Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · Nov 2012
Randomized Controlled Trial Comparative Study Clinical TrialRifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine.
Low-dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug-drug interactions. We examined the effect rifampicin, a well-known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S-ketamine in healthy volunteers. ⋯ Rifampicin decreased greatly the peak plasma concentration of oral S-ketamine by 81% (p < 0.001), but shortened only moderately the elimination half-life of intravenous and oral S-ketamine. Rifampicin decreased the ratio of norketamine AUC (0-∞) to ketamine AUC (0-∞) after intravenous S-ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S-ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S-ketamine, by inducing mainly its first-pass metabolism.
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Basic Clin. Pharmacol. Toxicol. · Nov 2012
Comparative StudyIncreasing membrane interactions of local anaesthetics as hypothetic mechanism for their cardiotoxicity enhanced by myocardial ischaemia.
While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, the pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly the site of cardiotoxic action of local anaesthetics and peroxynitrite is produced by cardiac ischaemia and reperfusion. We verified the hypothetic mechanism that local anaesthetics may interact with CL-containing biomembranes to change the membrane biophysical property and their membrane interactions may be increased by peroxynitrite. ⋯ Bupivacaine and lidocaine fluidized at 200 μM biomimetic membranes containing 10 mol% CL and their effects were increased by pre-treating the membranes with 0.1 and 1 μM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with CL-containing mitochondria model membranes which are relatively rigidified by peroxynitrite. Such an increasing membrane interaction may be, at least in part, responsible for the local anaesthetic cardiotoxicity enhanced by myocardial ischaemia.
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Basic Clin. Pharmacol. Toxicol. · Oct 2012
Changes in the neuronal glutamate transporter EAAT3 in rat brain after exposure to methamphetamine.
Methamphetamine (METH), an addictive psychostimulant, can induce glutamate release in several brain areas such as cerebral cortex, hippocampus and striatum. Excess glutamate is ordinarily removed from the synaptic cleft by glutamate transporters for maintaining homoeostasis. EAAT3, a subtype of glutamate transporter expressed mainly by neurons, is a major glutamate transporter in the hippocampus and cortex. ⋯ Our results of decreased EAAT3 in striatum and frontal cortex suggest deficits of cortico-striatal glutamatergic synapses after METH exposure. Increased EAAT3 expression in the hippocampus may be a compensatory response to possible deficits of glutamatergic neurotransmission induced by METH. Moreover, our findings provide further support for glutamatergic dysfunction with abnormalities involving a transporter important in the regulation of neuronal glutamate.
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Basic Clin. Pharmacol. Toxicol. · Aug 2012
Recurrent seizures in tramadol intoxication: implications for therapy based on 100 patients.
Tramadol is an atypical opioid analgesic used in the treatment of mild to moderate pain. Despite being a GABA(A) agonist, seizures are a prominent complication with its therapeutic use, abuse or overdose. For patients who have had a tramadol-induced seizure, the likelihood of recurrent seizures and the need for emergent anticonvulsant prophylaxis is unknown. ⋯ By our standard clinical protocol, none were treated with seizure prophylaxis after their first seizure. Only 7% had recurrent seizures and all patients recovered without sequelae. Because of the low risk of multiple seizures in tramadol poisoning and the lack of morbidity in patients who do seize, it appears to be unnecessary to administer prophylactic anticonvulsant therapy in patients with tramadol poisoning, even if they have an initial seizure.
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Basic Clin. Pharmacol. Toxicol. · Jun 2012
Randomized Controlled TrialAssessment of the analgesic effect of remifentanil using three pain models in healthy Korean volunteers: a randomized, controlled study.
Quantitative pain assessment in human beings is useful for developing new analgesics. This study assessed the analgesic effect of remifentanil in 20 healthy Korean men using three pain models to investigate whether these models can be used in Asians. The study was a double-blind, placebo-controlled, two-way cross-over study. ⋯ Remifentanil conferred a significantly higher pressure pain threshold and tolerance than placebo (p = 0.0001). There was a trend of increasing mechanical pain threshold with remifentanil, although it was not statistically significant. The results suggest that heat pain and pressure pain models are valid in East Asians for assessing analgesic effects.