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Procainamide and quinidine inhibition of the degradation of meperidine in human liver was investigated by incubation of two concentrations of either drug with meperidine in homogenates of human liver over 24 and 36 h. Meperidine concentrations declined by 26% after incubation for 24 h and by 42% after incubation for 36 h. In the presence of procainamide, however, they decreased by only 15% to 18% at 24 h and by only 26% to 28% at 36 h. In the presence of quinidine, they declined by only 18% to 19% at 24 h and by only 27% to 28% at 36 h. Procainamide and quinidine may inhibit human hepatic carboxylesterase hCE-1, which is responsible for catalyzing the hydrolysis of meperidine. This inhibition may prolong the biological half-life of meperidine in patients receiving the drug together with either procainamide or quinidine.

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An attempt is made to induce the pethidine suppressed gonadal activities by the administration of exogenous gonadotropins (hCG, PMSG, hCG + PMSG). Administration of 5 IU gonadotropins either separately or in combination to the rats treated with pethidine for 30 days resulted in the significant increase in the weight of testis, diameter of testis and seminiferous tubules. Gonadotropin(s) treatment stimulated the spermatogenic activity which was inhibited by pethidine. Therefore the number of spermatogonia, spermatocytes, spermatids in the seminiferous tubules and spermatozoa in cauda epididymis is increased significantly. Decreased testicular cholesterol, increased protein content and weight of accessory sex organs indicate the rejuvenation of steroidogenesis. Combination of both the gonadotropins is more effective in bringing all these activities.

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Several derivatives of thienylcyclidine (1-[1-(2-thienyl)cyclohexyl]piperidine, CAS 1867-65-8, TCP) were synthesized and characterized. The compounds were evaluated for analgesic agonism in mice using tail-flick test as a model for antinociceptive activity. The most potent compounds are 7 and 11, which are about twice as active as the standard pethidine. The influence of naloxone on the antinociceptive activity of these compounds is also reported. The present pharmacological data are discussed and compared with those previously reported for structurally related phencyclidine analgesics.

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This study was designed to evaluate the effects of flumazenil in reversing sedation from midazolam and meperidine after oral surgical procedures. Of the 35 patients entered, efficacy was evaluated in 33 and safety in 34. Patients were tested for sedation, psychomotor skills, and memory during a 3-hour period and at a 24-hour follow-up. Flumazenil almost totally reversed the effects of sedation for approximately 2 hours, after which some loss of effect was observed. A number of central nervous system-related side effects were observed in the flumazenil group, but none of these was considered serious. One patient in the flumazenil group had an episode of hypotension that precluded further testing.

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The aim of this study was to evaluate the effects of morphine and pethidine on human sphincter of Oddi motility. The action of these opioids on the sphincter of Oddi was evaluated by means of intraoperative manometry in 36 patients undergoing elective cholecystectomy. Both opioids were given in intravenous cumulative equipotent doses up to a maximum of 10 micrograms/kg morphine or 100 micrograms/kg pethidine. At these doses, morphine increased the mean(s.d.) frequency of contractions from 2.4(1.0) to 7.9(1.6) (P less than 0.001); this effect was reduced by naloxone (0.04 mg bolus, P less than 0.05). Pethidine inhibited the frequency of contractions from 1.5(0.8) to 0.8(0.5) (P less than 0.05); this response was blocked by atropine (0.6 mg bolus, P less than 0.01). Pretreatment with atropine or naloxone reduced the frequency of contractions significantly (P less than 0.05). The results illustrate different responses to pethidine and morphine of the sphincter of Oddi, and provide a pharmacological explanation for the suitability of pethidine over morphine as the analgesic of choice in patients experiencing biliary pain.

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Recent reports showed that aminophylline antagonizes the sedation caused by diazepam and narcotic agents. This study examined the antagonism of diazepam and meperidine in extracorporeal shock wave lithotripsy (ESWL) anesthesia by low dose aminophylline. Eighty patients, aged 20-60 year-old, ASA I-II were randomly selected. No premedication was given. Anesthesia was induced and maintained with diazepam (0.2-0.5 mg/kg) and meperidine (2-5 mg/kg). The patients were divided into two groups. Group A, the control group, was given physostigmine 1 mg iv and naloxone 0.4 mg im as antagonists for diazepam and meperidine immediately after the ESWL procedure. In group B, only aminophylline 2 mg/kg iv as antagonist was given. Recovery were assessed by the "arbitrary six point scale::and "psychomotor performance". There was no significant difference between the two groups for the arbitrary six point scale. However, in the psychomotor test, the aminophylline group did not completely reach the baseline value in one hour as the control group did. This implicated that patients can by physostigmine and naloxone but not by aminophylline.

