OBJECTIVE-Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2( 5 H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. METHODS-DFU NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript RESULTS-DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E 2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injuryinduced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain.CONCLUSION-These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.Keywords 2-Arachidonoyl glycerol; Caspase-3; COX2 inhibitor; Eicosanoids; Endocannabinoid; Neuroinflammation; Rat behavior Traumatic brain injury (TBI) initiates a central inflammatory response that results in the increased production of prostaglandins and reactive oxygen species. These products may cause secondary insults to the brain (55,90,94). Cyclooxygenases catalyze the first step in the formation of prostaglandins from arachidonic acid, producing reactive oxygen species in the process. Cyclooxygenase-1 (COX1), present normally in most tissues, is thought to maintain essential physiological functions, such as gastric mucosal integrity, renal function, and platelet homeostasis (87,101). COX2, the inducible isoform, is expressed in the normal brain (30,87) but is rare or absent in most organs under normal conditions. As in the periphery (32,79), COX2 in the brain can be regulated by inflammatory cytokines (87), and prostaglandin production increases in response to pathological conditions of the central nervous system (3,70,72,89,107). ...

The purpose of this study was to investigate the efficacy of a novel steroid, fluasterone (DHEF, a dehydroepiandrosterone (DHEA) analog), at improving functional recovery in a rat model of traumatic brain injury (TBI). The lateral cortical impact model was utilized in two studies of efficacy and therapeutic window. DHEF was given (25 mg/kg, intraperitoneally) at the initial time point and once a day for 2 more days. Study A included four groups: sham injury, vehicle treated (n = 22); injured, vehicle treated (n = 30); injured, pretreated (5-10 min prior to injury, n = 24); and injured, posttreated (initial dose 30 min postinjury, n = 15). Study B (therapeutic window) included five groups: sham injury, vehicle treated (n = 17); injured, vehicle treated (n = 26); and three posttreatment groups: initial dose at 30 min (n = 18), 2 h (n = 23), or 12 h (n = 16) postinjury. Three criteria were used to grade functional recovery. In study A, DHEF improved beam walk performance both with pretreatment (79%) and 30-min posttreatment group (54%; p < 0.01, Dunnett vs. injured vehicle). In study B, the 12-h posttreatment group showed a 97% improvement in beam walk performance (p < 0.01, Dunnett). The 30-min and 12-h posttreatment groups showed a decreased incidence of falls from the beam, which reached statistical significance (p < 0.05, Dunnett). Tests of memory (Morris water maze) and neurological reflexes both revealed significant improvements in all DHEF treatment groups. In cultured rat mesangial cells, DHEF (and DHEA) potently inhibited interleukin-1beta-induced cyclooxygenase-2 (COX2) mRNA and prostaglandin (PGE2) production. In contrast, DHEF treatment did not alter injury-induced COX2 mRNA levels in the cortex or hippocampus. However, DHEF (and DHEA) relaxed ex vivo bovine middle cerebral artery preparations by about 30%, with an IC(50) approximately 40 microM. This was a direct effect on the vascular smooth muscle, independent of the endothelial cell layer. Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model. Possible mechanisms of action for this novel DHEA analog are discussed. These findings suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.

BACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3–74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2–111.0 mg/dL). RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [Cl]: 0.52–0.90) and 1.11 (95% Cl: 0.83–1.49), with treatment-lipoprotein(a) interaction on MACE ( P interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% Cl: 0.72–0.92) and 0.89 (95% Cl: 0.75–1.06), with P interaction = 0.43. CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402 )

BackgroundIndividuals with type 2diabetes mellitus (T2DM) commonly present with gastro intestinal symptoms. Exact pathophysiology behind these symptoms is not elucidated. Previous studies reported the role of adrenoceptors on gut motility. However, no study has been conducted to observe whether adrenergic beta receptor (ADRB) 2 and 3 gene polymorphism could influence the gut motility in T2DM. Materials and Methods:Three hundred T2DM patients and 200 age and sex matched healthy controls were enrolled for this study. Participants were subjected to lactulose hydrogen breath test for estimation of orocecal transit time (OCTT). To carry out polymorphism study, buffy coat of EDTA blood was used for DNA isolation followed by polymerase chain reaction and restriction fragment length polymorphism. Results:In this study, the frequency of C allele as well as CC genotype of ADRB3 gene polymorphism and A allele as well as AA genotype of ADRB2 gene polymorphism were significantly higher in patients than controls and was associated with increased risk for T2DM. On comparison of gut motility, OCTT was found to be significantly prolonged (p<0.01) in individuals with CC genotype compared to TT or CT genotype in ADRB3 polymorphism and AA genotype, compared to AG and GG genotype in case of ADRB2 polymorphism. Combined effect of both adrenoceptors on gut motility revealed that individuals having AG or AA genotype in combination with other genotypes had significantly prolonged OCTT. Conclusion:It could be concluded that beta adrenoceptor gene polymorphism has significant role on regulation of gut motility in T2DM.

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