Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke.

Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.

Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis.

OBJECTIVE: The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. METHODS: In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. RESULTS: The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. CONCLUSION: GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.

Fluticasone propionate aqueous nasal spray improves nasal symptoms of seasonal allergic rhinitis when used as needed (prn).

BACKGROUND: Few published clinical trials document the efficacy of intranasal corticosteroids used as needed for treatment of seasonal allergic rhinitis. OBJECTIVE: To evaluate the efficacy and safety of 4 weeks' treatment with fluticasone propionate aqueous nasal spray 200 microg used as needed (FP200PRN) in patients with seasonal allergic rhinitis. METHODS: A randomized, double-blind, placebo-controlled study in 241 patients (> or = 12 years of age) with a positive skin test result to a relevant fall allergen and who were symptomatic at randomization. The primary endpoint was the mean change from baseline in total nasal symptom score (TNSS; the sum of nasal congestion, rhinorrhea, sneezing, and nasal itching, each rated on a 4-point scale from 0 = none to 3 = severe). RESULTS: The mean percentage of days that patients used the study medications in the FP200PRN and placebo groups was 61.8% (SD = 30.4%) and 70.1% (SD = 28.3%), respectively. Patients treated with FP200PRN had a significantly greater reduction from baseline in TNSS compared with those treated with vehicle placebo (mean +/- SE = -2.02 +/- 0.18 vs -1.06 +/- 0.22, P < 0.001), representing a 91% greater improvement with FP200PRN than vehicle placebo. The FP200PRN group also had a significantly greater (P < 0.001) mean reduction in individual nasal symptoms of rhinorrhea, sneezing, nasal itching, and nasal congestion compared with placebo. FP200PRN was well tolerated, with an incidence of adverse events comparable to vehicle placebo. CONCLUSIONS: FP200PRN in patients 12 years and older is effective for treatment of nasal symptoms associated with seasonal allergic rhinitis. It has a lower incidence of adverse events than typically associated with regular once-daily use.

Relief of sinus pain and pressure with fluticasone propionate aqueous nasal spray: a placebo-controlled trial in patients with allergic rhinitis.

Although allergic rhinitis is commonly associated most with symptoms of nasal congestion, rhinorrhea, sneezing, and itching, the symptom of sinus pain and pressure often prompts the patient to seek medical attention. The effect of fluticasone propionate on this symptom has not been studied. The purpose of this study was to compare the efficacy and safety of fluticasone propionate aqueous nasal spray to placebo vehicle in the treatment of patients with sinus pain and pressure arising from allergic rhinitis. A multicenter, double-blind, parallel-group trial was conducted in 206 symptomatic patients > or = 12 years with seasonal or perennial allergic rhinitis. Patients were treated for 14 days with either fluticasone propionate aqueous nasal spray, 200 mcg once daily, or placebo vehicle. Patients attended clinic visits and kept diary cards rating sinus pain and pressure (measured as one symptom) and nasal congestion symptoms during the study. Treatment with fluticasone propionate provided significantly greater relief of symptoms of sinus pain and pressure compared with placebo over the entire 14-day treatment period. Nasal congestion scores also were significantly reduced compared with placebo at each time point. Treatments were well tolerated, and the incidence of adverse events attributable to study treatments was similar between groups. Our data indicate that symptoms of sinus pain and pressure and nasal congestion can be significantly reduced in patients with allergic rhinitis when treated with fluticasone propionate aqueous nasal spray, 200 mcg once daily.

Efficacy and safety of low-dose fluticasone propionate compared with montelukast for maintenance treatment of persistent asthma.

OBJECTIVE: To compare the long-term effects of an inhaled corticosteroid with those of a leukotriene modifier on measures of clinical efficacy, subject preference, and safety in patients with persistent asthma. PATIENTS AND METHODS: Between November 17, 1998, and May 26, 2000, we conducted a multicenter, randomized, double-blind, double-dummy, parallel-group study of patients aged 15 years or older with persistent asthma. The patients were symptomatic while taking short-acting beta2-agonists alone and were treated with fluticasone propionate (88 microg [2 puffs of 44 microg] twice daily) or montelukast (10 mg/d) for 24 weeks. Measures of pulmonary function, asthma symptoms, albuterol use, nighttime awakenings, physician assessments of efficacy, patient satisfaction, asthma-related quality of life, and safety were evaluated. RESULTS: A total of 522 patients were randomized to receive fluticasone or montelukast, and 395 patients completed the study. At end point, treatment with fluticasone significantly improved pulmonary function, asthma symptom scores, the percentage of symptom-free days, rescue albuterol use, and the number of nighttime awakenings due to asthma when compared with montelukast (P< or = .002, each comparison). Significantly more patients were satisfied with fluticasone therapy (83%) compared with montelukast therapy (66%) (P<.001), and fluticasone therapy was rated as effective by a significantly greater portion of physicians (67%) than was montelukast therapy (54%) (P<.001). Treatment with fluticasone significantly improved asthma-related quality-of-life measures compared with montelukast (P< or =.01). The incidence of asthma exacerbations was similar in the fluticasone (19 patients, 7%) and montelukast (21 patients, 8%) treatment groups, although slightly more patients in the montelukast group were withdrawn from the study because of asthma exacerbations (6% vs 4%, respectively). CONCLUSION: Long-term treatment with a low dose of inhaled fluticasone is more effective than oral montelukast as first-line maintenance therapy for the treatment of persistent asthma.