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Valproate and baclofen dose-dependently inhibited both phases of the formalin test. Combination of valproate and baclofen exerted the additive antinociceptive effect on both phases of the formalin test.

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Newly diagnosed epileptic patients start their medication with monotherapy. Around 30% of epileptic patients require more than one antiepileptic drug. Results from experimental studies provide evidence that administration of two antiepileptic drugs may result in antagonistic, additive, or supra-additive (synergistic) anticonvulsant effects. If adverse effects of a synergistic combination also show supra-additive summation then the protective index may not change. In this context, drug combinations, possessing synergistic anticonvulsant effects and additive (or infra-additive) toxicity, are of clinical interest. Recent experimental data indicate that topiramate and gabapentin generally potentiate the protective activity of conventional antiepileptic drugs against maximal electroshock-induced convulsions in mice. The anticonvulsant action of carbamazepine, diphenylhydantoin, phenobarbital, and valproate was not modified in this test by felbamate at subprotective doses against threshold electroconvulsions. Interestingly, conventional antiepileptics (at subeffective doses) enhanced the protection offered by felbamate. It may indicate that beneficial effects of a drug combination may be observed at only some drug ratios.

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Vigabatrin and baclofen given together, at doses not affecting motor performance, produced dose-dependent inhibition of both phases in the formalin test in mice. Isobolographic analysis revealed a significant synergy between both drugs in both phases of the forrmalin test.

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The aim of present study was to determine the influence of nitric oxide (NO) synthesis on intrathecal (i.t.) clonidine or baclofen antinociception in the formalin test. Formalin injection into the hindpaw of a rat induces a biphasic response in pain-related behaviours, such that C-fiber activation (acute pain) during phase 1 triggers a state of spinal sensitization characterized by longer lasting phase 2 (tonic pain). Intrathecal clonidine and baclofen, at doses without effect upon motor performance, produced a dose-dependent inhibition of both phases of the formalin test. Potency of both drugs, defined by ID50 for phase 2 of the formalin test, was 3.5 and 0.6 nmol, respectively. Intrathecal coadministration of L-arginine, substrate of NO synthase (NOS) or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently reduced or potentiated, respectively, the antinociceptive effect of clonidine but not that of baclofen in the formalin test. The importance of NO formation in the antinociceptive effect of clonidine is further supported by the observation that neither D-arginine nor D-NAME were able to modify clonidine antinociception. These results suggest that the NO synthesis plays a modulatory role in the antinociceptive effect of clonidine, while the mechanism underlying the baclofen-induced antinociception seems to be different.

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The anti-emetic effects of ondansetron and droperidol were evaluated in 134 ASA Grade I and II female patients, scheduled for laparoscopic cholecystectomy and minor gynaecological laparoscopic surgery, who were randomly assigned to receive ondansetron 4 mg or droperidol 75 micrograms kg-1 intravenously immediately after induction of anaesthesia. The patients were assessed 1, 6, 12 and 24 h after surgery for intensity of nausea and number of vomiting episodes. In the case of the patients undergoing laparoscopy, vomiting episodes occurred in a similar proportion in patients treated with ondansetron or droperidol, with the probability of the Type I error of 0.05 and the Type error II of 0.1. Although there was no difference between the two groups in emetic episodes following all laparoscopic procedures and gynaecological laparoscopic surgery, there was a significant difference between these parameters after laparoscopic cholecystectomy. The patients treated with ondansetron experienced a lower intensity of nausea (P = 0.04) after laparoscopic cholecystectomy, less frequent severe nausea (P = 0.02) and episodes of vomiting (P = 0.04) when compared with those in the droperidol group. We conclude, that despite the result the droperidol prophylaxis appears to be an effective alternative to ondansetron in all patients undergoing laparoscopy, the ondansetron prophylaxis is superior to droperidol in patients undergoing laparoscopic cholecystectomy.

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The inhibition of both phases of the formalin response by intrathecal (IT) clonidine and baclofen, given alone or in combination at a fixed dose ratio, was studied. Both drugs, at doses not affecting motor performance, produced a dose-dependent inhibition of phase 2 of the formalin test. The potency of baclofen and clonidine, defined by their ID50's for phase 2 of the formalin test, was 0.56 and 3.4 nmol, respectively. The combination ID50 of baclofen and clonidine, with the equieffective dose ratio of 1:6, was found to be statistically lower than the theoretical additive ID50. These data suggest that co-administration of alpha2-adrenoceptor or GABA(B) receptor agonists may prove therapeutically useful in treating chronic pain.

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206 patients scheduled for spinal surgery (lumbar discopathy) were randomly premedicated with diclofenac, pethidine, diazepam or hydroxizine. The frequency of persisted postoperative pain was evaluated from the 3-ed. postoperative day to the end of hospitalisation--as the need for additional concomitant treatment with dexamethasone and intravenous analgesics. The frequency of persisted pain was significantly decreased in patients premedicated with diclofenac (together with diazepam) before spinal surgery (limited to fenestration) in comparison to patients premedicated with pethidine. The pre-emptive analgesic effect of diclofenac was even more evident in patients treated with non-steroidal anti-inflammatory drugs (NSAID) before surgery, but was not observed in patients after more traumatic surgery (laminectomy) premedicated with diazepam. The results are supporting the important role of NSAID given before surgery to decrease the frequency of persisted pain after spinal surgery (limited to fenestration), in patients treated with NSAID.