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Naloxone is an effective opiate antagonist, but its short half-life limits its usefulness. For outpatient procedures, a longer acting opiate antagonist could eliminate two to four hours of nursing observation in patients postoperatively. A controlled, randomized, double-blind trial comparing the effects of nalmefene, naloxone, and placebo in reversing opiate-induced sedation was carried out to determine efficacy, duration of action, and adverse effects in patients undergoing outpatient procedures. Each patient received 1.5 to 3.0 mg/kg meperidine intravenously before the procedure. After the procedure, each patient received either nalmefene, 1.0 mg; naloxone, 1.0 mg; or saline, 1.0 mL intravenously. Vital signs and assessments for alertness were performed for four hours. Naloxone significantly reversed sedation for only 15 minutes, whereas nalmefene was significantly effective (P less than .05) for up to 210 minutes. Nalmefene was significantly more effective than naloxone in reversing sedation at 60, 90, and 120 minutes. Nalmefene is an effective agent for the reversal of opiate-induced sedation after outpatient procedures.

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A rabbit tooth pulp antinociceptive model was used to investigate the effect of prior administration of diazepam or muscimol on the potency and duration of fentanyl and meperidine Potency experiments compared ED(50) values in all-or-none dose-response assays between both muscimol (0.25 mg/kg) and saline, and diazepam (1.5 mg/kg) and propylene glycol vehicle. An all-or-none effect was defined as doubling of voltage threshold to elicit a lick/chew evoked response. Duration experiments compared time (minutes) to 50% maximum possible effect (MPE) of an ED(90) dose of fentanyl (0.04 mg/kg) and to 50% and 20% MPE of an ED(98) dose of meperidine (17 mg/kg) 10 minutes after pretreatment with diazepam (1.5 mg/kg). Prior (10 minutes) injection of diazepam (1.5 mg/kg) increased the ED(50) value for meperidine (3.06 mg/kg) compared with its control (1.48 mg/kg), indicating a decrease in antinociceptive potency. The same dose of diazepam decreased the ED(50) value for fentanyl (1.1 µg/kg) compared with its control (13.1 µg/kg), indicating an increase in antinociceptive potency. Muscimol also had a similar effect on fentanyl (ED(50), 1.8 µg/kg) compared with saline control (ED(50), 13.8 µg/kg). Diazepam, vehicle, and muscimol by themselves had no effect on voltage thresholds to elicit a lick/chew response. Time to 50% MPE for diazepam-fentanyl was 38 minutes vs. 25 minutes for vehicle-fetanyl; time to 20% MPE for diazepam-meperidine was 38 minutes vs. 54 minutes for vehicle-meperidine (maximum percentage of MPE produced by diazepam-meperidine was 40% compared with 100% MPE for vehicle-meperidine). Percentages of MPE for diazepam-meperidine were significantly lower than those for vehicle-meperidine at all time intervals, whereas percentages of MPE for diazepam-fentanyl were significantly greater than those for vehicle-fentanyl over time.

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The combination of diazepam plus pethidine, reversed with naloxone, was compared in a double-blind randomized study with diazepam alone in 100 patients undergoing endoscopy. Patients accepted both methods of sedation equally well. There was no significant difference in sedation after endoscopy, but the addition of pethidine produced a significant improvement in patient co-operation during the endoscopy (P less than 0.001).

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The antinociceptive (radiant heat tail-flick), convulsant and lethal activities of meperidine (MEP) and normeperidine (NMEP) were studied after s.c. and i.c.v. administration to mice. Both compounds s.c. exhibited naloxone-reversible antinociceptive activity. MEP (ED50 = 23 mg/kg) was 2.5 to 5 times more potent, on a molar basis, than NMEP (ED50 = 72 mg/kg). NMEP was a convulsant [ED50 = 105 mg/kg (s.c.) and 64 micrograms/mouse (i.c.v.)], with a small therapeutic index relative to analgesia whose activity was potentiated by naloxone and antagonized by pentobarbital or morphine, s.c. Death due to s.c. MEP was preceded by convulsions, whereas i.c.v. MEP provoked a primarily depressant lethality. Naloxone antagonized death due to i.c.v. MEP while unmasking its convulsant activity. It is concluded that NMEP is the principal mediator of MEPs central nervous system excitation, that convulsions are mediated by a different population of receptors than either analgesia or respiratory depression and that naloxone exacerbates the convulsant activity of MEP and NMEP.

