Contribution of a heating element to topical anesthesia patch efficacy prior to vascular access: results from two randomized, double-blind studies.

CONTEXT: Pain associated with superficial procedures, including intravenous (IV) access procedures, should be prevented when possible, especially in children. OBJECTIVES: To evaluate a topical local anesthetic patch containing lidocaine 70 mg/tetracaine 70 mg with a heating element designed to warm the skin and facilitate rapid delivery of local anesthetics into the skin. The pilot study was designed to provide data to inform the design of the definitive study to evaluate the impact of controlled heat on the efficacy of the lidocaine/tetracaine patch (patch) when applied before IV cannulation. METHODS: Subjects in the pilot study were randomized to eight groups that varied by heated vs. unheated patch, 20 vs. 30 minute application, and 16 vs. 18 G catheter. Subjects in the definitive study were randomized in a double-blind manner to receive either the heated or unheated patch, 20 minutes before vascular access, using a 16 G catheter in the antecubital space of the arm. In both studies, the primary efficacy measure was subject-reported pain intensity using a visual analog scale. RESULTS: Pilot study: Subjects who received the heated patch (n=43) vs. the unheated patch (n=37) had lower mean pain intensity scores (14.7 vs. 23.5mm, P=0.04). Pain intensity scores did not differ significantly by application time, but the difference between the 16 and 18 G catheter groups approached statistical significance (22.8 vs. 14.9 mm, P=0.05). Definitive study: Mean pain intensity scores for the heated patch group (n=124) vs. the unheated patch group (n=126) were 14.2 and 20.5mm, respectively (P=0.006). CONCLUSION: Heated patches provided significantly better pain relief compared with unheated patches. All the subjects tolerated the patches well, with few adverse effects.

TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques.

The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.

Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept.

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor fusion protein, is FDA approved for psoriasis and psoriatic arthritis. TNFalpha increases the synthesis of proinflammatory cytokines and leads to the activation of multiple signaling pathways, including nuclear factor kappa B (NF-kappaB). The Rel/NF-kappaB transcription factors play a central role in numerous cellular processes, including the stress response and keratinocyte proliferation and differentiation. Utilizing a phosphorylation-specific antibody, we examined the expression of active nuclear NF-kappaB/RelA via immunohistochemistry in normal skin, non-lesional psoriatic skin, lesional psoriatic skin, and lesional skin from patients treated with etanercept. There was no expression of active nuclear NF-kappaB in the normal epidermis, whereas a basal level of constitutive active phosphorylated NF-kappaB/RelA was present in uninvolved epidermis from psoriasis patients. There was also significant upregulation of active phosphorylated NF-kappaB/RelA in the epidermis from psoriatic plaques. Serial biopsies from psoriasis patients treated with etanercept at 1, 3, and 6 mo demonstrated a significant downregulation of phosphorylated NF-kappaB/RelA, which correlated with decreases in epidermal thickness, restoration of normal markers of keratinocyte differentiation, and clinical outcomes. These data suggest that activation of NF-kappaB plays a significant role in the pathogenesis of psoriasis and that a potential mechanism of action for TNF-targeting agents is downregulation of NF-kappaB transcriptional activity.

Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-alpha monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris.

OBJECTIVE: Infliximab monotherapy provided a rapid and high degree of clinical benefit in patients with moderate to severe psoriasis in a previously conducted trial. Herein we describe the pharmacodynamic and pharmacokinetic results observed in this clinical trial. METHODS: Patients with psoriasis received 5 or 10 mg/kg of infliximab or placebo at weeks 0, 2, and 6. Immunohistochemical analysis of lesional (weeks 0, 2, 10) and nonlesional (week 0) biopsies was conducted. Median infliximab half-life and peak serum concentrations over time were calculated. RESULTS: Infliximab immunotherapy resulted in rapid and dramatic decreases in epidermal inflammation and normalization of keratinocyte differentiation in psoriatic plaques; these changes preceded maximal clinical response. Infliximab concentrations were maintained above the detection limit (0.1 mg/mL) in the majority of patients through week 14. CONCLUSION: The clinical and immunohistologic data demonstrate a pivotal role for tumor necrosis factor-alpha in the pathogenesis of psoriasis and support further development of drugs targeting tumor necrosis factor-alpha.