Frontiers in pharmacology
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Frontiers in pharmacology · Jan 2019
Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.
Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. ⋯ In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.
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Frontiers in pharmacology · Jan 2019
The Nimodipine-Sparing Effect of Perioperative Dexmedetomidine Infusion During Aneurysmal Subarachnoid Hemorrhage: A Prospective, Randomized, Controlled Trial.
Background: Nimodipine can block the influx of calcium into the vascular smooth muscle cell and prevent secondary ischemia in patients with aneurysmal subarachnoid hemorrhage. However, the reduction of blood pressure after long-term intravenous administration of nimodipine has been associated with neurological deterioration. Yet, no effective solutions have been suggested to address this phenomenon. ⋯ There were no significant differences among the three groups in consumption of propofol, cisatracurium, fentanyl, and vasoactive drugs during operation, recovery time at PACU, satisfaction of patients and neurosurgeon, and number of applied urapidil and GCS during the first 48 h after surgery. The incidence of symptomatic cerebral vasospasm during 7 days after surgery, GOS of 3 months, and cerebral infarction after 30 days were also comparable among the three groups. Conclusions: Dexmedetomidine (infusion at 0.5 µg·kg-1 for 10 min, then adjusted to 0.4 µg·kg-1·h-1 during the surgery) significantly reduced the total consumption of nimodipine during the first 48 h after surgery and promoted early rehabilitation of patients although the incidences of symptomatic cerebral vasospasm, GOS, and cerebral infarction were not reduced.
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Frontiers in pharmacology · Jan 2019
Edgeworthia gardneri (Wall.) Meisn. Water Extract Ameliorates Palmitate Induced Insulin Resistance by Regulating IRS1/GSK3β/FoxO1 Signaling Pathway in Human HepG2 Hepatocytes.
The flower of Edgeworthia gardneri (Wall.) Meisn is commonly used in beverage products in Tibet and has potential health benefits for diabetes. However, the mechanisms underlying anti-insulin resistance (IR) action of the flower of E. gardneri are not fully understood. This study aims to investigate the effects of the water extract of the flower of E. gardneri (WEE) on IR in palmitate (PA)-exposed HepG2 hepatocytes. ⋯ The GLUT2 and GLUT4 translocation were also promoted by WEE treatment in PA-treated HepG2 cells. Taken together, WEE has potential anti-IR effect in PA-exposed HepG2 cells; the underlying mechanism of this action may be associated with the regulation of IRS1/GSK3β/FoxO1 signaling pathway. This study provides a pharmacological basis for the application of WEE in the treatment of metabolic diseases such as type 2 diabetes mellitus.
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Frontiers in pharmacology · Jan 2019
Respiratory Fluoroquinolones Monotherapy vs. β-Lactams With or Without Macrolides for Hospitalized Community-Acquired Pneumonia Patients: A Meta-Analysis.
Background: The choice of empirical antibiotic treatment for patients with community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We systematically reviewed the efficacy and safety of strategies of empirical treatment with respiratory fluoroquinolone monotherapy and β-lactam with or without macrolide for non-ICU hospitalized CAP patients. Methods: We searched databases including PubMed, the Cochrane Library (Issue11, 2018), EMbase, China National Knowledge Internet (CNKI), WanFang Data, VIP, and China Biology Medicine disc (CBMdisc) to identify randomized controlled trials (RCTs) involving the comparison of respiratory fluoroquinolone monotherapy and β-lactam with or without macrolide for the non-ICU hospitalized patients with CAP up to November 2018. ⋯ The advantage of respiratory fluoroquinolone was statistically significant on the drug-related adverse events (RR 0.87, 95% CI 0.77-0.97). Conclusions: Current evidence shows that fluoroquinolone monotherapy has similar efficacy and favorable safety compared with β-lactam with or without macrolide for non-ICU hospitalized CAP patients. Since the limitation of region, quantity and quality of included studies, more RCTs with large scale and high quality are needed to verify the above conclusion.
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Frontiers in pharmacology · Jan 2019
Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms.
Sigma-1 (σ1) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether σ1 receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, σ1 antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of σ1 inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice. ⋯ The repeated administration of S1RA twice a day during 10 days reduced SNI-induced cold, mechanical, and heat hypersensitivity without inducing analgesic tolerance during treatment. These effects were observed up to 12 h after the last administration, when S1RA was undetectable in plasma or brain, indicating long-lasting pharmacodynamic effects. These data suggest that σ1 antagonism may have therapeutic value for the treatment of neuropathic pain induced by the transection of peripheral nerves.