RESUMO
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Psoríase/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Adulto , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Seguimentos , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
In 1995, the first Venezuelan equine encephalitis (VEE) outbreak in Colombia in 22 years caused an estimated 75,000 human cases, 3000 with neurologic complications and 300 fatal, in La Guajira State. Of the state's estimated 50,000 equines, 8% may have died. An epizootic IC virus, probably introduced from Venezuela, was rapidly amplified among unvaccinated equines. Record high rainfall, producing high densities of vector Aedes taeniorhynchus, led to extensive epidemic transmission (30% attack rate) in the four affected municipalities. Native Wayuu Indians, constituting 24% of the state's population, were at increased risk of infection (risk ratio, 3.3; 95% confidence interval, 2.2-5.3). Epidemiologic studies found no evidence of human-to-human transmission. A higher-than-expected number of abortions during the outbreak confirmed a previously suspected abortifacient role of VEE infection. Pesticide applications and a mass equine vaccination program contributed to preventing the outbreak's spread south of La Guajira.
Assuntos
Surtos de Doenças , Encefalomielite Equina Venezuelana/epidemiologia , Adulto , Animais , Criança , Colômbia/epidemiologia , Encefalomielite Equina Venezuelana/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
To determine whether yellow fever (YF) vaccine administered in pregnancy causes fetal infection, women who were vaccinated during unrecognized pregnancy in a mass campaign in Trinidad were studied retrospectively. Maternal and cord or infant blood were tested for IgM and neutralizing antibodies to YF and dengue viruses. One of 41 infants had IgM and elevated neutralizing antibodies to YF virus, indicating congenital infection. The infant, the first reported case of YF virus infection after immunization in pregnancy, was delivered after an uncomplicated full-term pregnancy and appeared normal. Congenital dengue 1 infection may have occurred in another case. The frequency of fetal infection and adverse events after such exposure could not be estimated; however, the neurotropism of YF virus for the developing nervous system and the now documented possibility of transplacental infection underscores the admonition that YF vaccination in pregnancy should be avoided.
Assuntos
Vacinas Virais/efeitos adversos , Febre Amarela/congênito , Reações Cruzadas , Vírus da Dengue/imunologia , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos Retrospectivos , Trinidad e Tobago/epidemiologia , Vacinas Virais/imunologia , Febre Amarela/epidemiologia , Febre Amarela/etiologia , Vírus da Febre Amarela/imunologiaRESUMO
To determine whether yellow fever (YF) vaccine administered in pregnancy causes fetal infection, women who were vaccinated during unrecognized pregnancy in a mass campaign in Trinidad were studied retrospectively. Maternal and cord or infant blood were tested for IgM and neutralizing antibodies to YF virus, indicating congenital infection. The infant, the first repotred case of YF virus infection after immunization in prgnancy, was delivered after an uncomplicated full-term pregnancy and appeared normal. Congenital dengue 1 infection may have occurred in another case. The frequency of fetal infection and adverse events after such exposure could not be estimated; however, the neurotropism of YF virus for the developing nervous system and the now documented possibility of trans-placental infection underscores the admonition that YF vaccination in pregnancy should be avoided (AU)
Assuntos
Humanos , Gravidez , Recém-Nascido , Feminino , Vacinas Virais/efeitos adversos , Febre Amarela/congênito , Reações Cruzadas , Vírus da Dengue/imunologia , Estudos Retrospectivos , Trinidad e Tobago/epidemiologia , Vacinas Virais/imunologia , Febre Amarela/epidemiologia , Febre Amarela/etiologia , Vírus da Febre Amarela/imunologiaRESUMO
Since it previously has been reported that IL-2 has profound circadian dependent effects upon DNA synthesis in the liver of mice (Scheving et al., 1988; Tsai et al., 1988) the effects of IL-2 on enzyme activities were studied. The objective was to determine the effect of IL-2 when administered at different times to mice who were fed ad libitum, and standardized to 12 h of light alternating with 12 h of dark. Three groups were injected intraperitoneally with either 1 or 4 mg/kg of IL-2, one group was given the vehicle only. The treatment time for each dose and the vehicle was a 2 h into the light for one group and the other was at 2 h into the dark span. Subgroups of 5 mice were killed 4, 8, 12, 16, 20, 24, and 30 h after each treatment, livers were taken and frozen to await preparation and analysis of enzyme activities by our standard procedures. When treatment was in the light span IL-2 had no statistically significant effect on enzymes of lipid, carbohydrate or amino acid metabolism. On the contrary when treatment was given in the dark span IL-2 produced statistically significant increases in enzymes of glycolysis, and lipid synthesis beginning 8 h after treatment (changes ranged from 20 to 43%) with both the higher and lower doses (higher doses always yielded higher activities), and these activities continued to increase through the 24 h post-treatment span (changes ranged from 42 to 64%). At 30 h, activities were returning to normal levels. Amino acid metabolism, on the other hand, was decreased during these post-treatment times (the range of decrease was from 18 to 44%). Thus, we report for the first time that the duration of time, pathway affected, as well as the magnitude of the effect seen and the dosage of IL-2 were all circadian-stage dependent even with two time point samplings. We believe, however, that these two time points represent different critical extremes in liver metabolism, but studies with denser sampling are planned. Interleukin-2 was generously supplied by Cetus Corp. of Emeryville, CA.
Assuntos
Ritmo Circadiano , Enzimas/metabolismo , Interleucina-2/farmacologia , Alanina Transaminase/metabolismo , Aminoácidos/metabolismo , Animais , Glicerol Quinase/metabolismo , Glicólise/efeitos dos fármacos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Piruvato Quinase/metabolismoRESUMO
Patients with deficient antibody-mediated immunity may develop a rare "dermatomyositis-like" syndrome, which is usually progressive and fatal. We have observed a child with hypogammaglobulinemia in whom a dermatomyositis-like syndrome was associated with a fatal, disseminated ECHO 24 infection. This association suggests that in some immunodeficient patients the fatal dermatomyositis-like syndrome is a manifestation of a viral infection in a compromised host. The use of maternal plasma, with a high titer of ECHO 24 neutralizing activity, was unsuccessful in arresting the progress of the infection.