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First Infusion (first + infusion)
Selected AbstractsPredictive model for the outcome of infliximab therapy in Crohn's disease based on apoptotic pharmacogenetic index and clinical predictorsINFLAMMATORY BOWEL DISEASES, Issue 4 2007Tibor Hlavaty Abstract Background: Infliximab (IFX) is an effective therapy for refractory luminal and fistulizing Crohn's disease (CD). Predictors of response could improve selection of patients with a higher probability of favorable outcomes and could improve the safety profile. We aimed to develop a predictive model for the response to infliximab in CD. Methods: Genetic and clinical data collected in a previous pharmacogenetic study of apoptosis genes were analyzed using SAS Enterprise miner modeling software and SPSS 12.0. We proposed a novel apoptotic pharmacogenetic index (API) with a score ranging from 0 (low apoptotic response) to 3 (high apoptotic response) and subsequently developed a decision tree model. Results: Response and remission rates significantly increased with API score (P = 0.005 in the group of patients with luminal CD, P = 0.02 in the group of patients with fistulizing CD). Patients with an API , 1 (n = 59) had the lowest response and remission rates in both the luminal CD (50% and 39.5%, respectively) and fistulizing CD (61.9% and 28.6%, respectively) groups, compared to those with an API of 2 (n = 158), whose response and remission rates were 73.8% and 56.1%, respectively, in the luminal CD group and 85.7% and 44.9%, respectively, in the fistulizing CD group; and those with an API of 3 (n = 10), whose response and remission rates were 100% and 85.7%, respectively, in the luminal CD group and 100% and 0% in the fistulizing CD group. Response in patients with an API , 1 was significantly influenced by concurrent azathioprine therapy in the luminal CD (21.4% versus 78.9%, P < 0.001) and in the fistulizing CD (46.6% versus 100%, P = 0.04) groups. In patients with an API of 2, we saw an interaction with age older than 40 years and location of disease (response 52.2% versus 83.9%, P = 0.008) in the luminal CD group and with baseline CRP greater than 5 mg/L (73.9% versus 93.9%, P = 0.04) in the fistulizing CD group. Conclusions: From our newly proposed apoptotic pharmacogenetic index and clinical predictors, we developed a model for prediction of low, medium, and high responses to the first infusion of IFX in patients with CD. Further studies are needed to confirm the hypothesis generated by our study. (Inflamm Bowel Dis 2007) [source] Infliximab efficacy in pediatric ulcerative colitis,INFLAMMATORY BOWEL DISEASES, Issue 3 2005Alexandra P Eidelwein MD Abstract Background: The effects of infliximab, a tumor necrosis factor-alpha (TNF-,) antibody, have been well established in adult patients with inflammatory and fistulizing Crohn's disease. This study evaluates short- and long-term efficacy of infliximab in children with ulcerative colitis. Methods: All pediatric patients with ulcerative colitis who received infliximab between July 2001 and November 2003 at the Johns Hopkins Children's Center were identified. Short- and long-term outcomes and adverse reactions were evaluated. Results: Twelve pediatric patients with ulcerative colitis received infliximab for treatment of fulminant colitis (3 patients), acute exacerbation of colitis (3), steroid-dependent colitis (5), and steroid-refractory colitis (1). Nine patients had a complete short-term response, and 3 had partial improvement. The mean per patient dose of corticosteroid after the first infliximab infusion decreased from 45 mg/day at the first infusion to 22.2 mg/day at 4 weeks (P = 0.02) and 7.8 mg/day at 8 weeks (P = 0.008). Eight patients were classified as long-term responders with a median follow-up time of 10.4 months. Of the 4 long-term nonresponders, 3 underwent colectomy, and the fourth has ongoing chronic symptoms. Three of 4 long-term nonresponders were steroid-refractory compared with 1 of 8 long-term responders. Patients receiving 6-mercaptopurine had a better response to infliximab. Conclusion: Infliximab should be considered in the treatment of children with symptoms of acute moderate to severe ulcerative colitis. [source] Efficacy and tolerance of infliximab in children and adolescents with Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 6 2004Dr. Thierry Lamireau Abstract Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn's disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3,17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8,7.3) of infliximab during a median time period of 4 months (1,17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey,Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn's disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment. [source] Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009Erik Fink Eriksen Abstract Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ,6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality. [source] Effect of First Treatment with Aminobisphosphonates Pamidronate and Ibandronate on Circulating Lymphocyte SubpopulationsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Martin Pecherstorfer Abstract Up to 60% of patients receiving their first infusion of the bisphosphonate pamidronate experience an acute-phase reaction. In this study, we used flow cytometry to determine the effects of pamidronate treatment on circulating lymphocyte subpopulations, and we investigated whether pamidronate and ibandronate treatment affect lymphocyte subpopulations