Hirame rhabdovirus (HIRRV) is a rhabdovirus that causes severe disease in fish. The mortality due to HIRRV infection occurs at temperatures below 15 °C, but no mortality is observed over 20 °C. In this study, Japanese flounder (Paralichthys olivaceus) was artificially infected with the HIRRV CNPo2015 strain at 10 °C or 20 °C. Absolute quantitative real-time PCR was employed to examine the viral replication in spleens after HIRRV infection. Expression profiles of four interferon-related genes (type I IFN, Mx, ISG15, MDA5) and two proinflammatory genes (TNF-α and IL-1β) were also investigated by quantitative real-time PCR. Results showed that viral copies in spleens increased gradually over time and peaked at 72 h post infection (hpi) in the 10 °C group, while viral copies in the 20 °C group increased within 24 hpi, but afterwards decreased to very low levels. Moreover, the expressions of IFNs in the 10 °C group reached the highest levels at 72 hpi, whereas their peak levels appeared much earlier in the 20 °C group, at 12 hpi. The expression levels of TNF-α and IL-1β in the 10 °C group peaked at 12 hpi and then quickly declined. However, the two genes were highly expressed during 6–24 hpi in the 20 °C group. Based on these findings, we concluded that HIRRV infection induced an efficient antiviral immune response at 20 °C, which might inhibit the viral transcription at early stages and finally prevent HIRRV infection.

BACKGROUND:In acute coronary syndromes, the inflammation and the coagulation systems are activated, implying an impaired outcome. In addition to platelet inhibition, recent evidence suggests that the glycoprotein IIb/IIIa receptor inhibitor abciximab attenuates inflammation and coagulation activity. METHODS:The Swedish Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) substudy included 404 patients with non-ST-elevation acute coronary syndromes. In addition to aspirin and dalteparin, all patients were randomized to receive abciximab infusion for 24 hours or 48 hours or corresponding placebo without early coronary revascularization. Plasma samples were obtained at baseline and 24, 48, and 72 hours. RESULTS:The median levels of the coagulation markers thrombin/antithrombin complex and soluble fibrin increased significantly from 3.1 to 3.7 ug/L (baseline to peak; P <.001) and from 20 to 23 nmol/L (P <.001), respectively. The fibrinolysis marker, tissue plasminogen-activator, also increased its median levels, from 11.7 to 17.5 ug/L (P <.001), whereas the median level of plasminogen-activator-inhibitor was unchanged. The inflammatory markers interleukin-6, C-reactive protein, and fibrinogen also increased their median levels (5.4-7.8 ng/L, P <.001; 4.4-8.7 mg/L, P <.001; 3.3-3.9 g/L, P <.001). However, there were no differences in median levels or in changes of median levels of any marker at any point between the placebo group and any of the abciximab groups. CONCLUSIONS:In non-ST-elevation acute coronary syndrome, there was a simultaneous activation of the inflammation, coagulation, and fibrinolysis systems, despite aspirin and dalteparin treatment. Prolonged treatment with abciximab had no influence of the activation of these systems.

Purpose The PK and PD of abciximab (Abx) were studied in a phase I clinical trial in patients with stable angina pectoris. Method: The trial involved 52 patients who were enrolled into 10 groups. Patients were treated with total doses from 0.15 to 1.123 mg/kg either as an IV bolus or as combinations of IV bolus and infusions of varying durations. Abx's plasma level and GPIIb/IIIa receptor (rpt) binding were determined. WINNONLIN software (Pharsight Corp) was used to develop a model that linked Abx PK via an effect-compartment with GPIIb/IIIa rpt blockade on platelets (PLT) using a sigmoid Emax model. Results: The PK of unbound Abx followed a tri-exponential decline in the plasma with α, β and γ t1/2 of 10 min, 1.7 h and 38.6 h respectively. Steady state volume of distribution of Abx was 1.44 L/kg and the clearance was 41 mL/kg. The initial rapid decline of Abx in the plasma was mainly due to its reversible binding to GPIIb/IIIa and αvβ3 rpt on the PLT and endothelial cells. The PK/PD model demonstrated that, despite the high proportion of Abx on the PLT, both the extent of GPIIb/IIIa blockade and the inhibition of platelet aggregation correlate with the free plasma concentrations of Abx in individual patients. Conclusion: A dynamic equilibrium exists between the relatively low plasma Abx concentrations and the extensive platelet bound Abx. This model has utility in estimating rebolus doses in patients undergoing percutaneous coronary intervention. Clinical Pharmacology & Therapeutics (2004) 75, P89–P89; doi: 10.1016/j.clpt.2003.11.342

PURPOSE: Lupus pernio is a chronic facial lesion due to sarcoidosis with a minimal rate of spontaneous remission. In order to quantitate response to therapy for lupus pernio, we developed a specific lupus pernio activity and severity index (LuPASI) based on the psoriasis activity and severity index.

