab- and 4/5 (80%) placebo-treated patients following tetanus toxoid exposure. Percentages of circulating immune cells were not affected by ustekinumab treatment. CONCLUSION: Results in nonhuman primates and human patients suggest that ustekinumab treatment does not significantly impair recall humoral immune system functions.
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Anticorpos Monoclonais/farmacologia , Imunidade Humoral/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Hemocianinas/imunologia , Humanos , Macaca fascicularis , Vacinas Pneumocócicas/imunologia , Toxoide Tetânico/imunologia , UstekinumabRESUMO
Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities. The side effect profile of murine Mab therapeutic agents restricted the clinical development of these agents to indications with high morbidity and/or mortality (ie, oncology, graft vs host rejection). Advances in genetic engineering and protein expression technologies resulted in the development of Mabs composed either predominately (ie, mouse/human chimeric, "humanized") or completely (ie, "fully human" Mabs) of the human amino acid sequence. The production of chimeric, humanized, and fully human Mabs significantly reduced the immune-mediated toxicities and expanded the utility for these agents in numerous therapeutic areas, particularly in chronic disorders requiring either long-term administration (ie, rheumatoid arthritis) or treatment upon the flare up of disease (Crohn's disease, psoriasis). This review provides an overview of the molecular, biochemical, and pharmacokinetic properties and clinical development history of Mabs and details how these factors currently affect the scope and design of early clinical development strategies for these drug candidates. Emphasis is placed on the criteria for selecting appropriate subject populations for phase I testing of Mabs.
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Anticorpos Monoclonais , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , HumanosRESUMO
Golimumab is a fully human antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum concentrations of golimumab were determined using a validated enzyme-linked immunosorbent assay method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentrationtime curve appeared to increase in a dose-proportional manner. The median half-life ranged from 7 to 20 days. A 2-compartment population pharmacokinetic model adequately described the pharmacokinetics of golimumab. The following pharmacokinetic parameters (typical value [% coefficient of variation]) were estimated from the population pharmacokinetic model: clearance (CL: 0.40 [10.1%] L/d), volume of distribution in the central compartment (V(c): 3.07 [6.4%] L), intercompartmental clearance (Q: 0.42 [15.5%] L/d), and volume of distribution in the peripheral compartment (V(p): 3.68 [11.8%] L). Interindividual variability of the pharmacokinetic parameters was quantified for CL (44.3%), V(c) (25.5%), Q (44.6%), and V(p) (44.6%). Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on V(c). Golimumab was generally well tolerated. The pharmacokinetics of golimumab appeared to be linear over the dose range evaluated in this study.
Assuntos
Anticorpos Monoclonais/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/sangue , Antirreumáticos/farmacocinética , Área Sob a Curva , Artrite Reumatoide/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Meia-Vida , Humanos , Infusões Intravenosas , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS). METHODS: A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL-12/23 mAb (0.3, 0.75, 1.5, and 3.0 mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration. RESULTS: IL-12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL-12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median Tmax ranged from 9.0 to 16.5 days, and the median T1/2 ranged from 20.2 to 30.9 days. CONCLUSION: Single subcutaneous administrations of IL-12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Subunidade p40 da Interleucina-12/imunologia , Esclerose Múltipla/terapia , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , PlacebosRESUMO
BACKGROUND: We postulated that antibodies to platelet factor 4/heparin complex might contribute to recurrent ischemic events in patients with acute coronary syndrome. METHODS AND RESULTS: We analyzed serum from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary end point (death, myocardial infarction [MI], or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary end point. An ELISA for anti-platelet factor 4/heparin antibodies was performed using 48-hour serum samples. The analyses were done by blinded investigators, and the results were correlated with clinical outcomes. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% versus 11.3%, P=0.011) or MI (21.7% versus 6.2%, P=0.008) than patients who were negative for the antibody. After multiple logistic regression analysis, anti-PF4/heparin antibodies remained a predictor of 30-day death or MI (odds ratio, 4.0; 95% CI, 1.4 to 11.3; P=0.0093) and MI (odds ratio, 4.6; 95% CI, 1.4 to 15.0; P=0.0108). The antibody was not associated with the composite end point (death, MI, or revascularization) or with death or revascularization alone. CONCLUSIONS: Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of myocardial infarction at 30 days in patients presenting with acute coronary ischemic syndromes. This finding may explain the previous association between thrombocytopenia and adverse events in patients with acute coronary syndrome and may have important implications for the choice of anticoagulant regimens.
