To evaluate the equivalence of the pharmacokinetic, pharmacodynamic and safety properties of two recombinant G-CSF formulations in healthy male volunteers, a standard 2-way randomized crossover double-blind study, with a 3 week washout period, was conducted. A single 300 microg G-CSF dose was administered subcutaneously. Hebervital (Heber Biotec, Havana, formulation A) and Neupogen (Hoffmann-La Roche S.A, formulation B) were compared. Twenty-four healthy male volunteers were included. The serum G-CSF level was measured by enzyme immunoassay (EIA) during the first 36 h after administration. Absolute neutrophils (ANC), white blood cells (WBC) and CD34+ cells counts were the pharmacodynamic variables measured up to 120 h. Other clinical and laboratory determinations were used as safety criteria. The pharmacokinetic parameters for formulation A and B were very close to each other (i.e. AUC, 235.9 vs 270.0 ng.h/ml; C(max), 29.2 vs 33.4 ng/ml; T(max), 4.2 vs 4.7 h; half-life, 3.2 vs 2.8 h; CL, 260.9 vs 277.2 ml/h; V(d), 1.2 vs 1.1 l; and MRT, 7.58 vs 7.38 h). The confidence intervals for the means ratio of all these parameters were within or very close to the 0.8-1.25 acceptance range. The pharmacodynamics showed high similarity since ANC and WBC had the same profiles for both products and no differences were detected for the estimated parameters. The CD34+ cells count increments were evident for both formulations in a similar way as well. The treatments were well tolerated. Registered adverse events were similar; back/spine pain was the most frequent. According to the overall results these formulations could be considered as clinically comparable.
Background: TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial
Background: The chemokine receptor CCR3 mediates the migration of cells that play an important role in the pathogenesis of asthma to inflammatory foci. Interferon (IFN)-γ is known to downregulate the expression of some chemokine receptors. Therefore, we decided to analyze the regulation of CCR3 by IFN-γ in asthmatics and to characterize the dependence of this process on immunoglobulin E (IgE) levels. Methods: Atopic asthmatics were treated with IFN-γ or placebo, and the IgE concentration in the blood was measured using an ultra-micro-ELISA for total IgE. Mononuclear cells from patients and controls were isolated by Ficoll-Hypaque gradient and incubated in the absence or presence of IFN-γ for different periods of time. After incubation, the cells were washed and lysed for RT-PCR analysis, which was performed using a Perkin-Elmer kit. Results: IFN-γ treatment apparently improved the evaluated clinical variables; however, the differences were not significant compared to the placebo group. We found that IFN-γ downregulated CCR3 mRNA expression ex vivo and in vivo in those patients with IgE levels higher than 500 IU/ml, whereas IFN-γ upregulated CCR3 mRNA expression in patients with IgE levels lower than 500 IU/ml. Correspondence between ex vivo and in vivo results was observed using this approach. There was found to be a direct correlation between total serum IgE and CCR3 mRNA expression. Conclusions: In those asthmatic patients with high levels of IgE, who are thus susceptible to downregulation of CCR3 by IFN-γ, a significant therapeutic effect with systemic IFN-γ might be expected.
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