differently. Twenty patients received a pamidronate infusion, 20 patients received intravenously injected ibandronate, and 10 controls received a clodronate infusion. Pamidronate treatment was followed by a significant increase in median body temperature at the 10-hour measurement and a significant decrease in counts of circulating lymphocytes, natural killer cells, T cells, and CD4+ and CD8+ T-cell subsets. Ibandronate treatment did not affect median body temperature, and it was associated at the 10-hour measurement with maximum increases in total lymphocyte count, B cells, T cells, and CD4+ and CD8+ T-cell subsets. Thus, there is a substantial difference in the hematologic response to initial treatments with pamidronate and ibandronate. Clodronate treatment did not induce changes in body temperature or significantly affect the number of circulating T cells and NK cells. The reduction in lymphocyte subsets after initial pamidronate therapy might be mediated by the release of tumor necrosis factor ,, whose source in the acute-phase reaction could be T cells. [source] Infliximab improves inflammation and anthropometric measures in pediatric Crohn's diseaseJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010Daniel M Sinitsky Abstract Background and Aim:, Infliximab (IFX) is a monoclonal antibody licensed to treat medically refractory Crohn's disease (CD). Our aim was to elucidate the effects of IFX therapy on clinical, growth and serum parameters in children with CD in a single pediatric center in Sydney, Australia. Methods:, A retrospective case series review of children treated with IFX for CD at Sydney Children's Hospital, Australia was undertaken, with a review of outcomes after starting IFX. Main outcome measures were response and remission (as measured according to improvements in Pediatric Crohn's Disease Activity Index scores and Physician Global Assessment), laboratory markers (C-reactive protein, erythrocyte sedimentation rate, hemoglobin, white cell count, lymphocytes, neutrophils, platelets, albumin) and growth (Z scores). Results:, The 16 patients included had a mean age at first infusion of 13.0 years (1.25,17.5 years). Six of 12 patients (with adequate data available) were in remission at 2 weeks following the first infusion. At 1 year, 10 of 12 patients (83%) were in remission. Mean C-reactive protein and erythrocyte sedimentation rate had fallen significantly (P < 0.05) at 2 weeks (from 29 to 7 mg/L and 40 to 19 mm/h, respectively). Positive trends were observed for all other parameters, excluding lymphocytes and white cell count. At 1 year, mean Z score for body mass index improved significantly from ,0.9 to ,0.1 (P < 0.01). Conclusions:, Disease activity subsides in most children treated with IFX for CD. IFX therapy also improves some growth parameters. The pattern of improvement requires further elucidation, as the results in the present study suggest differing dosing frequency of infusion may achieve better efficacy. [source] Persistent serpentine supravenous hyperpigmented eruption associated with docetaxelJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 3 2005I Aydogan ABSTRACT Various mucocutaneous reactions have been reported with the use of systemic docetaxel. We describe a 47-year-old man who developed a persistent serpentine supravenous hyperpigmented eruption (PSSHE), beginning at the site of docetaxel injection and spreading along the superficial venous network in the anterior aspect of the right forearm and distal arm. The eruption occurred after the first infusion of docetaxel following insufficient venous washing. A second infusion was administered through a vein in the other forearm, but this time, abundant venous washing was performed and a similar eruption did not occur. To our knowledge, this is the second report of docetaxel-induced supravenous discoloration and we discussed the terminology and mechanism of this unique reaction. [source] Infliximab safety profile and long-term applicability in inflammatory bowel disease: 9-year experience in clinical practiceALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2010Y. ZABANA Aliment Pharmacol Ther,31, 553,560 Summary Background, Most available data on infliximab therapy come from large, short-term, pivotal RCTs and concerns about long-term safety profile still remain. Aim, To evaluate the long-term safety profile of infliximab in inflammatory bowel disease (IBD) in a clinical practice setting. Methods, Since 1999, all IBD patients treated with infliximab were registered and clinical outcomes prospectively recorded up to March 2008, loss of follow-up or patient's death. Infliximab regimens and preventive measures were in accordance with the prevalent guidelines or with the manufacturer's recommendations. Results, One hundred fifty-two patients were included (121 Crohn's disease, 24 ulcerative colitis, 7 indeterminate colitis), with a median of 5 infliximab infusions (IQR 3,8) and 87% of patients received at least three infusions. Seventy-nine per cent of them received concomitant immunomodulators and 70% were pre-medicated with hydrocortisone from the first infusion. After a median follow-up of 142 weeks, 13% presented infusion reactions, 13% viral or bacterial infections and two patients developed neoplasia. The mortality rate was 2.6% (four patients). Conclusions, Infliximab therapy is safe when the recommended preventive measures are implemented, with a rate of serious adverse events less than 10%. No new safety signals were found. [source] Mass spectrometry study of hemoglobin-oxaliplatin