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Anticorpos/sangue , Heparina/imunologia , Infarto do Miocárdio/diagnóstico , Isquemia Miocárdica/complicações , Fator Plaquetário 4/imunologia , Doença Aguda , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/mortalidade , Prognóstico , SíndromeRESUMO
Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naïve to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2-4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood-brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8-10 hours and 5.9-6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40-83%). The clear penetration of iduronate-2-sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome.
Assuntos
Iduronato Sulfatase/administração & dosagem , Iduronato Sulfatase/farmacocinética , Administração Intravenosa , Animais , Disponibilidade Biológica , Terapia de Reposição de Enzimas , Feminino , Humanos , Iduronato Sulfatase/líquido cefalorraquidiano , Injeções Espinhais , Macaca fascicularis , Masculino , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/líquido cefalorraquidiano , Proteínas Recombinantes/farmacocinéticaRESUMO
The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.
Assuntos
Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Interleucina-12/imunologia , Subunidades Proteicas/imunologia , Psoríase/imunologia , Psoríase/terapia , Adulto , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Subunidade p40 da Interleucina-12 , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: The PlA2 polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. METHODS: Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 Pl(A1/A1) and 21 PlA1/A2 patients undergoing percutaneous coronary interventions. The affinity of abciximab for the PlA1 and PlA2 receptors was determined with use of transfected cells. RESULTS: Compared with PlA1/A1 homozygotes, PlA1/A2 platelets were less completely inhibited after abciximab bolus (P =.002) and at 24 hours (P =.02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that Pl(A1/A2) platelets were less completely inhibited after abciximab bolus (P =.05). The radiometric abciximab binding assay demonstrated that the PlA1/A2 platelets had fewer baseline fibrinogen receptors than did the PlA1/A1 platelets (P =.04) and more free fibrinogen receptors at 24 hours (P =.008). Cells transfected to express homozygous PlA1 or PlA2 demonstrated a nonsignificant trend (P =.12) for reduced abciximab affinity for PlA2. CONCLUSIONS: PlA1/A2 platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of PlA2-positive platelets may contribute to a less favorable outcome in these patients.
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Anticorpos Monoclonais/metabolismo , Antígenos de Plaquetas Humanas/metabolismo , Plaquetas/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Polimorfismo Genético , Abciximab , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos de Plaquetas Humanas/genética , Plaquetas/metabolismo , Células CHO , Cricetinae , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Integrina beta3 , Masculino , Pessoa de Meia-Idade , TransfecçãoRESUMO
Because of its potential for antigenicity, theoretical concerns related to readministration of abciximab have been raised. We conducted the ReoPro Readministration Registry to assess the efficacy and safety of abciximab readministration. A total of 1,342 patients who underwent percutaneous coronary intervention and who received abciximab for at least a second time were recruited. Safety end points were hypersensitivity reactions, major bleeding, and thrombocytopenia (TCP). Human antichimeric antibody (HACA) titers were determined before and after readministration. Procedural success was 98% and was not influenced by the number of courses of abciximab or the presence of HACA. There were no cases of anaphylaxis. There were 5 minor allergic reactions, none of which required termination of the infusion. Clinically significant bleeding occurred in 31 patients (2.3%), including 1 (0.07%) with intracranial hemorrhage. TCP (<100 x 10(9)/L) developed in 5% of patients; profound TCP (<20 x 10(9)/L) occurred in 2%. In patients who received abciximab within 1 month of a previous treatment (n = 115), the risk of developing TCP and profound TCP was 16.5% and 12.2%, respectively. Having a positive HACA before readministration was not correlated with adverse clinical outcomes or bleeding, but was associated with TCP (14.1% vs 4.4%, p = 0.002) and profound TCP (5.6% vs 1.6%, p = 0.036). Readministration of abciximab can be accomplished without severe allergic responses and with a bleeding and efficacy profile similar to first-time administration. However, the rate of severe and profound TCP is increased relative to first-time administration, particularly when the time between treatments is <30 days or when HACA is present.
