OBJECTIVES: The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazole, an inhibitor of CYP2E1, could prevent acetaminophen-induced liver injury in mice. METHODS: Acetaminophen, at doses ranging from 200 to 600 mg/kg, was injected into the peritoneum of female C57BL/6 inbred mice fasted for four hours. Chlormethiazole (60 mg/kg) or 5% dextrose water was given 30 min before or 2 h after acetaminophen. Serum aminotransferase activities, histologic index score, survival rate and hepatic malondialdehyde levels were compared. RESULTS: Pretreatment with chlormethiazole 30 min before 400 mg/kg of acetaminophen completely inhibited acetaminophen-induced liver injury (median 118.5 U/L, range 75 to 142 vs. 14,070 U/L, range 5980 to 27,680 for AST; 49 U/L, range 41 to 64 vs. 15,330 U/L, range 13,920 to 15,940 for ALT). In mice receiving chlormethiazole 2 h after acetaminophen, the mean AST and ALT levels were also less elevated, reaching only 20% of the value of acetaminophen-only group. These protective effects were confirmed histologically. Whereas more than 50% of mice died at 500 mg/kg of acetaminophen, all the mice pretreated with chlormethiazole survived at the same dose. CONCLUSION: Chlormethiazole effectively reduces acetaminophen-induced liver injury in mice. Further studies are needed to assess its role in humans.
Acetaminophen/toxicity* ; Acetaminophen/metabolism ; Acetaminophen/antagonists & inhibitors ; Analgesics, Non-Narcotic/toxicity* ; Analgesics, Non-Narcotic/metabolism ; Analgesics, Non-Narcotic/antagonists & inhibitors ; Animal ; Chlormethiazole/pharmacology* ; Cytochrome P-450 CYP2E1/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology ; Female ; Human ; Liver/metabolism ; Liver/injuries* ; Liver/drug effects* ; Mice ; Mice, Inbred C57BL ; Sedatives, Nonbarbiturate/pharmacology* ; Support, Non-U.S. Gov't

Aconitine ; analogs & derivatives ; pharmacology ; Analgesics, Non-Narcotic ; pharmacology ; Animals ; Female ; Intestine, Small ; physiology ; Male ; Mice ; Muscle Contraction ; drug effects ; Muscle, Smooth ; physiology ; Rabbits

OBJECTIVEBased on the therapeutic claims of Angong Niuhuang pill, a series of pharmacodynamic experiments were designed, where pharmacological effects were investigated comparatively with its simplified prescription(realgar and cinnabar are removed from the original pill) as a parallel control in order to explore possible contribution of cinnabar and realgar to pharmacodynamic activities of the pill as a whole.

METHODAnti-pyretic, sedative, anti-convulsive, and mice-protected effects of the pill and its simplified prescription as a control were observed, respectively, in rabbits with fever induced by typhoid bacillus, in pentobarbital sodium-induced sleeping mice, in mice with convulsion induced by strychnine, or pentylenetetrazole, and in mice with anoxia induced by NaNO2.

RESULTBoth the pill and its simplified prescription were found to have Anti-pyretic action and protective effect against the mouse death induced by anoxia, and synergistic interaction with pentobarbital sodium in sedative activity, although neither of them was found to have any effects on the convulsion of mice.

CONCLUSIONNo significant difference between Angong Niuhuang pill and its simplified prescription was found in the above pharmacodynamic experiments.

Analgesics, Non-Narcotic ; pharmacology ; Animals ; Anticonvulsants ; pharmacology ; Arsenicals ; pharmacology ; Drug Combinations ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Hypnotics and Sedatives ; pharmacology ; Male ; Materia Medica ; isolation & purification ; pharmacology ; Mercury Compounds ; pharmacology ; Mice ; Plants, Medicinal ; chemistry ; Rabbits ; Sulfides ; pharmacology

Spinal alpha-2 adrenoceptors and cholinergic receptors are involved in the regulation of acute nociception and the facilitated processing. The aim of this study was to examine the pharmacological effect of an intrathecal alpha-2 agonist and a cholinesterase inhibitor on the facilitated pain model induced by formalin injection and to determine the nature of drug interaction using an isobolographic analysis. Both intrathecal clonidine and neostigmine dose-dependently suppressed the flinching during phase 1 and phase 2. Intrathecal pretreatment with atropine reversed the antinociceptive effects of clonidine and neostigmine in both phases. Pretreatment with intrathecal yohimbine attenuated the effect of clonidine. The antinociception of clonidine and neostigmine was not reversed by mecamylamine. Isobolographic analysis showed that intrathecal clonidine and neostigmine acted synergistically in both phase 1 and 2. Intrathecal pretreatment with atropine and yohimbine antagonized the effect of the mixture of clonidine and neostigmine in both phases, but no antagonism was observed with mecamylamine pretreatment. These data indicate that spinal clonidine and neostigmine are effective to counteract the facilitated state evoked formalin stimulus, and these two drugs interact in a synergistic fashion. In addition, the analgesic action of intrathecal clonidine is mediated by spinal muscarinic receptors as well as alpha-2 adrenoceptors.
Adrenergic alpha-Agonists/*pharmacology ; Analgesics, Non-Narcotic/*pharmacology ; Animal ; Cholinesterase Inhibitors/*pharmacology ; Clonidine/administration & dosage/*pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; Formaldehyde ; Injections, Spinal ; Male ; Neostigmine/administration & dosage/*pharmacology ; Pain/drug therapy ; Rats ; Rats, Sprague-Dawley

