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Shogaols are a group of the active constituents of ginger that have been identified to have various biological activities. The aim of the current study was to investigate the antitumor activity of 6-shogaol in hepatocellular carcinoma (HCC) and the possible involvement of reactive oxygen species as a putative mechanism of action. HCC cell lines, HepG2 and Huh-7, were used to study the in vitro anti-cancer activity of 6-shogaol via the application of various molecular biology techniques. Results showed that 6-shogaol effectively inhibited the cell viability, caused cell cycle arrest at G2/M phase and induced apoptosis in HCC cells as indicated by MTT assay, DAPI nuclear staining, annexin V assay, cell cycle analysis, and activation of caspase-3. Western blot analysis revealed the ability of 6-shogaol to target cancer survival signaling pathways mediated by mitogen-activated protein kinase (MAPK), 5' AMP-activated protein kinase (AMPK) and Akt. In addition, 6-Shogaol induced alteration of cyclin proteins expression and caused cleavage of protein kinase C delta. Furthermore, 6-Shogaol was able to induce the production of reactive oxygen species and endoplasmic reticulum (ER) stress-associated proteins and the consequent activation of autophagy in HepG2 cells. Taken together, the current study highlights evidences that 6-shogaol induces apoptosis, modulates cyclins expression and targets cancer survival signaling pathways in HCC cell lines, at least in part, via the production of reactive oxygen species. These findings support 6-shogaol's clinical promise as a potential candidate for HCC therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. Our data demonstrated that orphenadrine and lidocaine elicited dose-dependent spinal blockades on the motor function, sensory, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potency in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01). At equipotent doses (ED25, ED50, ED75), the block duration elicited by orphenadrine was greater than that elicited by lidocaine (P<0.01). Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the relative potency was bupivacaine [2.05 (1.95-2.21) μmol/kg]>propranolol [9.21 (9.08-9.42) μmol/kg] (P<0.01 for each comparison). Subcutaneous epinephrine (0.012 μmol/kg) did not produce cutaneous analgesia. Mixtures of epinephrine (0.012 μmol/kg) with drugs (propranolol or bupivacaine) at ED50 or ED95, respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED95 with epinephrine (0.012 μmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to examine whether thioxanthine-type antipsychotics (chlorprothixene and cis(z)-flupenthixol) and phenothiazine-type antipsychotics (chlorpromazine and fluphenazine) produced spinal anesthesia. Using a rat model of intrathecal injection, we evaluated spinal anesthesia of antipsychotic drugs (chlorprothixene, cis(z)-flupenthixol, chlorpromazine, and fluphenazine) and bupivacaine, a known local anesthetic. At a same dose of 2.31 μmol/kg, chlorprothixene had the most potent spinal blockades (P<0.001) and the longest duration of action (P<0.001) of motor function and nociception among those antipsychotic drugs. On the 50% effective dose (ED(50)) basis, the ranks of potencies were chlorprothixene=bupivacaine>cis(z)-flupenthixol>chlorpromazine>fluphenazine (P<0.01 for the differences) in dose-response studies. At an equianesthetic basis (ED(25), ED(50), and ED(75)), the spinal block duration caused by chlorprothixene, cis(z)-flupenthixol, chlorpromazine or fluphenazine was longer than that caused by bupivacaine (P<0.05). These results showed that chlorprothixene produced a similar potency and longer duration of spinal anesthesia than did bupivacaine, whereas several other antipsychotics produced less potency than did bupivacaine., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED(50)), the rank of potencies was bupivacaine [1.8 (1.7-2.0)]>memantine [19.1 (17.6-21.8)]>amantadine [36.1 (32.0-40.3)] (P<0.05). On ED(25), ED(50) and ED(75) basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the local anesthetic effect of nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with nisoxetine, dose-response curves were constructed. The cutaneous anesthetic effect of nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was nisoxetine>MK-801>lidocaine (P<0.01) as infiltrative anesthesia of skin. On an equianesthetic doses (20% effective dose [ED₂₀], ED₅₀, and ED₈₀), nisoxetine produced longer action of cutaneous anesthesia than that of lidocaine or MK-801 (P<0.01). Coadministration of nisoxetine or lidocaine with MK-801 showed an additive cutaneous anesthesia. Neither local injection of a large dose of nisoxetine, MK-801 nor lidocaine in the thigh area produced cutaneous anesthesia (data not shown). In conclusion, nisoxetine had a local anesthetic effect as infiltrative cutaneous analgesia with durations of actions longer than that of lidocaine or MK-801. That N-methyl-d-aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of nisoxetine or lidocaine., (© 2011. Published by Elsevier B.V.)

The aim of this study was to evaluate the local anesthetic effects of pheniramine and diphenhydramine, two histamine H₁ receptor antagonists, on spinal anesthesia and their comparison with lidocaine, a commonly used local anesthetic. After rats were injected intrathecally with diphenhydramine and pheniramine, the dose-response curves were obtained. The potency and duration of diphenhydramine and pheniramine on spinal anesthesia were compared with lidocaine. We showed that diphenhydramine and pheniramine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED₅₀) basis, the rank of potency of drugs was diphenhydramine=pheniramine>lidocaine (p<0.05 for the differences). In equianesthetic doses (ED₂₅, ED₅₀, and ED₇₅), the block duration caused by diphenhydramine was longer than that caused by pheniramine or lidocaine (p<0.01 for the differences). Diphenhydramine, but not pheniramine or lidocaine, elicited longer duration of sensory block than that of motor block at the same dose of 1.75 μmol. These preclinical data reported that diphenhydramine with a more sensory-selective action over motor blockade demonstrated more potent and longer-lasting spinal blockades, compared with pheniramine or lidocaine., (Copyright © 2011 Elsevier B.V. All rights reserved.)

To prevent cardiovascular effects of peripherally administered propranolol, the aim of this study was to evaluate the spinal anesthetic effect of propranolol, a Na(±) channel blocker. After rats were injected with drugs intrathecally, the spinal anesthetic effect of propranolol was compared with that of lidocaine, which is known to produce local anesthesia. We also evaluated the effect of the addition of clonidine with propranolol on spinal anesthesia. Our results showed that propranolol produced a dose-dependent spinal blockade in motor, proprioception, and nociception. On a 50% effective dose (ED(50)) basis, the spinal anesthetic effect of propranolol in motor, proprioception, and nociception [1.16 (1.01-1.34), 1.10 (0.92-1.31), 1.05 (0.89-1.24)] was equal to lidocaine [1.03 (0.94-1.13), 0.95 (0.84-1.07), 0.87 (0.79-0.96)], respectively. On an equipotent basis (0.5, 1.0, 2.5 μmol), the sensory/nociceptive block duration caused by propranolol was longer than that caused by lidocaine (P≤0.01). Co-administration of propranolol (1.1 μmol) and clonidine (0.5 μmol) produced greater spinal anesthesia than propranolol (1.1 μmol) or clonidine (0.5 μmol) alone. These preclinical findings demonstrated that propranolol produces similar spinal anesthesia to lidocaine and that α(2)-adrenergic receptors also contribute to improve the quality and duration of the spinal anesthetic effect of propranolol. Propranolol with a more sensory-selective action over motor blockade elicited longer spinal blockade than did lidocaine., (Copyright © 2011. Published by Elsevier B.V.)