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The formalin test, an experimental model of injury-induced central sensitisation, was used. The antinociceptive interaction between intrathecal morphine and clonidine was evaluated based on the inhibition of the phase 1 and 2 of the formalin response, induced by both drugs, given alone or in combinations with fixed dose ratios. Morphine and clonidine, at doses not affecting motor performance, produced dose-dependent inhibition in the formalin test, with similar ID50 values in phase 1 and 2; 0.66 and 0.45 nmol and 4.1 and 3.5 nmol, respectively. Isobolographic analysis revealed a significant synergy. The combination ID50 was found to be significantly lower than the respective theoretical additive ID50 for both fixed dose ratios (1:3 and 1:10) in both phases of the formalin test. The similar total dose fraction of the additive ID50 in phase 1 and 2 indicates the same magnitude of synergy and may suggest that the mechanisms of the spinal clonidine-morphine synergy do not differ significantly between both phases of the formalin test.

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Thrombotic complications constitute a significant problem connected with maintaining arteriovenous fistulas (A-V) for a long time. It has been established that platelets play an important role in the development of thrombosis in high flow systems. Aspirin and dipyridamole do not decrease the frequency of shunt thrombosis. Some of the more recently synthetised antiplatelet drugs (i.e. indobufen, 2-p-oxo-isoindolinyl-phenyl-butyric acid) could be promising in the prevention of such complications. The study group consisted of 40 patients in the terminal stage of renal failure treated with intermittent peritoneal dialysis (IPD). The A-V fistulas were formed by the same surgeon anesthetist team and this allowed for the elimination of technical errors. All patients were divided into two groups. Group I received indobufen at the dose of 2 x 100 mg/24 h orally. Group II received no antiplatelet treatment. The therapy started 24 h before A-V formation. The treatment was continued for 3 weeks. The following tests of platelet function were performed before indobufen therapy, after 9 h and 3 weeks of treatment: ADP and adrenaline induced platelet aggregation, platelet circulating aggregates, MDA level, platelet factor 3 and 4 and bleeding time. During indobufen treatment only a significant decrease in ADP induced aggregation was observed. No prolongation of the bleeding time was noted. No case of fistula thrombosis in indobufen group was observed. This complication, however, appeared in 3 patients (15%) of the control group (without antiplatelet therapy).

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The influence of indobufen (200 mg twice daily for 10 days) on platelet lipid peroxidation and phospholipid metabolism in diabetic patients was investigated. We have studied 18 patients with type I of diabetes mellitus. The duration of disease varied between 3 and 25 years (average 11 years). All patients showed symptoms of diabetic angiopathy. Investigations were carried out after restoring the carbohydrate balance. The following tests were performed before and after a 10 day treatment with indobufen: malondialdehyde, conjugated dienes and lipid hydroperoxides, phospholipids, fatty acids. We observed a significantly higher production of lipid peroxidation products in diabetic platelets compared to control platelets. After a 10 day treatment with indobufen the intensity of peroxidation lowered significantly. The phospholipid composition of diabetic platelets showed a significant increase in lysophosphoglycerides fraction compared to the control platelets. After the indobufen treatment a significant decrease in sphingomyelin content was observed. In other phospholipid fractions no significant differences were observed.

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The effect of agonists and antagonists of GABA-ergic system on analgesia induced by clonidine was investigated in the rat. The compounds activating (muscimol, 1 mg/kg and aminooxyacetic acid; AOAA, 25 mg/kg) or inhibiting GABA-ergic receptors (bicuculline and picrotoxin, in subconvulsive doses 0.5-1 mg/kg) do not change clonidine-induced analgesia. Only the higher dose (2 mg/kg) of muscimol, bicuculline or picrotoxin affected clonidine-induced analgesia. Baclofen, contrary to other GABA agonists, markedly potentiated clonidine-induced analgesia in the dose dependent manner. These results suggest that compounds activating and inhibiting GABA A receptors (muscimol, AOAA, bicuculline and picrotoxin) have a weak influence on clonidine induced analgesia as compared to the effect of baclofen (agonist of GABA B receptors).

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Bradykinin (BK) injected intraventricularly (ivc) at doses of 0.25-0.5 mug per rat potentiated the depth of fluphenazine catalepsy and depressed or abolished the symptoms of sterotypy produced by amphetamine or apomorphine. BK did not affect the level of dopamine (DA), but elevated the level of homovanillic acid in the brain, and accelerated DA turnover as measured by the rate of dopamine disappearance following treatment with alpha-methyltyrosine. The results suggest that BK inhibits the central dopamine structures by blocking the DA receptors.

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Propranolol (100mug) ivc together with phentolamine (60 mug) decreased spontaneous locomotor activity and weakened post-nialamide locomotor activity in rat. When applied separately in the above doses, neither of the two compounds had this action. Depression of amphetamine-induced locomotor activity was observed after propranolol (250 mug) together with phetolamine (60 mug). Phentolamine alone, had hypothermic action but when applied together with propranolol, it increased after 4 hrs body temperature. The tested compounds prolonged hexobarbital-induced sleeping time but did not affect noradrenaline or dopamine levels in rat's brain.

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