Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice.

BACKGROUND: Curcumin, the active ingredient of turmeric (Curcuma longa), has a wide range of beneficial effects including anti-inflammation and analgesia. However, poor bioavailability of curcumin hinders its clinical application. To overcome this limitation, we modified the structure of curcumin and synthesized new derivatives with favourable pharmacokinetic profiles. Recently, curcumin has been shown to have an antagonizing effect on transient receptor potential vanilloid type 1 (TRPV1) ion channels. We investigated the antinociceptive activity of KMS4034 which had the most favourable pharmacokinetics among the tested curcumin derivatives. METHODS: To evaluate the mechanism of the antinociceptive effects of KMS4034, capsaicin (I(CAP))- and heat (I(heat))-induced currents in TRPV1 expressing HEK293 cells were observed after the application of KMS4034. Nociceptive behavioural measurement using the hot-plate test, formalin test, and chronic constriction injury (CCI) model were evaluated in mice. Also, calcitonin gene-related peptide (CGRP) was stained immunohistochemically in the L4/5 dorsal horns in mice with neuropathic pain. RESULTS: I(CAP) (P<0.01) and I(heat) (P<0.05) of TRPV1 were significantly blocked by 10 µM KMS4034. Behaviourally, noticeable antinociceptive effects after 10 mg kg(-1) of KMS4034 treatment were observed in the first (P<0.05) and second phases (P<0.05) of the formalin and hot-plate tests. The mechanical threshold of CCI mice treated with 10 mg kg(-1) KMS4034 was significantly increased compared with control. Immunohistochemical CGRP expression was decreased in the lamina I-II of the lumbar dorsal horns in KMS4034-treated CCI mice compared with the control (P<0.05). CONCLUSIONS: KMS4034 may be an effective analgesic for various pain conditions.

In vitro effects of ulinastatin on blood coagulation using thromboelastography.

AIM: The effects of ulinastatin, urinary trypsin inhibitor, on coagulation are not fully understood. The aim of the present study was to examine the in vitro effects of ulinastatin on coagulation using modified computerised thromboelastography (ROTEM®) with InTEM®. METHODS: A venous blood sample was obtained from the antecubital vein without stasis from 12 healthy adult men. A 290 µL aliquot of blood was combined with either 10 µL of ulinastatin (100 [U100], 200 [U200] or 1000 [U1000] U/mL) or 10 µL of normal saline. The samples were analysed simultaneously at 37 ºC on a four channel ROTEM® with InTEM®. RESULTS: Clotting time was significantly increased in the U200 (155.8±9.3 s) and U 1000 (173.6±14.5 s) groups, compared with the control group (136.1±12.6 s). The U 1000 group significantly increased clot formation time (77.6±16.2 s; control group, 63.8±13.4 s) and significantly decreased α angle (74.6±3.3º; control group, 77.4±2.4º). No significant difference in maximum clot firmness or maximum lysis was found between the control and ulinastatin groups. CONCLUSION: In-vitro ulinastatin had a direct anticoagulant effects, as assessed by ROTEM® with InTEM®, and the results were within the normal ranges.

Only tetracaine and not other local anaesthetics induce apoptosis in rat cortical astrocytes.

BACKGROUND: The potential risks of neurotoxicity due to local anaesthetics after regional anaesthesia have been suggested recently. To evaluate the neurotoxicity of commonly used local anaesthetics, primary cultured rat cortical astrocytes were treated with lidocaine, ropivacaine, bupivacaine, levobupivacaine, and tetracaine. METHODS: Cell death after local anaesthetic treatment was evaluated with a lactate dehydrogenase (LDH) assay. To examine the mechanisms of cell death, reactive oxygen species (ROS) measurement and western blots of poly-ADP ribose polymerase (PARP), procaspase-3, and mitogen-activated protein kinases family members were performed. RESULTS: Of the local anaesthetics, which were applied at <1 mM for 18 h, only tetracaine significantly increased LDH leakage (P<0.05) and cell death in a dose- and time-dependent manner. Hoechst 33258-propidium iodide staining and western blots with PARP and procaspase-3 antibodies suggested that tetracaine induced apoptosis. ROS levels increased 2-fold at 30 min after tetracaine treatment compared with the control and then decreased. The antioxidants, N-acetylcysteine and trolox, markedly inhibited tetracaine-induced apoptosis. CONCLUSIONS: Tetracaine induced apoptosis through ROS generation. Further studies focusing on the neurotoxicity of tetracaine are needed.

Bupivacaine induces apoptosis via ROS in the Schwann cell line.

