RESUMO
Although inflammation is emerging as a candidate prostate cancer risk factor, the T-helper cytokine-rich [interleukins (IL)-5, 13 and 4] chromosomal region at 5q31.1 has been implicated in prostate cancer pathogenesis. In particular, IL-4 has been associated with prostate cancer progression, whereas the IL-4 -589C>T (rs2243250) promoter variant has been associated with differential gene expression. We genotyped rs2243250 and 11 tag single-nucleotide polymorphisms (SNPs) spanning 200 kb across the 5q31.1 region on 825 cases and 732 controls from the Risk Factors for Prostate Cancer Study. The minor alleles of rs2243250 and an IL-4 tagSNP rs2227284 were associated with a small increase in prostate cancer risk. Per allele odds ratios (ORs) are 1.32 [95% confidence interval (CI) 1.08-1.61, P = 0.006] and 1.26 (95% CI 1.07-1.48, P = 0.005), respectively. Although these associations were not replicated in an analysis of the Melbourne Collaborative Cohort Study, including 810 cases and 1733 controls, no clinicopathological characteristic was implicated for this divergence. Correlating rs2243250 genotypes to IL-4 gene transcript levels and circulating IL-4 plasma levels, we observe in contrast to previous reports, a non-significant trend toward the minor T-allele decreasing the likelihood of IL-4 activity. From our observed association between a low IL-4 producing promoter T-allele and prostate cancer risk, our study suggests an antitumor role for IL-4 in prostate cancer. Although we saw no association for IL-5 or IL-13 gene variants and prostate cancer risk, our findings call for further evaluation of IL-4 as a contributor to prostate cancer susceptibility.
Assuntos
Cromossomos Humanos Par 5 , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Interleucina-4/sangue , Masculino , Regiões Promotoras Genéticas , RNA Mensageiro/análiseRESUMO
Analysis of SNPs for association, linkage, haplotype, and pharmacogenetic studies has led to a dramatic increase in the number and evolution of medium- to high-throughput genotyping technologies. This study introduces Plexor as a new method for medium-throughput (single SNP) genotyping. We compare this fluorescent-based chemistry for call rate, accuracy, affordability, throughput, and overall efficiency against two commonly used technologies. These include fluorescent-based TaqMan allelic discrimination for single SNP analysis (medium-throughput) and the homogenous MassEXTEND (hME) chemistry using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for multiple SNP analysis (high-throughput). Analysis of 11 SNPs, including all six possible nucleotide substitutions, showed Plexor to be highly comparable for both call rate (94.7%) and accuracy (99.2%) to the TaqMan (94.6% and 99.8%, respectively) and hME (91.9% and 98.1%, respectively) chemistries. We demonstrate that this novel method is an efficient, cost-effective alternative to TaqMan genotyping commonly used in diagnostic settings.
Assuntos
Análise Mutacional de DNA/métodos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Genótipo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-2/genética , Interleucina-4/genética , Interleucina-6/genética , Interleucina-8/genética , Modelos Biológicos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.
Assuntos
Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Receptores do Fator de Necrose Tumoral/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Etanercepte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: To study the functional status and health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) after treatment with celecoxib, compared with placebo and naproxen. METHODS: This was a prospective, randomized, double-blind, parallel group trial conducted at 79 sites in the United States and Canada over a 12-week treatment period. Patients were randomly assigned to 5 groups: placebo, 100 mg twice a day of celecoxib, 200 mg twice a day of celecoxib, 400 mg twice a day of celecoxib, and 500 mg twice a day of naproxen. The Health Assessment Questionnaire (HAQ) disability index was used to measure functional status. The Medical Outcomes Study Short Form 36 (SF-36) was used to measure general HRQOL. RESULTS: Enrollees were 1,149 patients with diagnosed and active RA. At the end of the treatment period, patients in the 4 active treatment groups had significant improvement in both functional status and overall HRQOL in comparison with the placebo group. Patients in the twice-daily 100 mg celecoxib group significantly differed from placebo at weeks 2 and 6 on HAQ scores and at week 12 on 5 domains and both summary scores of the SF-36. Patients treated with twice-daily 200 mg celecoxib had significantly better functional status than placebo at all times of testing with the HAQ, and also had significantly better function than those treated with naproxen after 2 and 12 weeks of treatment. Patients in the twice-daily 200 mg and 400 mg celecoxib groups showed similar improvement in HRQOL as determined by the 8 domain scores and 2 summary scores of the SF-36. CONCLUSION: Celecoxib was better than placebo and comparable with naproxen in improving functional status and overall HRQOL among RA patients.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/psicologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Qualidade de Vida , Sulfonamidas/uso terapêutico , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Celecoxib , Método Duplo-Cego , Esquema de Medicação , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Naproxeno/uso terapêutico , Estudos Prospectivos , Pirazóis , Inquéritos e Questionários , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Algoritmos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Qualidade de Vida , Receptores do Fator de Necrose Tumoral/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estatística como AssuntoRESUMO