Analgesics, Non-Narcotic ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Azetidines ; chemical synthesis ; chemistry ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Molecular Structure ; Nicotinic Agonists ; chemical synthesis ; chemistry ; pharmacology ; Pyridines ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship

Using patch clamp technique the effects of dragon's blood and its component loureirin B on tetrodotoxin-sensitive sodium channel currents in dorsal root ganglion cells were observed. The experimental data were simulated with Hodgkin-Huxley model and the corresponding parameters were estimated. In addition, computer-simulated neuron action potentials in the absence and presence of drugs were produced using Hodgkin-Huxley model. The results show that the conductance of tetrodotoxin-sensitive sodium channel was fitted with m3h model well, the half-activated potentials of the sodium channel in the presence of drugs were shifted to the depolarizing direction and the threshold intensity of the cells in the presence of drugs was increased. These results demonstrate that dragon's blood and loureirin B did not resemble the tetrodotoxin which inhibited tetrodotoxin-sensitive sodium channel currents completely. Perhaps the analgesic effects of dragon's blood were partly caused by loureirin B affecting the activation, blocking the action potential generation and interfering with the transmission of painful signals into the central nervous system.
Action Potentials ; drug effects ; Analgesics, Non-Narcotic ; pharmacology ; Animals ; Computer Simulation ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Ganglia, Spinal ; cytology ; Models, Biological ; Neurons ; drug effects ; Rats ; Resins, Plant ; pharmacology ; Sodium Channels ; drug effects ; Tetrodotoxin ; pharmacology

OBJECTIVETo clarify the resource of medicinal plants of genus Polygonum s. lat. distributed in Anhui Province.

METHODConducting field investigation and consulting related specimens and data.

RESULT AND CONCLUSIONThe distribution, growing environment and medicinal use of 32 taxa have been clarified. A scientific basis for further study for these medicinal plants has been provided.

Analgesics, Non-Narcotic ; pharmacology ; Antidiuretic Agents ; pharmacology ; China ; Conservation of Natural Resources ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Ecosystem ; Pharmacognosy ; Plants, Medicinal ; anatomy & histology ; chemistry ; classification ; Polygonum ; anatomy & histology ; chemistry ; classification

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.
Analgesics, Non-Narcotic ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; toxicity ; Animals ; Female ; Male ; Mice ; Pain Measurement ; Piperazines ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; toxicity ; Random Allocation ; Receptors, Opioid ; metabolism ; Structure-Activity Relationship

OBJECTIVETo observe the effect and mechanism of Tianyuan Ketong recipe (TKR) on the pain reaction in formalin induced pain model rats.

METHODSThe analgesic effect of TKR was evaluated using pain behavior graded scoring, the c-fos gene expression and P substance contents in superficial lamella of spinal cord dorsal horn in model rats were analyzed by means of immunohistochemical analysis and computer image analysis technique.

RESULTSTKR could markedly inhibit the pain reaction in model rats (P < 0.05), and the pain induced elevation of c-fos expression and P substance contents could also be suppressed (P < 0.05).

CONCLUSIONTKR shows definite analgesic effect on formalin induced pain model rats, the reduction of neuron's reaction in spinal cord dorsal horn to afferent noxious stimulation is possibly one of the pathways for its analgesic effect.

Analgesics, Non-Narcotic ; pharmacology ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Female ; Formaldehyde ; Immunohistochemistry ; Male ; Oncogene Proteins v-fos ; biosynthesis ; genetics ; Pain ; chemically induced ; metabolism ; Posterior Horn Cells ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; metabolism ; Substance P ; metabolism

A series of aralkyl-ketone-4-piperidol derivatives were synthesized and tested for their analgesic activities. All of the novel 30 compounds were prepared from 4-piperidone and alpha-halo-aralkyl-ketone through five steps, including Boc protection, nucleophilic addition in presence of CeCl3/NaI catalyst, deprotection, condensation and salification. Their structures were confirmed by 1H NMR and HRMS. Preliminary in vivo pharmacological trials showed that most of the synthesized compounds revealed analgesic effects. Among the tested compounds, 8, 13 and 22 exhibited potent analgesic activities in both mice writhing and mice hot plate model. The three compounds have low affinity for mu, delta, kappa receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.
Analgesics, Non-Narcotic ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Mice ; Molecular Structure ; Pain Measurement ; Pain Threshold ; drug effects ; Piperidones ; chemical synthesis ; chemistry ; pharmacology ; Receptors, Opioid, delta ; metabolism ; Receptors, Opioid, kappa ; metabolism ; Receptors, Opioid, mu ; metabolism ; Structure-Activity Relationship