Local anesthetics have been generally accepted as being safe. However, recent clinical trials and basic studies have provided strong evidence for the neurotoxicity of local anesthetics, especially through apoptosis. We hypothesized that local anesthetics cause neural complications through Schwann cell apoptosis. Among local anesthetics tested on the Schwann cell line, RT4-D6P2T, bupivacaine significantly induced cell death, measured by the methyl tetrazolium (MTT) assay, in a dose- (LD50 = 476 microM) and time-dependent manner. The bupivacaine-induced generation of reactive oxygen species (ROS), which was initiated within 5 hrs and preceded the activation of caspase-3 and poly ADP-ribose polymerase (PARP) degradation, was suggested to trigger apoptosis, exhibited by Hoechst 33258 nuclear staining and DNA fragmentation. Furthermore, concomitant block of ROS by anti-oxidants significantly inhibited bupivacaine-induced apoptosis. Among the local anesthetics for peripheral neural blocks, bupivacaine induced apoptosis in the Schwann cell line, which may be associated with ROS production.

Noninvasive cardiac output monitoring in paediatric cardiac surgery: correlation between change in thoracic fluid content and change in patient body weight.

OBJECTIVE: Change in thoracic fluid content (TFC) derived via a bioreactance technique with a noninvasive cardiac output monitoring device (NICOM) reportedly shows a good correlation with the amount of fluid removed. The present study prospectively evaluated the utility and clinical application of TFC in the intraoperative fluid management of paediatric patients with congenital heart disease, undergoing cardiac surgery with bioreactance-based noninvasive monitoring. METHODS: Haemodynamic parameters, patient body weight and parameters derived from the NICOM device (including cardiac output, cardiac index, TFC, percentage change in TFC compared with baseline [TFCd0%] and stroke volume variation) were recorded after anaesthesia induction but before surgical incision, and just before departure from the operating room to the intensive care unit. RESULTS: In the 80 paediatric patients included in this study, linear regression analyses demonstrated good correlations between body weight gain and TFCd0%, between body weight gain % and TFCd0%, and between intra operative fluid balance and TFCd0%. CONCLUSION: TFCd0% may be a useful indicator for intraoperative fluid management in paediatric patients with congenital heart disease, undergoing cardiac surgery.

The effect of ulinastatin on postoperative blood loss in patients undergoing open heart surgery with cardiopulmonary bypass.

This prospective, randomized, double-blind study evaluated the effect of ulinastatin on postoperative blood loss and transfusion requirements of patients undergoing open-heart surgery with cardiopulmonary bypass (CPB) and aortic cross-clamping (ACC). CPB and ACC produce variable systemic inflammatory reactions that are associated with multiorgan dysfunction via leucocytes, especially polymorphonuclear neutrophils (PMNs). PMNs increase blood loss and transfusion requirements. Ulinastatin, a urinary trypsin inhibitor, inhibits PMN activity and reduces the systemic inflammatory response. Patients received either 5000 U/kg ulinastatin or the equivalent volume of normal saline (control group) before ACC. Postoperative blood loss and transfusion requirements were recorded. Duration of intubation and length of stay in the intensive care unit (ICU) were also noted. There were no statistically significant between-group differences in postoperative blood loss and transfusion requirements. Ulinastatin caused a non-significant decrease in duration of intubation. Patients who received ulinastatin had significantly shorter ICU stays than control patients.

Myocardial injury in remifentanil-based anaesthesia for off-pump coronary artery bypass surgery: an equipotent dose of sevoflurane versus propofol.

This randomised controlled trial compared the effect of equipotent anaesthetic doses of sevoflurane (S group) versus propofol (P group), during remifentanil-based anaesthesia for off-pump coronary artery bypass surgery, on myocardial injury. Either sevoflurane or propofol was titrated to maintain bispectral index values between 40 and 50. In both groups, a targeted concentration of remifentanil 20 ng x ml(-1) was maintained during anaesthesia. The concentrations of creatine kinase MB and troponin I were measured before the start of surgery, on admission to the intensive care unit, and at 12 and 24 hours after intensive care unit admission. The postoperative values of creatine kinase MB (S group: 15.08 +/- 18.97, 20.78 +/- 20.92, 12.76 +/- 12.82 vs 2.09 +/- 1.54 ng x ml(-1); P group: 10.99 +/- 13.15 27.16 +/- 56.55 11.88 +/- 18.80 vs 1.84 +/- 1.67 ng x ml(-1)) and troponin I (S group: 3.56 +/- 5.19, 566 +/- 7.89, 3.35 +/- 4.55 vs 0.52 +/- 1.90 ng x ml(-1); P group: 2.42 +/- 3.33, 4.11 +/- 6.01, 3.04 +/- 5.31 vs 0.43 +/- 1.28 ng x ml(-1)) were significantly higher than preoperative values in both groups but there were no significant differences between the two groups. There were no significant differences in time to extubation (S group, 476 +/- 284 minutes; P group, 450 +/- 268 minutes) and intensive care unit length of stay (S group, 2775 +/- 1449 minutes; P group, 2797 +/- 1534 minutes) between the two groups. In conclusion, sevoflurane and propofol at equipotent doses guided by bispectral index with remifentanil 20 ng x ml(-1) had similar creatine kinase MB and troponin I values.