Postgraduate medical journal
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Concomitant administration of flupirtine maleate at a single low dose (15 mg/kg, mice; 35 mg/kg, rats) with a wide range of doses of each of the peripherally acting analgesics enhanced the antinociceptive activity of paracetamol, acetylsalicyclic acid and ibuprofen in the acetic acid writhing test, acetylsalicylic acid in the hot plate test and paracetamol, acetylsalicyclic acid and ibuprofen in the Randall-Selitto test. The concomitant administration of a single low dose of the peripherally acting analgesics (at about 1/2 ED50) with a wide range of doses of flupirtine maleate resulted in enhancement of flupirtine maleate analgesic activity by paracetamol (in the hot plate and Randall-Selitto tests), acetylsalicyclic acid (in the acetic acid writhing test), ibuprofen (in the Randall-Selitto test) and indomethacin (in the acetic acid and Randall-Selitto tests). Thus flupirtine maleate enhanced the analgesic activity of paracetamol, acetylsalicyclic acid and ibuprofen in mice and rats. Each of the peripherally acting analgesics enhanced the analgesic activity of flupirtine maleate in one or more of the analgesic tests used.
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Flupirtine maleate is a centrally acting analgesic with a novel chemical structure and pharmacological profile. Because of its central mechanism(s) of action, flupirtine maleate was studied for physical dependence liability and abuse potential using the following four laboratory animal models: (1) mouse jumping test--jumping behaviour after narcotic antagonist challenge; (2) Hosoya test in rats--body weight reduction after drug withdrawal or narcotic antagonist challenge; (3) tolerance in mice--reduced analgesic activity after repeated dosing; and (4) self-administration in addicted Rhesus monkeys. Unlike the narcotic analgesic agents morphine and codeine, flupirtine maleate did not display evidence of physical dependence liability or abuse potential as measured by jumping behaviour in mice or body weight reduction in rats following repeated oral administration. ⋯ No tolerance developed to the analgesic activity of flupirtine maleate in mice or rats dosed for up to 19 consecutive days. Finally, in morphine-dependent Rhesus monkeys, there was no difference in the rate of self-administration of flupirtine maleate when compared to the saline vehicle. Therefore, these results clearly show that flupirtine maleate, in animals, is without abuse potential and physical dependence liability.
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Comparative Study
Comparative physical dependence studies in rats with flupirtine and opiate receptor stimulating analgesics.
In physical dependence studies in rats the principle criterion was loss of body weight after withdrawal of the dependence producing drug. Other typical signs of withdrawal were also observed. In contrast to buprenorphine, codeine and tramadol, flupirtine caused no decrease in body weight and no other withdrawal symptoms. Flupirtine does not produce opiate type physical dependence.
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The antinociceptive activity of flupirtine was measured in various test procedures predictive of analgesic activity. In the electrostimulated pain test in mice the oral ED50 for flupirtine was 25.7 mg/kg p.o. Thus, flupirtine was approximately 31.7 times more potent than paracetamol (ED50: 814 mg/kg p.o.) and as potent as pentazocine (ED50: 38.5 mg/kg p.o.). ⋯ Whereas buprenorphine and tramadol showed a striking similarity in the pharmaco-electroencephalogram recorded from different parts of the brain (frontal cortex, thalamus, striatum and the mesencephalic reticular formation) of the freely moving rat, flupirtine was clearly different in action. It produced dose dependent increases in nearly all frequency bands but its effects were different from those of the minor tranquillizer diazepam and the anticonvulsant phenobarbitone. These findings show that the central antinociceptive activity of flupirtine is not based on an opiate mechanism and is not comparable with that of diazepam and phenobarbitone.
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The mechanisms of the antinociceptive action of flupirtine, a novel non-opioid analgesic, were investigated in animals. It was found that this effect could be abolished by pre-treatment with reserpine. Furthermore, it could be dose-dependently antagonized by yohimbine and changes in the EEG of the rat observed after administration of flupirtine were closely related to those obtained after giving clonidine. On these pharmacological results, it is likely that the antinociceptive activity of flupirtine is due to activation of descending noradrenergic pathways.