Dexmedetomidine inhibits LPS-induced inflammatory responses through peroxisome proliferator-activated receptor gamma (PPARγ) activation following binding to α2 adrenoceptors.

Over the past decade, dexmedetomidine (DEX) has been found to possess an anti-inflammatory effect. However, the local anti-inflammatory mechanism of DEX has not been fully clarified. Some intracellular inflammatory pathways lead to negative feedback during the inflammatory process. The cyclooxygenase (COX) cascade synthesizes prostaglandins (PGs) and plays a key role in inflammation, but is known to also have anti-inflammatory properties through an alternative route of a PGD2 metabolite, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), and its receptor, peroxisome proliferator-activated receptor gamma (PPARγ). Therefore, we hypothesized that DEX inhibits LPS-induced inflammatory responses through 15d-PGJ2 and/or PPARγ activation, and evaluated the effects of DEX on these responses. The RAW264.7 mouse macrophage-like cells were pre-incubated with DEX, followed by the addition of LPS to induce inflammatory responses. Concentrations of TNFα, IL-6, PGE2, and 15d-PGJ2 in the supernatants of the cells were measured, and gene expressions of PPARγ and COX-2 were evaluated in the cells. Furthermore, we evaluated whether a selective α2 adrenoceptor antagonist, yohimbine or a selective PPARγ antagonist, T0070907, reversed the effects of DEX on the LPS-induced inflammatory responses. DEX inhibited LPS-induced TNFα, IL-6, and PGE2 productions and COX-2 mRNA expression, and the effects of DEX were reversed by yohimbine. On the other hand, DEX significantly increased 15d-PGJ2 production and PPARγ mRNA expression, and yohimbine reversed these DEX's effects. Furthermore, T0070907 reversed the anti-inflammatory effects of DEX on TNFα and IL-6 productions in the cells. These results suggest that DEX inhibits LPS-induced inflammatory responses through PPARγ activation following binding to α2 adrenoceptors.

Assessing the Effectiveness of Combined Analgesics for Bilateral Ramus Osteotomies.

Pain management is important for alleviating patients' suffering and early recovery. Although analgesic combinations are known to be effective, a comparison of the effectiveness of different combinations has never been performed specifically for ramus osteotomy procedures. Therefore, the purpose of this observational retrospective cohort study was to identify an effective combination for pain management throughout the intraoperative and immediate postoperative period for patients undergoing bilateral ramus osteotomy procedures. Inclusion criteria consisted of patients who had undergone bilateral mandibular ramus osteotomies over a 2-year period. The analyzed predictor variables included patient gender, age, body weight, operation, anesthetic method, duration of operation, intraoperative use of fentanyl, nonsteroidal anti-inflammatory drugs (NSAIDs), and intravenous acetaminophen administered in the operating room at the end of the surgery. The outcome variable was the necessity for additional rescue analgesics (yes/no) in the recovery room. Bivariate statistics and multivariate analysis were computed with a p-value of <0.05. The study sample was comprised of 78 patients requiring bilateral mandibular ramus osteotomies. From the multivariate analysis, the combination of NSAIDs-acetaminophen-fentanyl was an independent factor for no additional rescue analgesics during the first 1 hour after bilateral ramus osteotomies, indicating that the combination is significantly effective for bilateral ramus osteotomies compared with the other combinations. Considering that this study consisted of a small sample size, the results of this study suggest that some of the combinations, particularly NSAIDs-acetaminophen-fentanyl, are more effective than NSAIDs alone for postoperative pain control immediately following bilateral ramus osteotomy procedures.

Multi-drug therapy for epilepsy influenced bispectral index after a bolus propofol administration without affecting propofol's pharmacokinetics: a prospective cohort study.

Some previous studies have indicated that valproate (VPA) might change the pharmacokinetics and enhance the effects of propofol. We evaluated whether clinical VPA therapy affected the propofol blood level, the protein-unbound free propofol level, and/or the anesthetic effects of propofol in the clinical setting. The subjects were divided into the control group (not medicated with antiepileptics), the mono-VPA group (medicated with VPA alone), and the poly-VPA group (medicated with VPA, other antiepileptics, and/or psychoactive drugs). General anesthesia was induced via the administration of a single bolus of propofol and a remifentanil infusion, and when the bispectral index (BIS) exceeded 60 sevoflurane was started. There were no significant differences in the total blood propofol level at 5, 10, 15, and 20 min or the protein-unbound free propofol level at 5 min after the intravenous administration of propofol between the 3 groups. However, the minimum BIS was significantly lower and the time until the BIS exceeded 60 was significantly longer in the poly-VPA group. In the multivariate regression analysis, belonging to the poly-VPA group was found to be independently associated with the minimum BIS value and the time until the BIS exceeded 60. Clinical VPA therapy did not influence the pharmacokinetics of propofol. However, multi-drug therapy involving VPA might enhance the anesthetic effects of propofol.

Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

BACKGROUND: Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. METHODS: After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells. RESULTS: The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNF-alpha in the incubated cells. CONCLUSION: The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.

In vitro changes in the proportion of protein-unbound-free propofol induced by valproate.

PURPOSE: It has been reported that oral valproate (VPA) reduces the dose of propofol required for sedation. As  a potential reason for this, it is considered that VPA displaces serum protein-bound propofol and increases the proportion of protein-unbound-free propofol. To examine this hypothesis, the present in vitro study investigated the influence of VPA on the proportion of protein-unbound-free propofol in human serum samples. METHODS: Serum samples were collected from 10 healthy volunteers, who were not taking any medication. VPA (final concentration: 0.05, 0.1 or 1 mg/mL) and propofol (final concentration: 1 or 5 µg/mL) were mixed with serum samples with normal (4.0 g/dL) or low (2.5 g/dL) albumin concentrations. Then, protein-unbound-free propofol was extracted from the samples, and its concentration was measured using high-performance liquid chromatography. We compared the proportion of protein-unbound-free propofol in each of the VPA-containing samples with that in serum samples without VPA (control). RESULTS: In the serum samples with normal albumin concentrations, 1 mg/mL VPA significantly increased the proportion of protein-unbound-free propofol at 1 and 5 µg/mL propofol. Furthermore, in the serum samples with low albumin concentrations, the proportion of protein-unbound-free propofol was significantly increased by both 0.1 and 1 mg/mL VPA at propofol concentrations of 1 and 5 µg/mL. CONCLUSION: VPA might increase the proportion of protein-unbound-free propofol in human serum via displacement reactions.