The clinical consequences of immune antibodies generated to abciximab (ReoPro) and infliximab (Remicade) are described. Abciximab, a chimaeric Fab fragment that binds to the beta3 integrin of the GPIIb/IIIa and alphavbeta3 receptors on human platelets, is approved in the US and Europe for use in percutaneous coronary intervention (PCI) to prevent cardiac ischaemic complications. The effects of induced antibodies upon the safety and efficacy of repeat administration of abciximab have been evaluated in the ReoPro Re-administration Registry Study, in which 5.7% of patients were HACA positive before re-treatment. An interim evaluation of 1000 patients has indicated that re-administration of abciximab can be accomplished in the setting of PCI with an acceptable safety and efficacy profile. Infliximab is a chimaeric IgG1 antibody specific for human TNFalpha, and is approved in the US and Europe for the acute treatment of the signs and symptoms of Crohn's disease and for the chronic treatment of rheumatoid arthritis (RA). The incidence of antibodies to infliximab is reported to be approximately 10%; however, an inverse dose-immunogenicity relationship was observed, indicating that higher doses of infliximab (> or = 3 to 10 mg/kg) could reduce the incidence of immune antibodies. The induction of immune antibodies could also be reduced by concomitant administration of low-dose methotrexate and other immunosuppressant agents. Although antibodies to infliximab appeared to be associated with lower serum infliximab concentrations and a slightly higher incidence of infusion reactions, these immune antibodies were generally not associated with a reduction in clinical efficacy. In addition, the antibodies induced to infliximab are specific for infliximab, and do not cross-react with other currently available therapeutic antibodies.

OBJECTIVES We sought to evaluate C-reactive protein (CRP) and troponin T (TnT) as predictors of risk of the individual end points of mortality and myocardial infarction (MI) in a large cohort of patients with acute coronary syndrome (ACS).BACKGROUND Both CRP and TnT predict risk of future coronary events in patients with ACS. However, the relationships between the levels of the markers and the individual end points are still unclear.METHODS Baseline levels of CRP and TnT were determined in 7,108 patients with ACS not undergoing early revascularization in the Global Use of Strategies To Open occluded arteries trial IV (GUSTO-IV) trial and related to outcome at 30 days.RESULTS Quartiles of TnT related to 30-day mortality, which was 1.1%, 3.7%, 3.7%, and 7.4% (p < 0.001) and to the rate of MI: 2.5%, 6.7%, 7.2%, and 5.6% (p < 0.001). Quartiles of CRP also related to 30-day mortality, which was 2.0%, 3.3%, 3.9%, and 6.3% (p < 0.001), whereas there was no relationship to the 30-day rate of MI: 5.6%, 4.7%, 5.2%, and 5.9% (p = 0.48). On multivariable analysis, both TnT and CRP were independent predictors of mortality, but only TnT was a predictor of MI. The combination of CRP and TnT provides an even better risk stratification of mortality, with 0.3% and 9.1% death rates, respectively, when both markers are in the bottom versus top quartiles.CONCLUSIONS In ACS, baseline levels of TnT and CRP are independently related to 30-day mortality. Any detectable elevation of TnT, but not of CRP, is also associated with an increased risk of subsequent MI. Regarding mortality, the combination of both markers provides a better risk stratification than either one alone. (C) 2003 by the American College of Cardiology Foundation.

In a pooled analysis of the EPIC, EPILOG, and EPISTENT patient cohorts, abciximab provided a late (3-year) survival advantage. A multivariate proportional hazards model identified age, diabetes, serum creatinine, smoking, as well as a history of congestive heart failure, coronary bypass surgery, hypertension, peripheral vascular disease, and prior myocardial infarction as predictive of late mortality.

