Basic & clinical pharmacology & toxicology
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Basic Clin. Pharmacol. Toxicol. · Dec 2008
Increased hepatotoxicity and cardiac fibrosis in cocaine-treated butyrylcholinesterase knockout mice.
In mice, cocaine is detoxified to inactive products by butyrylcholinesterase (BChE) and carboxylesterase. In human beings, cocaine detoxification is primarily by BChE. The focus of this investigation was to elucidate the importance of BChE in reducing pathophysiological effects following cocaine exposure. ⋯ Liver and cardiac histology sections were analysed following a 20 mg/kg intraperitoneally dose of cocaine administered daily for 7 days. BChE-/- mice treated for 7 days with the chronic low dose showed significant hepatotoxicity and cardiac perivascular fibrosis compared to BChE+/+ mice. The observed functional changes following acute high-dose and chronic low-dose cocaine in BChE-/- and +/- mice warrants further investigation into the possibility of increased cocaine toxicity in human beings with BChE deficiency.
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Basic Clin. Pharmacol. Toxicol. · Nov 2008
Comparative StudyAntinociceptive and adverse effects of mu- and kappa-opioid receptor agonists: a comparison of morphine and U50488-H.
Although mu-opioids such as morphine are undoubtedly effective in the treatment of acute and postoperative pain, kappa-opioids are of interest for the modulation of visceral pain. In the present study, we compared a kappa-opioid agonist (U50488-H; 0.63-40 mg/kg) with a mu-opioid agonist (morphine; 0.63-40 mg/kg) in different pain models (tail withdrawal, writhing, formalin and plantar test) to represent acute, peritoneovisceral and inflammatory pain states in rats. The effects of the respective receptor agonists on gastrointestinal motility, muscle rigidity and abuse liability were also studied in appropriate animal models (charcoal, castor oil, rotarod and drug discrimination learning). ⋯ Although U50488-H did not elicit any gastrointestinal inhibition, a loss of muscle tone following administration of the compound led to detrimental effects on rotarod performance. The findings presented here indicate that kappa-opioids possess antinociceptive efficacy in visceral and inflammatory pain settings, but their administration can lead to a loss of muscle tone. In contrast, mu-opioids are highly active as analgesics against a range of nociceptive stimuli, but also concomitantly elicit strongly adverse effects.
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Basic Clin. Pharmacol. Toxicol. · Sep 2008
Tramadol-induced seizurogenic effect: a possible role of opioid-dependent gamma-aminobutyric acid inhibitory pathway.
The present study has been designed to pharmacologically investigate the role of opioid and gamma-aminobutyric acid receptors on the seizurogenic effect of tramadol. A single injection of pentylenetetrazole (80 mg/kg) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub's tail phenomenon, onset of jerky movements of whole body, convulsions and death. ⋯ Moreover, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Furthermore, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, also attenuated the seizurogenic activity exerted by tramadol per se. Therefore, it is suggested that tramadol exerts a seizurogenic effect on mice possibly via an opioid-dependent gamma-aminobutyric acid inhibitory pathway.
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Basic Clin. Pharmacol. Toxicol. · Mar 2008
Acute acetaminophen overdose is associated with dose-dependent hypokalaemia: a prospective study of 331 patients.
Hypokalaemia is a recognized complication of acute acetaminophen overdose. It is unclear whether this might be a pharmacological effect of acetaminophen, or due to association with confounding factors. The present study sought to better characterize the relationship between acetaminophen concentrations and risk of hypokalaemia. ⋯ A receiver operating characteristic showed that high acetaminophen concentrations were predictive of hypokalaemia (P = 0.0001 versus zero discriminatory line), and 4 hr acetaminophen concentration >156 mmol/l gave 81% sensitivity and 48% specificity. The risk of hypokalaemia after acute acetaminophen overdose depends on the extent of acetaminophen exposure, irrespective of N-acetylcysteine administration and independent of whether vomiting occurred. Acetaminophen appears to cause concentration-dependent hypokalaemia after overdose, and the pharmacological basis requires further consideration.
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Basic Clin. Pharmacol. Toxicol. · Mar 2008
Comparative StudyEffects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle.
Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. ⋯ Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC(50) of 1.2 +/- 0.1 and 1.5 +/- 0.2 mg/kg for azumolene and dantrolene sodium, respectively. Azumolene, 10 microM, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro. These studies provide evidence that azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that azumolene should be efficacious for treatment/prevention of malignant hyperthermia.