complexes in colorectal cancer patients and potential association with chemotherapeutic responsesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2006Rupasri Mandal Oxaliplatin is the most active platinum (Pt)-containing anticancer drug for the treatment of advanced colorectal cancer. We report here the study of potential association of the levels of oxaliplatin-protein complexes in 19 cancer patients with treatment efficacy using size-exclusion high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICPMS) and nanoelectrospray ionization mass spectrometry (nanoESI-MS) techniques. Blood samples from 19 colorectal cancer patients were collected at 1 and 48,h after the first infusion of oxaliplatin. HPLC/ICPMS quantification of the oxaliplatin-protein complexes showed that the levels of Pt-protein complexes in plasma samples at 48,h were reduced by approximately 50% compared to those at 1,h, whereas those in hemolysates did not change significantly. The concentrations of hemoglobin (Hb)-oxaliplatin complexes determined by HPLC/ICPMS ranged from 3.1 to 8.7,µM. NanoESI-MS analysis of the patient hemolysates showed three distinct mass spectral profiles of the Hb-oxaliplatin complexes: (1) 1:1, (2) 1:1 with 1:2, and (3) multiple complexes of 1:1, 1:2, 1:3, and 1:4, corresponding to the Hb-oxaliplatin complex concentrations determined by HPLC/ICPMS. Potential association of variables including Hb-oxaliplatin complex concentrations with time to progress as the treatment efficacy indicator was analyzed using the Cox model. Multivariate analysis of the potential predictors showed that the statistically significant variables were Hb-oxaliplatin complex concentration (p,=,0.02), performance status (p,=,0.02), baseline neutrophil count (p,=,0.05), and the site of the primary cancer (colon vs. rectal, p,=,0.01). The hazard ratio for the concentration of the Hb-oxaliplatin complexes was 2.4, suggesting that the risk of cancer progression significantly increased with increasing of Hb-oxaliplatin complexes in patients. These results demonstrate that the level of the Hb-oxaliplatin complexes in erythrocytes is a potential biomarker for indicating inter-patient variations in oxaliplatin treatment efficacy. Copyright © 2006 John Wiley & Sons, Ltd. [source] Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: Results of a randomized, double-blind, placebo-controlled, phase I/II study,ARTHRITIS & RHEUMATISM, Issue 8 2010Mikkel Østergaard Objective To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to ,1 disease-modifying antirheumatic drug. Methods This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. Results AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. Conclusion Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA. [source] Management of nonresponse to rituximab in rheumatoid arthritis: Predictors and outcome of re-treatmentARTHRITIS & RHEUMATISM, Issue 5 2010E. M. Vital Objective A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle. Methods Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 × 109 cells/liter. Results At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response. Conclusion RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses. [source] Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatmentARTHRITIS & RHEUMATISM, Issue 7 2006Myew-Ling Toh Objective Synoviolin is a novel E3 ubiquitin ligase that has been implicated in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to examine the expression and regulation of synoviolin by tumor necrosis factor , (TNF,), both in vivo and in vitro. Methods A total of 54 RA patients and 23 healthy control subjects were analyzed before, 4 hours after the first infusion, and at week 22 of infliximab treatment. Clinical response was assessed by the American College of Rheumatology criteria for 20% improvement and the Disease Activity Score in 28 joints (DAS28) at 6 months. Synoviolin messenger RNA expression was measured by real-time reverse transcription,polymerase chain reaction in peripheral blood (PB) and fibroblast-like synoviocytes (FLS) and with and without TNF, or interleukin-1, (IL-1,) stimulation. Results Synoviolin expression was increased in whole PB obtained from RA patients as compared with that from healthy controls and was significantly reduced early and late after infliximab treatment in responders, but in not nonresponders. Reduction in synoviolin expression was associated with reduced levels of markers of disease activity, including C-reactive protein levels. Nonresponders to infliximab therapy had significantly higher synoviolin expression at baseline as compared with responders, and this elevation persisted despite infliximab therapy. PB CD14+ monocytes expressed increased synoviolin levels compared with CD3+ lymphocytes, and TNF, or IL-1, induced a further increase in expression in CD3+ cells. TNF, or IL-1, induced sustained synoviolin expression in RA FLS. Conclusion Elevated PB levels of synoviolin were identified in circulating PB mononuclear cells and were associated with nonresponse to infliximab treatment. Sustained up-regulation of synoviolin by IL-1, and TNF, may contribute to prolonged survival of immune cells and dysregulated FLS proliferation, leading to RA chronicity. [source] Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1,2 studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Bertrand Coiffier Summary The purpose of this phase 1,2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden. The trial was registered at http://www.clinicaltrials.gov (NCT00093314). [source] | ||||||||||