Browsing by Author "Prostran, Milica Š. (7004009031)"

Gentamicin is readily used for suspected or proven sepsis in neonates, yet it shows considerable inter-individual pharmacokinetic variability, which limits achievements of therapeutic levels. Hence, the aim of this study was to compare peak and trough gentamicin concentrations according to dosing regimen, to evaluate pharmacokinetic parameters, and to consider adjustments of dosing regimen. Babies with infection were treated with 1 h infusion, and daily dose of 5 or 7.5 mg/kg depending on the age. Patients were randomized into two groups: I - dosing interval 12 h (n=8), II - 24 h (n=11). Two steady-state blood samples were obtained. Pharmacokinetic parameters were calculated using one-compartment model. The results showed a difference (p<0.05) in peak gentamicin concentrations between the groups, and tendency of lower trough levels in the group II. Calculated pharmacokinetic parameters included the volume of distribution (Vd) 0.52±0.47 l/kg, clearance (CL) 0.055±0.036 l/hkg and a half-life (t1/2) of 6.89±3.21 h. Based on the method for dosing regimen adjustments, there was a need to extend dosing interval to 36 h in 6 patients. © 2014 Versita and Springer-Verlag.

Background: Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. Methods: The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED50), and type of interaction was determined by isobolographic analysis. Results: Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED50) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED50) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED50. Conclusions: The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain. Copyright © 2010 International Anesthesia Research Society.

The antinociceptive effects of carbamazepine and oxcarbazepine, and the influence of caffeine, were examined in a paw pressure test in rats. Carbamazepine (10-40 mg/kg; intraperitoneal, i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A), intraplantarly (i.p1.). A comparable pattern of antinociceptive effect of carbamazepine and oxcarbazepine was observed; the only difference is their potency, in that carbamazepine was about three times more potent than oxcarbazepine. Caffeine (5-20 mg/kg; i.p.), a non-selective adenosine receptor antagonist, significantly depressed the antinociceptive effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Also, a significant depression of the antinociceptive effects of carbamazepine and oxcarbazepine was observed by pretreatment with 1,3-dipropyl-8-cyclopentylxantine (DPCPX, 0.4 and 0.8 mg/kg; i.p.), an adenosine A1 receptor antagonist. These findings indicate that, in a paw inflammatory hyperalgesia in rats, the antinociceptive effects of both drugs are, at least partially, mediated by adenosine A1 receptors. In conclusion, the present study suggests the potential clinical importance of carbamazepine and oxcarbazepine in the treatment of inflammatory pain. In addition, caffeine consumption could possibly depress the analgesic effects of both anticonvulsive drugs. © 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The antinociceptive effects of carbamazepine and oxcarbazepine, and the influence of caffeine, were examined in a paw pressure test in rats. Carbamazepine (10-40 mg/kg; intraperitoneal, i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A), intraplantarly (i.p1.). A comparable pattern of antinociceptive effect of carbamazepine and oxcarbazepine was observed; the only difference is their potency, in that carbamazepine was about three times more potent than oxcarbazepine. Caffeine (5-20 mg/kg; i.p.), a non-selective adenosine receptor antagonist, significantly depressed the antinociceptive effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Also, a significant depression of the antinociceptive effects of carbamazepine and oxcarbazepine was observed by pretreatment with 1,3-dipropyl-8-cyclopentylxantine (DPCPX, 0.4 and 0.8 mg/kg; i.p.), an adenosine A1 receptor antagonist. These findings indicate that, in a paw inflammatory hyperalgesia in rats, the antinociceptive effects of both drugs are, at least partially, mediated by adenosine A1 receptors. In conclusion, the present study suggests the potential clinical importance of carbamazepine and oxcarbazepine in the treatment of inflammatory pain. In addition, caffeine consumption could possibly depress the analgesic effects of both anticonvulsive drugs. © 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

BACKGROUND: There is evidence supporting the antinociceptive effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in various models of neuropathic pain as well as inflammatory somatic pain. Data are lacking on the antinociceptive potential of these drugs against visceral pain. In this study, we examined and compared the effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in the writhing test as a visceral pain model in the mouse. In addition, the influence of these anticonvulsants on motor performance was examined to compare the tolerability of these anticonvulsants when used against acute visceral pain. METHODS: The antinociceptive effects of these anticonvulsants were examined in the acetic acid writhing test in mice. The side effect propensity of these drugs was examined using the rotarod test. RESULTS: Carbamazepine (25-60 mg/kg; p.o.), oxcarbazepine (10-40 mg/kg; p.o.), gabapentin (10-70 mg/kg; p.o.), and topiramate (5-30 mg/kg; p.o.) caused a significant dose-dependent reduction the number of writhes in the writhing test. In the rotarod test, carbamazepine (60-140 mg/kg; p.o.) and oxcarbazepine (120-450 mg/kg; p.o.) significantly reduced the time spent on the rotarod in a dose- and time-dependent manner. Gabapentin (1000-2000 mg/kg; p.o.) and topiramate (400-1500 mg/kg; p.o.) did not produce significant impairment of motor performance at the highest doses used. The therapeutic index (motor impairing dose TD50/writhing ED50) values were topiramate (>148.5) > gabapentin (>60.2) > oxcarbazepine (15.2) > carbamazepine (2.3). CONCLUSIONS: These results indicate that oxcarbazepine, gabapentin, and topiramate are effective in the writhing model in mice, in a dose range, which is not related to motor impairment; topiramate is the most potent and the most tolerable drug. © 2008 International Anesthesia Research Society.

In this study, the effects of yohimbine (α 2 -adrenoceptor antagonist) and clonidine (α 2 -adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED 50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic α 2 -receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated. © 2006 International Association for the Study of Pain.

In this study, the effects of yohimbine (α 2 -adrenoceptor antagonist) and clonidine (α 2 -adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED 50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic α 2 -receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated. © 2006 International Association for the Study of Pain.

BACKGROUND: We studied whether peripheral α2-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective α2-adrenoceptor antagonist), BRL 44408 (selective α2A-adrenoceptor antagonist), MK-912 (selective α2C-adrenoceptor antagonist), and clonidine (α2-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. METHODS: Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: 1) the development of hyperalgesia induced by Con A; 2) the effects of oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. RESULTS: Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.pl.), BRL 44408 (100 and 200 nmol/paw; i.pl.) and MK-912 (10 and 20 nmol/paw; i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/paw; i.pl.) in a dose-dependent manner. The effects of antagonists were due to local effects since they were not observed after administration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED50 (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. Isobolographic analysis revealed an additive antihyperalgesic effect. CONCLUSIONS: Our results indicate that the peripheral α2A and α2C adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia. © 2007 by International Anesthesia Research Society.