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1 The effect of selective inhibition of 5-hydroxytryptamine (5-HT) re-uptake by fluoxetine and zimelidine on morphine- and pethidine-induced antinociception was studied in rats. The hot plate (55 degrees C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception. 2 Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base). 3 Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine-induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine-induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine. 4 These and other results support (a) a role for 5-HT in the expression of morphine-induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5-HT in pethidine-induced antinociception remains unclear.

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The effects on mature newborn have been compared at 0.5, 4, 8 12 24 and 48 hr after birth, of maternally administered epidural bupivacaine (11 babies) or pethidine (18 babies) or pethidine reversed by naloxone administered intramuscularly to the newborn (15 babies). Bupivacaine (mean dose 130 mg) had less effect that pethidine (mean dose 183.3 mg) on alveolar carbon dioxide tension (PACO2) at 0.5 hr after birth, but had a similar effect to pethidine on feeding, elicited reflexes and produced more depression of muscle tone up to 48 hr. Bupivacaine had more effect on PACO2 feeding measures, elicited reflexes and muscle tone at almost all examination periods than pethidine (mean dose 157.0 mg) reversed by naloxone (200 micrograms intramuscularly). Except at delivery, the effects of bupivacaine or pethidine on respiration and feeding up to 48 hr after birth were similar. There were more signs of depression with both drugs than when pethidine had been reversed by naloxone.

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Nalorphine and naloxone were compared as to their effectiveness as pethidine antagonists. 85 infants were divided into a control group containing 19 newborn babies whose mothers did not receive pethidine and the babies received no antagonist, and three groups in which the mothers all received pethidine and the babies had either no antagonist (24), nalorphine IV (16), or naloxone IV (26). All the babies were assessed by measuring their neurobehavioural states and respiratory functions. A further 12 newborn babies had naloxone plasma levels measured by radioimmunoassay. Although standard doses of nalorphine effectively antagonised the depressive effect on respiration induced by pethidine, there was a pronounced and undesirable excitatory agonist action. Naloxone was not observed to have any agonist activity, but the recommended IV dose (0.01 mg/kg) had only a slight and delayed antagonist action as measured by respiratory function tests. A more rapid and improved antagonism was noted after this dose was doubled (0.02 mg/kg). The plasma elimination-phase half-life of naloxone after intravenous cord injection was about 3 hours.20

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The effects of morphine and pethidine upon body temperature and upon the reversal of reserpine hypothermia in the mouse were investigated. Both morphine and pethidine produced a dose-dependent fall in body temperature, that of morphine being totally antagonized by nalorphine and partially by naloxone, while that of pethidine was antagonised by naloxone and enhanced by nalorphine. Both drugs reversed reserpine-induced hypothermia. The reversal by morphine, but not by pethidine, was partially antagonized by naloxone. Adrenalectomy prevented the reversal of reserpine hypothermia by pethidine but morphine produced a partial reversal. Ganglion blockade and alpha-and beta-blockade all prevented reversal of reserpine hypothermia by both drugs. The results are discussed with regard to differences between pethidine and morphine and possible involvement of opiate receptors.

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Parturients in whom meperidine HCl, propiomazine HCl, and scopolamine were used for analgesia and amnesia in labor and delivery were studied to determine the efficacy and safety of physostigmine reversal after delivery. Of a total of 120 patients, 108 received physostigmine salicylate at the completion of episiotomy closure, awakening in an average of 7.5 minutes compared with 137.8 in 12 controls. Physostigmine appears to be a safe, rapidly effective agent for reversing the prolonged somnolence of this sedation regimen.

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With a single parenteral introduction of thyrocalcitonin (TCT) the algesthesia of soft tissues (tall skin, paw) is moderately increasing, while the algesic action of morphine and promedol against the background of TCT-gets weaker. And contrarywise algesthesia of hard tissues of the tooth becomes significantly lower under the effect of TCT and this continues for a long time.

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