OBJECTIVE: Gastric (GU) and duodenal ulcers (DU) are common adverse effects of nonsteroidal anti-inflammatory drugs (NSAID). Endoscopically diagnosed upper gastrointestinal (GI) ulceration occurs in about 24% of longterm NSAID users. Coadministration of misoprostol with the NSAID reduces the incidence of NSAID induced GU and DU and their complications. However, compliance is limited by the different dosing regimens of misoprostol and NSAID and GI symptoms associated with misoprostol at its recommended q.i.d. dose. We compared the efficacy, safety, and incidence of endoscopic upper GI ulceration associated with the administration of 2 combinations of diclofenac (50 or 75 mg) and misoprostol 200 microg (D50/M200 t.i.d., D75/M200 b.i.d.), diclofenac 75 mg b.i.d., and placebo in a 6 week, randomized, double blind study in patients with osteoarthritis (OA) of the knee or hip. METHODS: A total of 572 patients with symptomatic OA of the knee or hip and history of GU, DU. or 10 or more erosions were randomized to receive D50/M200 t.i.d., D75/M200 b.i.d., diclofenac 75 mg b.i.d., or placebo for 6 weeks. Arthritis assessments were performed at baseline, 2, and 6 weeks, and upper GI endoscopies at baseline and end of treatment. RESULTS: All active treatment groups were significantly better than placebo, at all visits, in improving OA symptoms. There were no significant differences in arthritis efficacy between the diclofenac/ misoprostol combinations and diclofenac. However, endoscopically diagnosed GU and/or DU were significantly less frequent in patients receiving D50/M200 t.i.d. (8%), D75/M200 b.i.d. (7%), and placebo (4%) compared to diclofenac 75 mg b.i.d. (17%). Adverse events were not different between the active treatment groups, except for higher incidences of flatulence with D75/M200 and diarrhea with D50/M200. CONCLUSION: Diclofenac 50 mg/misoprostol 200 microg t.i.d. and diclofenac 75 mg/misoprostol 200 microg b.i.d. are as efficacious as diclofenac 75 mg b.i.d. in the treatment of OA, but are associated with a significantly lower incidence of gastric and/or duodenal ulcers.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/uso terapêutico , Misoprostol/uso terapêutico , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Úlcera Duodenal/induzido quimicamente , Endoscopia Gastrointestinal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Misoprostol/administração & dosagem , Misoprostol/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Úlcera Gástrica/induzido quimicamente , Falha de TratamentoRESUMO
BACKGROUND: Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc). METHODS: In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria. RESULTS: Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples. CONCLUSIONS: In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.
Assuntos
Antígenos CD , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral , Proteínas Recombinantes de Fusão/uso terapêutico , Anticorpos/sangue , Antígenos CD/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the effectiveness and tolerability of three misoprostol dosing regimens for the prevention of gastric and duodenal ulcers associated with long-term nonsteroidal anti-inflammatory drug (NSAID) therapy. DESIGN: A multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel, four-limb study. PATIENTS: Eligibility criteria included upper gastrointestinal symptoms during NSAID therapy and no endoscopic evidence of gastric or duodenal ulcers. A total of 1623 patients was enrolled; 1197 of these met major accession and regimen-compliance criteria and completed the trial. These 1197 patients composed the evaluable group. INTERVENTIONS: Patients were randomly assigned to one of four regimens: placebo four times daily; 200 micrograms of misoprostol twice daily and placebo twice daily; 200 micrograms of misoprostol three times daily and placebo once daily; and 200 micrograms of misoprostol four times daily. MEASUREMENTS: Upper gastrointestinal endoscopic examinations for ulcers were done after 4, 8, and 12 weeks of therapy. Tolerability and safety of the regimens were assessed by adverse-event monitoring. RESULTS: In the placebo group, the incidence of gastric ulcers was 15.7% and the incidence of duodenal ulcers was 7.5%. The incidence of gastric ulcers was significantly lower in the groups receiving misoprostol twice daily (8.1%; difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (3.9%; difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (4%; difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) compared with placebo. The gastric ulcer rate was significantly higher in patients receiving misoprostol twice daily compared with those receiving misoprostol three times daily (difference, 4.2% [95% CI, 0.7% to 7.7%]; P = 0.02). A significant (P = 0.02) misoprostol dose-response effect was noted in the prevention of gastric ulcers. The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol twice daily (2.6%; difference, 4.9% [CI, 1.5% to 8.2%]; P = 0.004), three times daily (3.3%; difference, 4.2% [CI, 0.6% to 7.7%]; P = 0.019), and four times daily (1.4%; difference, 6.1% [CI, 2.6% to 9.6%]; P = 0.007) compared with placebo. No significant difference was detected between patients receiving misoprostol twice daily and those receiving misoprostol three times daily, and no dose-response effect was noted with duodenal ulcers. The incidence of withdrawals for adverse events was significantly lower in the groups receiving misoprostol twice daily (12%) and three times daily (12%) than in the group receiving it four times daily (20%). The incidence of gastrointestinal adverse events was significantly higher in the group receiving misoprostol four times daily (74%) than in the placebo group (62%). CONCLUSION: Misoprostol, 200 micrograms twice or three times daily, offers substantial protection against gastric and duodenal ulcers in patients receiving long-term NSAID therapy. These dosages were better tolerated than the currently approved regimen of 200 micrograms four times daily.