Appropriate Timing of Fluoxetine and Statin Delivery Reduces the Risk of Secondary Bleeding in Ischemic Stroke Rats

Background: Ongoing clinical trials are testing the effect of fluoxetine delivered post-stroke where a majority of patients are taking statins. This study determined the influence of the timing of administration of fluoxetine and statin on the final infarct volume and the risk of secondary bleeding in an animal model of ischemic stroke. Methods and findings: Ischemic strokes were induced by endothelin-1 injection into two cortical sites of 10-12 month old female rats, targeting the forelimb motor cortex. Combined medications (5 mg/kg fluoxetine and 1 mg/kg simvastatin) were orally administered either beginning 6-12 hours or 20-26 hours after stroke induction and continued daily for 90 days. Infarct volumes were assessed at poststroke day 91 using Nissl stained coronal brain sections. Control animals typically had 5-13 mm3 infarct volumes following endothelin-1 induced stroke. Animals that received fluoxetine and simvastatin (FS) beginning 20- 26 hours after stroke induction showed a strong trend of reduced infarct volume (3±0.3447 mm3 SEM, P=0.0563). Earlier drug delivery (6-12 hours after stroke) resulted in significantly larger infarct volumes (15.44.260 mm3 SEM, P=0.0157) when the drug groups were directly compared. Examination of the infarcts showed that earlier drug delivery induced secondary hemorrhagic infarcts, while later delivery did not (P=0.0427; Fisher’s exact test). Conclusion: There is a danger of secondary bleeding if fluoxetine and simvastatin are combined within 6-12 hours of ischemic stroke induction in rats resulting in larger infarct volumes. Delaying fluoxetine and simvastatin delivery to 20-26 hours after stroke induction in rats, however, reduces infarct volume and significantly lowers the risk of secondary hemorrhagic infarcts

The Deformation of Expanded Clay Syntactic Foams during Compression Characterized by Acoustic Emission

The deformation and failure mechanisms in syntactic foams with different metal matrices were investigated in this study. The syntactic foams were produced by the infiltration method using lightweight expanded clay particles (LECA) as a space holder and commercially pure Al or eutectic Al-12%Si alloy for the matrices. The samples were compressed at room temperature; simultaneously, the acoustic emission (AE) response and the surface deformation were monitored and collated with the deformation curves. In the case of the Al foam, ductile behavior with long plateau stress was observed. During this plateau regime, multiple active shear bands were detected. In contrast, the AlSi12 foam exhibited more brittle deformation behavior. At the end of the quasi-linear stage, the localization of the strain started within one large shear band, accompanied by a significant stress drop. The AE analysis revealed that the deformation was mostly governed by the fracture of LECA particles and the plastic deformation of the matrix material for both types of foams. After strain localization, in the case of the AlSi12 foam, the fracture of the matrix became significant, causing the deterioration of the sample. As for the Al foam, besides the fracture of the LECA particles, the plastic deformation of the matrix played an important role in preventing the foam from falling apart

Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI – Mel.A.) [ISRCTN75125874]

BACKGROUND: High-dose interferon alfa-2b (IFNalfa-2b), according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma patients by the FDA and EMEA. However, the risk/benefit profile has been questioned limiting its world-wide use. In the late nineties, the Italian Melanoma Inter-group started a spontaneous randomized clinical trial (RCT) to verify if a more intense, but shorter than the ECOG 1684 regimen, could improve survival without increasing the toxicity profile. The safety analysis in the first 169 patients who completed the treatment is here described. METHODS: Stage III melanoma patients were randomized to receive IFNalfa-2b 20 MU/m(2)/d intravenously (IV) 5 days/week × 4 weeks, repeated for three times on weeks 9 to 12, 17 to 20, 25 to 28 (Dose-Dense/Dose-Intense, DD/DI, arm), or IFNalfa-2b 20 MU/m(2)/d IV 5 days/week × 4 weeks followed by 10 MU/m(2 )subcutaneously (SC) three times per week × 48 weeks (High Dose Interferon, HDI, arm). Toxicity was recorded and graded, according to the WHO criteria, as the worst grade that occurred during each cycle. RESULTS: The most common toxicities in both arms were flu-like and gastrointestinal symptoms, leukopenia, liver and neuro-psichiatric morbidities; with regard to severe toxicity, only leukopenia was statistically more frequent in DD/DI arm than in HDI arm (24% vs 9%) (p = 0.0074), yet, this did not cause an increase in the infection risk. Discontinuation of treatment, due to toxicity, was observed in 13 and 17% of the patients in the DD/DI and HDI arm, respectively. The median actual dose intensity delivered in the DD/DI arm (36.4 MU/m(2)/week) was statistically higher than that delivered in the HDI arm (30.7 MU/m(2)/week) (p = 0.003). CONCLUSION: Four cycles of intravenous high-dose IFNalfa-2b can be safely delivered with an increase in the median dose intensity. Efficacy results from this trial are eagerly awaited

Phytopharmacologic preparations as predictors of plant bioactivity: A particular approach to Echinacea purpurea (L.) Moench antioxidant properties

Objective A large body of evidence has confirmed a multitude of health benefits of plant products and their derived formulations. Echinacea purpurea (L.) Moench is a good example, widely used due to its therapeutic properties. In the present study, the chemical composition of the different samples and antioxidant properties of E. purpurea hydroethanolic and aqueous extracts obtained from dry or fresh raw material were evaluated and compared with dietary supplements based on the same plant (tablets and syrup), to determine the most active phytopharmacologic preparation or formulation. Methods Chemical composition of the different samples was assessed through the determination of free sugars, organic acids and tocopherols. The in vitro antioxidant properties were determined using four assays: 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals scavenging activity, reducing power, inhibition of b-carotene bleaching and inhibition of lipid peroxidation by thiobarbituric acid reactive substances (TBARS) assay. Total phenolics and flavonoids were also determined. Results Overall, the hydroethanolic extract of fresh plant revealed the highest activity, directly related with its higher contents in phenolic (229.22 ± 4.38 mg gallic acid equivalent [GAE]/mL), flavonoids (124.83 ± 7.47 mg GAE/mL), organic acids (8.89 ± 0.10 g/100 g), and tocopherols (4.55 ± 0.02 mg/100 g). Tablets followed by syrup revealed the worst effect, positively correlated with the lowest abundance in bioactive molecules. The weak in vitro antioxidant potential of commercial phytopharmacologic formulations could be related to their chemical composition, including the addition of excipients. Conclusion Further studies are necessary to deepen knowledge on this area, namely focusing on in vivo experiments, to establish upcoming guidelines to improve the quality and bioavailability of phytopharmacologic formulations.The authors are grateful to Foundation for Science and Technology (FCT, Portugal) for financial support to the research center CIMO (strategic project PEst-OE/AGR/UI0690/2014) and L. Barros researcher contract under “Programa Compromisso com Ciência – 2008”