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Anticorpos Monoclonais/administração & dosagem , Anticoagulantes/administração & dosagem , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Abciximab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticoagulantes/efeitos adversos , Anticoagulantes/imunologia , Hipersensibilidade a Drogas/etiologia , Hemorragia/etiologia , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Fragmentos Fab das Imunoglobulinas/imunologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/imunologia , Sistema de Registros , Segurança , Trombocitopenia/etiologiaRESUMO
INTRODUCTION: Platelet aggregates form by fibrinogen binding to the membrane receptor glycoprotein IIb/IIIa (GPIIb/IIIa). While GPIIb/IIIa inhibitors block fibrinogen-platelet binding, stimulation of other functionally important platelet receptors may still occur. Blocking the GPIIb/IIIa receptor prevents platelet aggregation but not activation and the subsequent effect on other platelet pathways is largely unknown. MATERIALS AND METHODS: As activated platelets release reactive oxygen species that may influence thrombosis or vascular function, the effect of GPIIb/IIIa inhibitors on the platelet release of nitric oxide (NO) and superoxide was determined using an electrochemical detector and luminescence, respectively. Location of relevant platelet proteins and the interaction between platelets and leukocytes in the presence or absence of GPIIb/IIIa inhibition was determined. RESULTS: Although incubation with GPIIb/IIIa inhibitors completely abolished platelet aggregation, stimulation dependent NO release was significantly enhanced. Superoxide is known to alter the bioavailability of NO, and its contribution to the GPIIb/IIIa dependent increase in NO release was determined. In the presence of GPIIb/IIIa inhibitors, platelet superoxide release was significantly decreased. Preincubation with GPIIb/IIIa inhibitors also modified aggregation induced membrane translocation of the platelet proteins, endothelial NO synthase (eNOS) and NADPH oxidase (p67phox and p47phox), known to contribute to the generation of NO and superoxide, respectively. In the presence of leukocytes, abciximab incubation led to enhanced NO release and attenuated superoxide generation. CONCLUSION: These observations suggest that the pharmacological effects of GPIIb/IIIa antagonists on platelet function, apart from inhibition of aggregation, may contribute to their efficacy.
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Plaquetas/metabolismo , Óxido Nítrico/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Abciximab , Alanina/farmacologia , Anticorpos Monoclonais/farmacologia , Plaquetas/química , Plaquetas/efeitos dos fármacos , Cálcio/análise , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Leucócitos Mononucleares/metabolismo , NADPH Oxidases/efeitos dos fármacos , NADPH Oxidases/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Pirrolidinas/farmacologia , Superóxidos/metabolismoRESUMO
BACKGROUND: The nature of bronchial mucosal inflammation and its physiologic and clinical significance in rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal inflammatory response and its association with physiologic and clinical outcomes in an experimental model of rhinovirus-induced asthma exacerbations. METHODS: We used immunohistochemistry methods to detect phenotypes of inflammatory cells infiltrating the bronchial mucosa before and after experimental rhinovirus infection in 10 subjects with asthma and 15 normal subjects. RESULTS: Compared with baseline, rhinovirus infection significantly increased the number of epithelial (P = .005) and subepithelial (P = .017) neutrophils in subjects with asthma only and subepithelial CD68+ macrophages in both subjects with asthma (P = .009) and normal subjects (P = .018) but more so in those with asthma (P = .021). Numbers of CD45+, CD68+, and CD20+ cells; neutrophils; and eosinophils at day 4 postinfection were positively associated with virus load (r = 0.50-0.72, P = .016-0.03). At acute infection in subjects with asthma, CD4+ cells correlated with chest symptom scores (r = 0.69, P = .029), the fall in the 10% fall in FEV1 (PC10) correlated with neutrophils (r = -0.89, P = .029), the PC10 correlated inversely with CD4+ (r = -0.67, P = .023) and CD8+ cells (r = -0.65, P = .03), the 20% fall in FEV1 was inversely associated with CD20+ cells (r = -0.65, P = .03), and higher epithelial CD8+ cell counts were significantly associated with a greater maximum fall in FEV1 (r = -0.72, P = .03), whereas higher subepithelial mast cell counts were significantly associated with a lower maximum percent fall in peak expiratory flow (r = 0.8, P = .024). CONCLUSIONS: In subjects with asthma, rhinovirus infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infiltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function.
