Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · Aug 2009
Effects of intrathecal injection of nicotine on the analgesic effects of isoflurane in a model of inflammatory pain.
The present study was designed to investigate the role of spinal neuronal nicotinic acetylcholine receptors in the analgesic effects of isoflurane. After having established the mice model of analgesia by intraperitoneally injecting (i.p.) appropriate doses of isoflurane, nicotine, a neuronal nicotinic acetylcholine receptor agonist was intrathecally injected. ⋯ Nicotine can partially antagonize the effects induced by isoflurane above. Spinal neuronal nicotinic acetylcholine receptors may be important targets for the analgesic effects of isoflurane in formalin pain.
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Basic Clin. Pharmacol. Toxicol. · Jul 2009
5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases myocardial glucose uptake during reperfusion and induces late pre-conditioning: potential role of AMP-activated protein kinase.
Late pre-conditioning protects against myocardial ischaemic-reperfusion injury. AMP-activated protein kinase (AMPK) is activated by exercise and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Early pre-conditioning involves AMPK activation and increased myocardial glucose uptake. ⋯ AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre-conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre-conditioning.
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Basic Clin. Pharmacol. Toxicol. · Jun 2009
Neuroprotective effects of diazepam, carbamazepine, phenytoin and ketamine after pilocarpine-induced status epilepticus.
Cell damage and spatial localization deficits are often reported as long-term consequences of pilocarpine-induced status epilepticus. In this study, we investigated the neuroprotective effects of repeated drug administration after long-lasting status epilepticus. Groups of six to eight Wistar rats received microinjections of pilocarpine (2.4 mg/microl, 1 microl) in the right dorsal hippocampus to induce a status epilepticus, which was attenuated by thiopental injection (35 mg/kg, i.p.) 3 hrs after onset. ⋯ Treatments improved spatial navigation during training trials and probe trial, with exception of ketamine. Interestingly, in the probe trial, only diazepam-treated animals showed preference for the goal quadrant. Our data point to significant neuroprotective effects of repeated administration of diazepam against status epilepticus-induced cell damage and cognitive disturbances.
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Basic Clin. Pharmacol. Toxicol. · May 2009
Necrotic actions of nitrogen-containing bisphosphonates and their inhibition by clodronate, a non-nitrogen-containing bisphosphonate in mice: potential for utilization of clodronate as a combination drug with a nitrogen-containing bisphosphonate.
Nitrogen-containing bisphosphonates (NBPs) exhibit powerful anti-bone-resorptive effects (ABREs) via inhibition of farnesyl pyrophosphate synthase during cholesterol biosynthesis. Clinical applications have disclosed an unexpected side effect, namely osteonecrosis of jaw bones, and although thousands of cases have been documented in the last few years the mechanism remains unclear. Since NBPs accumulate in bone-hydroxyapatite, more jaw bone osteonecrosis cases may come to light if NBPs continue to be used as they are being used now. ⋯ Clodronate, when injected together with an NBP, reduced or prevented the necrosis induced by that NBP, but not its ABRE. Clodronate reduced the amount of each NBP retained within tissues. These results, together with those of previous studies, suggest that (i) clodronate inhibits the inflammatory and necrotic actions of NBPs by inhibiting their incorporation into cells related to inflammation and/or necrosis, (ii) clodronate could be useful as a combination drug with NBPs for preventing their necrotic actions while retaining their ABREs and (iii) clodronate could also be useful as a substitution drug for NBPs in patients at risk of osteonecrosis of jaw bones.
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Basic Clin. Pharmacol. Toxicol. · Apr 2009
Randomized Controlled TrialThe hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism.
Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity, extensive metabolizers (EM). The objective of the study was to determine if the analgesic effect of oxycodone in human experimental pain depends on its metabolism to oxymorphone. ⋯ In the cold pressor test, there was less reduction in pain AUC on oxycodone for PM compared with EM (14% vs. 26%, P = 0.012, a difference of 12%, CI: 3%-22%). The plasma oxymorphone/oxycodone ratio was significantly lower in PM compared with EM (P < 0.001). Oxycodone analgesia seems to depend both on oxycodone itself and its metabolite oxymorphone.