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Úlcera Duodenal/prevenção & controle , Misoprostol/administração & dosagem , Úlcera Gástrica/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Esquema de Medicação , Úlcera Duodenal/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Misoprostol/efeitos adversos , Úlcera Gástrica/induzido quimicamenteRESUMO
BACKGROUND: This study was developed to compare the incidence of endoscopically diagnosed ulcers in elderly patients taking nabumetone, ibuprofen, or concomitant ibuprofen/misoprostol. Further research is indicated to better establish the clinical relevance of these endoscopy findings. METHODS: We conducted a prospective, multicenter, randomized, endoscopist-blinded, 12-week study involving 171 patients with osteoarthritis aged 60 years and older. Patients were randomized to receive nabumetone, 1000 mg (n = 58); ibuprofen, 600 mg four times daily (n = 53); or ibuprofen, 600 mg four times daily, administered concomitantly with misoprostol, 200 micrograms four times daily (n = 60). Endoscopy was performed at baseline and at weeks 2, 6, and 12. Endoscopy results were scored on a scale of 1 to 9. Significant ulcers were defined as breaks in the mucosa greater than 5 mm with appreciable depth. RESULTS: Of the 171 randomized patients, 148 completed the study. There was no significant difference in the incidence of significant ulcers between the nabumetone group and the ibuprofen/misoprostol group (one vs zero). There were significantly fewer significant ulcers in the nabumetone and ibuprofen/misoprostol groups than in the ibuprofen monotherapy group (one and zero vs eight; P < .01). There also was a significant difference in the time to ulcer development, with a greater risk of developing an ulcer sooner with ibuprofen treatment (P < .01) than either nabumetone or ibuprofen/misoprostol treatment. The severity of osteoarthritis, based on physicians' assessments, improved in 64% of patients in the nabumetone group, 55% of those in the ibuprofen group, and 63% of those in the ibuprofen/misoprostol group. CONCLUSIONS: Nabumetone is equivalent in ulcerogenicity to concomitant ibuprofen/misoprostol and is significantly less ulcerogenic than ibuprofen alone.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Butanonas/efeitos adversos , Ibuprofeno/efeitos adversos , Misoprostol/uso terapêutico , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/prevenção & controle , Idoso , Análise de Variância , Endoscopia do Sistema Digestório , Feminino , Mucosa Gástrica/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Nabumetona , Osteoartrite/tratamento farmacológico , Estudos Prospectivos , Método Simples-CegoRESUMO
Twenty-two patients with fibrositis and 22 control patients selected from a general medical outpatient population were given 3 standardized psychological questionnaires: the Beck Depression Inventory, the Spielberger State and Trait Anxiety Inventory, and the SCL-90-R. There were no statistically significant differences between fibrositis patients and control patients on any of these tests, a finding at variance with a commonly held belief that patients with fibrositis have an underlying psychological disorder. While psychological factors may be important in some patients with fibrositis, these results indicate that the presence of a psychopathologic condition is not mandatory for the persistence of fibrositis.
Assuntos
Fibromialgia/psicologia , Adulto , Idoso , Ansiedade/diagnóstico , Ensaios Clínicos como Assunto , Transtorno Depressivo/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes PsicológicosAssuntos
Artrite Infecciosa/complicações , Gonorreia/fisiopatologia , Osteomielite/complicações , Adulto , Cabeça do Fêmur/microbiologia , Necrose da Cabeça do Fêmur/etiologia , Necrose da Cabeça do Fêmur/cirurgia , Quadril/diagnóstico por imagem , Prótese de Quadril , Humanos , Masculino , Neisseria gonorrhoeae/isolamento & purificação , Osteomielite/microbiologia , Radiografia , Supuração/microbiologiaRESUMO
Twenty-two patients with fibrositis, selected from a general medical outpatient population by a screening questionnaire and subsequent evaluation, were compared with age-, sex-, and clinic-matched patients without fibrositis. Although there was a high prevalence of musculoskeletal complaints in both groups, the fibrositis patients had a uniform constellation of symptoms, including axial pain, severe aching and stiffness, morning fatigue, and modulation by specific factors. They also had a higher incidence of tension headache and irritable bowel syndrome. The use of a dolorimeter demonstrated that fibrositis patients had many more areas of localized tenderness than control patients, but also that fibrositis patients did not have diffusely diminished pain threshold and tolerance. Using the criteria of this study, fibrositis appears to be a common and readily definable syndrome within the spectrum of soft tissue rheumatism.