Assuntos
Asma/imunologia , Resfriado Comum/imunologia , Pneumonia/imunologia , Pneumonia/virologia , Rhinovirus , Adulto , Asma/virologia , Resfriado Comum/complicações , Comorbidade , Eosinófilos/patologia , Feminino , Humanos , Pulmão/fisiopatologia , Pulmão/virologia , Linfócitos/patologia , Macrófagos Alveolares/patologia , Masculino , Mastócitos/patologia , Neutrófilos/patologia , Rhinovirus/isolamento & purificação , Índice de Gravidade de Doença , Carga ViralRESUMO
Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Descoberta de Drogas/tendências , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados , Descoberta de Drogas/métodos , Previsões , Humanos , Psoríase/imunologia , Transdução de Sinais/imunologia , Resultado do Tratamento , UstekinumabRESUMO
Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human immunoglobulin (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor ß1 subunit of the IL-12 and IL-23 receptor complexes. Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and has demonstrated efficacy in Crohn disease and psoriatic arthritis. The clinical characterization of ustekinumab continues to clarify our understanding of human immune pathologies and may offer a novel therapeutic option for certain immune-mediated diseases.
Assuntos
Anticorpos Monoclonais/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Psoríase/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Humanos , Camundongos , Psoríase/imunologia , Resultado do Tratamento , UstekinumabRESUMO
The development of ustekinumab as a first-in-class anti-interleukin (IL) 12/23p40 therapeutic agent for psoriasis represents an important example of modern and rational drug design and development. Psoriasis is a chronic, systemic, immune-mediated skin disorder with considerable clinical, psychosocial, and economic burden. Ustekinumab is a human monoclonal antibody (mAb) that binds the p40 subunit common to IL-12 and IL-23, key cytokines in psoriasis pathogenesis. The therapeutic mAb was developed using human gamma-1 immunoglobulin (IgG)-expressing transgenic mice, which created a molecule with endogenous IgG(1) biologic properties and low immunogenicity. Ustekinumab was well tolerated in clinical studies and yielded rapid, significant, and sustained efficacy plus improved quality of life/work performance and reduced depression/anxiety. Its pharmacologic properties afford the most convenient dosing regimen among approved biologics, representing a significant advancement in the treatment of moderate to severe psoriasis. Ustekinumab also holds promise for other immune-mediated disorders with significant unmet need.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Desenho de Fármacos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais Humanizados , Descoberta de Drogas/tendências , Previsões , Humanos , Fatores Imunológicos/uso terapêutico , Interleucina-12/imunologia , Interleucina-23/imunologia , Camundongos , Modelos Biológicos , UstekinumabRESUMO
OBJECTIVE: To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (s.c.) administrations of a human monoclonal antibody against the p40 subunit of IL-12/23 (IL-12/23 mAb) in subjects with moderate-to-severe psoriasis. METHODS: Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7 mg/kg) and randomized to IL-12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharmacokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1. RESULTS: Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (Cmax and AUC) of IL-12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL-12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL-8, IL-18, and IFN-gamma in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement. LIMITATIONS: Interpretation of results is limited due to the small sample size in each dose cohort. CONCLUSION: A single s.c. administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Subunidade p40 da Interleucina-12/imunologia , Psoríase/terapia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Imunoterapia/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Placebos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To assess safety, clinical response, and pharmacokinetics of subcutaneous (SC) and intramuscular (IM) doses of an experimental formulation of infliximab [including experimental SC doses following administration of commercially-formulated intravenous (IV) infliximab] in patients with rheumatoid arthritis (RA) refractory to methotrexate. METHODS: In this randomized, open-label, 3-stage design, 43 subjects were enrolled in 7 dose groups. In Stage I, 15 subjects received single SC doses of 0.5, 1.5, or 3.0 mg/kg. In Stage II, 21 subjects received one of 3 regimens: 100 mg SC every 2 weeks (3 injections); 3 mg/kg commercially-formulated IV infliximab every 2 weeks (2 infusions) followed by 100 mg SC every 2 weeks (3 injections); or 100 mg IM every 2 weeks (3 injections). In Stage III, 7 subjects received 100 mg SC every 4 weeks (3 injections). RESULTS: No treatment-related serious adverse events were observed, and there were no serious injection site reactions. A low-titer infliximab antibody response was detected in 27% of subjects receiving single SC doses, 5% receiving multiple SC doses, and 43% receiving IM doses. SC administration yielded roughly dose-proportional increases in Cmax and AUC. American College of Rheumatology 20% response (ACR20) was achieved 2 weeks after the last injection by 86.7% of subjects receiving single SC doses, 85.7% receiving SC doses every 2 weeks, 85.7% receiving both IV and SC doses, 57.1% receiving multiple IM doses, and 80.0% receiving SC doses every 4 weeks. CONCLUSION: SC and IM treatment with this experimental infliximab formulation was well tolerated and was associated with a favorable ACR response.