Background Glycoprotein IIb/IIIa blockers reduce procedure-related thrombotic complications of percutaneous coronary intervention, and the risk of death and myocardial infarction in patients with acute coronary syndromes. The effect on risk of death and myocardial infarction is particularly apparent in patients undergoing early percutaneous coronary interventions. We did a randomised, multicentre trial to study the effect of the glycoprotein IIb/IIIa blocker abciximab on patients with acute coronary syndromes who were not undergoing early revascularisation.Methods We enrolled 7800 patients who were admitted to hospital with chest pain and either ST-segment depression or raised troponin T or I concentrations. 2598 were randomly assigned placebo, 2590 an abciximab bolus and 24 h infusion, and 2612 an abciximab bolus and 48 h infusion; all patients received aspirin and either unfractionated or low-molecular-weight heparin. The primary endpoint was death or myocardial infarction at 30 days after randomisation. Analysis was by intention to treat.Findings There were no dropouts. 209 (8.0%) patients on placebo, 212 (8.2%) on 24 h abciximab, and 238 (9.1%) on 48 h abciximab died or had a myocardial infarction before day 30 (odds ratio 1.0 [95% CI 0.83-1.24], for difference between placebo and 24 h abciximab, and 1.1[0.94-1.39] for difference between placebo and 48 h abciximab). The lack of benefit from treatment with abciximab was consistent in most subgroups investigated; in particular, no benefit was seen in patients with raised cardiac troponin T or concentrations at enrolment, although these patients did have a strongly increased risk of subsequent events. Bleeding rates were low, but increased with abciximab, particularly when continued for 48 h. Additionally, thrombocytopenia was more frequent with abciximab than with placebo.Interpretations Although the explanations for our findings are unclear, this study indicates that abciximab is not beneficial as first-line medical treatment in patients admitted with acute coronary syndromes.

Background and Purpose-Abciximab is a potent parenterally administered platelet glycoprotein IIb/IIIa antagonist, Because:this agent has been shown to improve outcomes in coronary artery disease, there is interest to evaluate whether it could improve cerebral perfusion and outcomes after ischemic stroke. This study was designed to evaluate the safety of abciximab in acute ischemic stroke and to obtain pilot efficacy data.Methods-We conducted a randomized, double-blind, placebo-controlled, dose-escalation trial. Seventy-four eligible and consenting patients presenting within 24 hours after ischemic stroke onset at 38 study sites were randomly allocated to receive either an escalating dose of abciximab (54 patients)or placebo (20 patients) in a ratio of 3:1, We studied 4 escalating doses of abciximab. Patients underwent a scheduled follow-up head CT scan 24 to 36 hours after the completion:of study agent administration to monitor for bleeding complications and were evaluated through 3 months.Results-There were no cases of major intracranial hemorrhage, Asymptomatic parenchymal hemorrhages were detected on post-study agent CT in 4 of 54 abciximab patients (7%) and in 1 of 20 placebo patients (5%). Six additional abciximab patients had asymptomatic hemorrhagic lesions detected by unscheduled brain imaging during their follow-up period. Nine of 1 1 patients with asymptomatic hemorrhage had a:baseline National Institutes of Health Stroke Scale-score > 14. At 3 months, there was a trend toward a higher rate of minimal residual disability (Barthel Index greater than or equal to 95 or modified Rankin scale less than or equal to 1) among abciximab patients compared with those who received placebo.Conclusions-Abciximab appears to be safe when administered up-to 24 hours after stroke onset, and it might improve functional outcome.

Background-Low-dose alteplase with standard-dose abciximab enhances reperfusion 90 minutes after acute myocardial infarction (MI). We combined standard-dose abciximab with low-dose reteplase for acute M1 in 3 phases, Two heparin doses were also explored.Methods and Results-Phase A patients were randomized 4:1 to receive an abciximab bolus with infusion alone (n=63) or with 5 U, 7.5 U, 10 U, 5 U+2.5 U, or 5 U+5 U of reteplase (total n=241). Phase B tested the best phase A strategy (abciximab plus 5 U+5 U reteplase, expressed as abciximab-reteplase 5+5 U; n=115) against 10 U+10 U reteplase alone (n=109). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 60 to 90 minutes, In phase A, 62% of the abciximab-reteplase 5+5 U group had TIMI grade 3 now versus 27% of the abciximab-only patients (P=0.001). In phase B, 54% of the abciximab-reteplase 5+5 U group had grade 3 flow versus 47% of the reteplase-only patients (P=0.32). Grade 3 now rates were 61% for a 60 U/kg hepar in bolus and abciximab-reteplase 5+5 U, 51% for a 40 U/kg heparin bolus and abciximab-reteplase 5+5 U (P=0.22), and 47% for reteplase alone (P=0.05 versus the 60 U/kg heparin group). Major bleeding rates in phase A were 3.3% fur abciximab alone and 5.3% for abciximab-reteplase 5+5 U; rates in phase B were 9.8% for abciximab-reteplase 5+5 U and 3.7% for reteplase alone. Major bleeding was similar with standard- or low-dose heparin (6.3% versus 10.5%, P=0.30).Conclusions-In this phase II trial, adding reteplase to abciximab treatment of acute M1 versus reteplase alone enhanced the incidence of early complete reperfusion after the initiation of therapy in the emergency department.