Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · Apr 2009
Antinociceptive properties of the hydroalcoholic extract and the flavonoid rutin obtained from Polygala paniculata L. in mice.
The present study examined the antinociceptive effects of a hydroalcoholic extract of Polygala paniculata in chemical and thermal behavioural models of pain in mice. The antinociceptive effects of hydroalcoholic extract was evaluated in chemical (acetic-acid, formalin, capsaicin, cinnamaldehyde and glutamate tests) and thermal (tail-flick and hot-plate test) models of pain or by biting behaviour following intratecal administration of both ionotropic and metabotropic agonists of excitatory amino acids receptors glutamate and cytokines such as interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) in mice. When given orally, hydroalcoholic extract (0.001-10 mg/kg), produced potent and dose-dependent inhibition of acetic acid-induced visceral pain. ⋯ The hydroalcoholic extract (0.1 mg/kg orally) antinociception, in the glutamate test, was neither affected by intraperitoenal treatment of animals with l-arginine (precursor of nitric oxide, 600 mg/kg) and naloxone (opioid receptor antagonist, 1 mg/kg) nor associated with non-specific effects such as muscle relaxation or sedation. In addition, oral administration of hydroalcoholic extract produced a great inhibition of the pain-related behaviours induced by intrathecal injection of glutamate, N-methyl-D-aspartate (NMDA), IL-1beta and TNF-alpha, but not by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), kainate or trans-1-amino-1.3-cyclopentanediocarboxylic acid (trans-ACPD). Together, our results suggest that inhibition of glutamatergic ionotropic receptors, may account for the antinociceptive action reported for the hydroalcoholic extract from P. paniculata in models of chemical pain used in this study.
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Basic Clin. Pharmacol. Toxicol. · Jan 2009
Ethylene glycol toxicity presenting with non-anion gap metabolic acidosis.
Ethylene glycol classically produces an elevated anion gap metabolic acidosis. We report a series of patients with ethylene glycol toxicity with a component of non-anion gap metabolic acidosis without known associated confounding factors. A retrospective review of Poison Control Center records were searched more than 8 years (2000-2007) for ethylene glycol and antifreeze. ⋯ The absence of a significant anion gap elevation in the setting of metabolic acidosis after ethylene glycol ingestion without other confounding factors (such as ethanol, lithium carbonate or bromide) has not previously been recognized. Clinicians should be aware of the potential for non-anion gap metabolic acidosis in patients with ethylene glycol toxicity, and should not exclude the diagnosis in patients who present with a non-anion gap metabolic acidosis. Further study is needed to determine the mechanisms by which this occurs.
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Basic Clin. Pharmacol. Toxicol. · Jan 2009
Comparative StudyComparison of the intramuscular, intranasal or sublingual routes of midazolam administration for the control of soman-induced seizures.
This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when midazolam was administered by different routes (intramuscular, intranasal or sublingual) at one of two different times after the onset of seizure activity. Guinea pigs previously prepared with cortical electrodes to record brain electroencephalographic activity were pre-treated with pyridostigmine (0.026 mg/kg, intramuscularly) 30 min. before challenge with a seizure-inducing dose of the nerve agent soman (56 microg/kg, subcutaneously), and 1 min. later, they were administered 2.0 mg/kg atropine sulfate admixed with 25.0 mg/kg 2-PAM Cl (intramuscularly). Groups of animals were administered differing doses of midazolam by the intramuscular, intranasal or sublingual route at either the onset of seizure activity or 40 min. after the onset of seizure activity that was detected in the electroencephalographic record. ⋯ Higher doses of midazolam were required to stop seizures at the 40-min. treatment delay time compared to immediate treatment. The speed of seizure control for intramuscular or intranasal midazolam was the same while sublingual midazolam acted significantly slower. Midazolam was effective in treating soman-induced seizures when given by all three routes, but with differences in potency and speed of action.
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Basic Clin. Pharmacol. Toxicol. · Jan 2009
Halothane-anaesthetized, closed-chest, guinea-pig model for assessment of drug-induced QT-interval prolongation.
For the halothane-anaesthetized, closed-chest, guinea-pig model, corrected QT interval (QTc) has been empirically used to estimate the extent of drug-induced QT-interval prolongation. In the present study, we employed an atrial pacing method to clarify a net effect of a drug on the QT interval in this model. ⋯ Using the QT/RR relationship under the sinus rhythm, we obtained the following two types of QT-interval correcting formulae; namely, QTc = QT - 0.207(RR - 300) by a linear regression method; and QTc = QT/(RR/300)0.332 by a non-linear regression method, the latter of which is equal to 0.67 times of Fridericia's formula, providing rationale for the use of mathematical correction in this model. Thus, the halothane-anaesthetized, closed-chest, guinea-pig model may be highly useful for assessing the drug-induced QT-interval prolongation, which may become an alternative to current models for the in vivo QT assay.
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Basic Clin. Pharmacol. Toxicol. · Jan 2009
Capsaicin- and mustard oil-induced extracellular signal-regulated protein kinase phosphorylation in sensory neurons in vivo: effects of neurokinins 1 and 2 receptor antagonists and of a nitric oxide synthase inhibitor.
Stimulation of primary sensory neurons with capsaicin or mustard oil leads to phosphorylation of extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) via activation of transient receptor potential V1 (TRPV1) or TRPA1, respectively. p-ERK1/2 was determined by Western immunoblotting in the dorsal root ganglia and in the sciatic nerve of rats following either systemic or perineural capsaicin treatment, or mustard oil application to the hind paw skin. To investigate the possible involvement of neurokinin 1 (NK(1)) and NK(2) receptors as well as of nitric oxide, the selective antagonists, SR140333 for NK(1) and SR48968 for NK(2), and the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), were employed. The increase of p-ERK1/2 after systemic capsaicin treatment was markedly attenuated by SR140333, while only the increase in the dorsal root ganglia was impaired by SR48968; in contrast, inhibition of nitric oxide synthase had no effect. ⋯ This effect was not influenced by SR140333 or L-NAME. We found for the first time that mustard oil application to the hind paw skin caused an increase in p-ERK1/2 in the sciatic nerve and in the dorsal root ganglia and only the phosphorylation in the latter was attenuated by SR140333 while L-NAME showed no effect. From the present results, it may be assumed that capsaicin- or mustard oil-induced p-ERK1/2 in sensory neurons is not solely directly linked to TRPV1 or TRPA1 channels, but under certain conditions NK(1)- and NK(2)-mediated mechanisms are involved.