Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia

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Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia
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  Pharmacological interaction between oxcarbazepine and two COX inhibitors in a ratmodel of in 󿬂 ammatory hyperalgesia Radica M. Stepanovi ć -Petrovi ć  a, ⁎ , Ma ja A. Tomi ć  a , Sonja M. Vu č kovi ć  b , Goran Poznanovi ć  c ,Nenad D. Ugre š i ć  a , Milica  Š . Prostran b , Bogdan Bo š kovi ć  d a Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, P. O. Box 146, 11221 Belgrade, Serbia b Department of Pharmacology, Clinical Pharmacology & Toxicology, School of Medicine, University of Belgrade, Dr Suboti ć  a 1, P. O. Box 38, 11000 Belgrade, Serbia c Institute for Biological Research, Department of Molecular Biology, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia d Medical Military Academy, Crnotravska 17, 11 000 Belgrade, Serbia a b s t r a c ta r t i c l e i n f o  Article history: Received 26 March 2010Received in revised form 9 November 2010Accepted 11 November 2010Available online 17 November 2010 Keywords: OxcarbazepineIbuprofenEtodolacIn 󿬂 ammatory hyperalgesiaSynergismAdditivity Oxcarbazepine, ibuprofen and etodolac have ef  󿬁 cacy in in 󿬂 ammatory pain. The combination of different drugsactivatesbothcentral andperipheralpaininhibitorypathwaystoinduceadditiveorsynergisticantinociception,and this interaction may allow lower doses of each drug combined and improve the safety pro 󿬁 le, with lowerside-effects. This study aimed to examine the effects of oxcarbazepine – ibuprofen and oxcarbazepine – etodolaccombinations,inaratmodelofin 󿬂 ammatoryhyperalgesia,anddeterminethetypeofinteractionbetweendrugs.Rats were intraplantarly injected with carrageenan (0.1ml, 1%) and the hyperalgesia was assessed by modi 󿬁 edpaw pressure test. The anti-hyperalgesic effects of oxcarbazepine, ibuprofen and etodolac and oxcarbazepine – ibuprofen and oxcarbazepine – etodolac combinations were examined. Drugs were co-administered in a  󿬁 xed-dose fractions of the ED 50  and the type of interaction was determined by isobolographic analysis.Oxcarbazepine(40 – 160 mg/kg;p.o.),ibuprofen(10 – 120 mg/kg;p.o.)andetodolac(5 – 20 mg/kg;p.o.)produceda signi 󿬁 cant, dose-dependent anti-hyperalgesia in carrageenan-injected rats. ED 50  values (mean±SEM) foroxcarbazepine, ibuprofen and etodolac were 88.17±3.65, 47.07±10.27 and 13.05±1.42 mg/kg, respectively.Oxcarbazepine – ibuprofen and oxcarbazepine – etodolac combinations induced signi 󿬁 cant and dose-dependentanti-hyperalgesia. Isobolographic analysis revealed that oxcarbazepine exerts a synergistic interaction withibuprofen,withalmost4-foldreductionofdosesofbothdrugsincombination.Incontrast,therewasanadditiveinteraction with etodolac.Synergistic interaction of oxcarbazepine with ibuprofen and its additive interaction with etodolac provide newinformationaboutthecombinationpaintreatmentandcouldbeexploredfurtherinpatientswithin 󿬂 ammatorypain. Adverse effect analysis of the combinations is necessary to verify possible clinical use of the mixtures.© 2010 Elsevier Inc. All rights reserved. 1. Introduction Oxcarbazepine,ketoanalogofcarbamazepine,isusedprincipallyfortreating epilepsy and occasionally for relieving neuropathic pain(Beydoun and Kutluay, 2002). Increasing evidence for antinociceptiveeffects of oxcarbazepine has been obtained in models of nerve injury(Foxetal.,2003;Kiguchietal.,2004;Jangetal.,2005;Dograetal.,2005),as well as somatic and visceral tissue injury followed by in 󿬂 ammation(Kiguchi et al., 2004; Tomi ć  et al., 2004; Shannon et al., 2005;Stepanovi ć -Petrovi ć  et al., 2008a). Ibuprofen, a nonselective cyclo-oxygenase-1/2 (COX-1/2)-inhibitor is effective especially againstin 󿬂 ammatory pain, which is a consequence of tissue damage. Etodolac,a cyclo-oxygenase-2 (COX-2) selective inhibitor is also effective inin 󿬂 ammatory pain, but recent evidence showed that it alleviateshyperalgesia inneuropathic painmodels in rats and mice, too (Suyamaet al., 2004; Inoue et al., 2009). All three drugs are without substantiveeffect in models of acute pain in uninjured animals, but normalize thelowered nociceptive threshold induced by some kind of tissue injury(Kiguchietal.,2004;Hurleyetal.,2002).Tissueinjuryprovokesdamageto peripheral nerves and spinal cord changes, causing hypersensitivityandspontaneous 󿬁 ringofafferentnerve endings atthesiteofinjury,aswell as in central nervous system (Hurley et al., 2002; Kolosov et al.,2010). Several receptors and neurotransmitters are involved inthis hyperexcitability, as well as an increased expression of Na + - andCa +2 -channels in sensory neurons and spinal cord (Waldmeier et al.,1995; Li et al., 2006; Kolosov et al., 2010). Antinociceptive effect of oxcarbazepine is mediated via Na + -channels and neurotransmitterreceptors, centrally and peripherally (Waldmeier et al., 1995; Ichikawaetal.,2001;Kiguchietal.,2004;Tomi ć etal.,2004;Vu č kovi ć etal.,2006; Pharmacology, Biochemistry and Behavior 97 (2011) 611 – 618 ⁎  Corresponding author.Department ofPharmacology,FacultyofPharmacy, VojvodeStepe 450, POB 146, 11221 Belgrade, Serbia. Tel.: +381 11 39 51 374; fax: +381 11 3970 840. E-mail address:  racabbr@eunet.rs (R.M. Stepanovi ć -Petrovi ć ).0091-3057/$  –  see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.pbb.2010.11.007 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior  journal homepage: www.elsevier.com/locate/pharmbiochembeh  Stepanovi ć -Petrovi ć etal.,2008b).Ibuprofenexertsitsanti-hyperalgesicactivitybydecreasingproductionoftheprostaglandins(PGs)mainlyonperipheral, but also on central levels. PGs sensitize nociceptors toin 󿬂 ammatory mediators and enhance  󿬁 ring frequency in nociceptiveneurons by phosphorylation of Na V  1.8, high-threshold Na + channelisoformwhichis expressed onlyinnociceptiveneurons(Akopianetal.,1996; Momin and McNaughton, 2009). In the spinal cord, PGs developsensitization partly by activating nonselective cation current in dorsalhorn neurons (Baba et al., 2001). It has been suggested that etodolacattenuates mechanical allodynia in a mouse model of neuropathic painbysuppressingtheexpressionofgenesforCa +2 -channel α 2 δ subunitinthe dorsal root ganglion (Inoue et al., 2009).A hypothesis assumes that the simultaneous activation of differentpaininhibitingpathwaysmaybeeffectiveinpaintherapy(HorvathandKekesi, 2006). Thus, the co-administration of drugs that are ef  󿬁 caciousin in 󿬂 ammatory pain, and interfere with different systems may be aneffective method to its relief. The combination of different drugsactivatesbothcentralandperipheralpaininhibitorypathwaystoinduceadditive or synergistic antinociception, and this interaction may allowlower doses of each drug combined and improve the safety pro 󿬁 le,with lower side-effects (Desmeules et al., 2003; Miranda et al., 2009).The purpose of this study was to determine the type of interaction(additive or synergistic) between oxcarbazepine and different COXinhibitors as ibuprofen (COX 1/2-inhibitor) and etodolac (COX 2-inhibitor). The type of interaction was evaluated by means of theisobolographic analysis using in 󿬂 ammatory paw pressure test in rats. 2. Methods  2.1. Animals Experiments were performed on 180 – 220 g male Wistar rats(Military Academy Breeding Farm, Belgrade, Serbia). The animalswere housed in groups of four in home cages (42.5×27×19 cm) andmaintained on a 12/12 h light/dark cycle at 22±1 °C. Food and waterwere freely available, except during the experimental procedure. Allexperiments were carried out at the same time of the day between8:00 and 16:00 h to avoid diurnal variation in behavioral tests. Allexperimental groups consisted of 6 to 8 rats. All experiments wereperformed according to a protocol approved by the InstitutionalAnimal Care and Use Committee and were carried out in compliancewith the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication No. 85-23, revised 1985).  2.2. Drugs administration Oxcarbazepine (TRILEPTAL, Novartis Pharma AD, Basel, Switzerland),ibuprofen (gift from Galenika, Belgrade, Serbia) and etodolac (gift fromAlkaloid, Skopje, Macedonia) were suspended in distilled water with theaddition of one drop of Tween 80. Drugs/drug combinations wereadministered to fasted rats orally in a volume of 2ml/kg. Carrageenan(Sigma-AldrichChemie,Germany)wasdissolvedinsaline(1%m/v),24hbefore the experiment and was injected intraplantarly (i.pl.) in a  󿬁 nalvolume of 0.1ml/paw, using 1ml syringe and 24G (0.55×25mm)needle.  2.3. Model of in  󿬂 ammatory hyperalgesia The carrageenan-induced hyperalgesia and the anti-hyperalgesicactivity of drugs/drug combinations were determined by a modi 󿬁 ed “ pawpressure ” test(RandallandSelitto,1957;Tomi ć etal.,2004).Theapparatus (Hugo Sachs Elektronik, March-Hugstetten, Germany) wasused to evaluate the force exerted by rat hind paws in order todetermineright/leftdifferences.Theratwasplacedwithitshindpawson two transducer platforms and pushed slowly and smoothlydownwards with investigator hand, so that the force (pressure) isappliedsimultaneouslytobothpaws.Thepressureisapplieduntiloneof the paws exceeds the trigger level set at 100 g. At this point, anaudible click by the apparatus is heard and the measurement isstoppedautomatically. Theforcesappliedonthepawsarereadonthedisplays, and the difference ( d ) is calculated as (Tomi ć  et al., 2004): d  = force g ð Þ applied on un  inflamed paw − force g ð Þ applied on inflamed paw : Measurements were repeated 3 times at each time point, and theaverage  d  for each rat was used for further calculations.Pre-treatment  d  was obtained before the induction of in 󿬂 ammationandperoral(p.o.)administrationofdrugs/drugcombinations.In 󿬂 amma-tory hyperalgesia was induced immediately after p.o. drug/drug combi-nationadministrationbyinjectingcarrageenan(CAR)intraplantarly(i.pl.)intotherighthindpaw(Morris,2003).Accordingtodataaboutthetime-course of carrageenan hyperalgesia and the time-course of anti-hyperalgesic effect and/or pharmacokinetic properties of examineddrugs (Cayen et al., 1981; Khan and Akhter, 2005; Tomi ć  et al., 2010),administering the drugs and carrageenan at the same time was suitablefor recording the appearance and increase of effect, its peak and thedecreaseduringtimeforallexamineddrugsanddrugcombinations.Post-treatment  d  was measured 1, 2, 3, 4, and 5h after the treatment. Controlanimalsreceivedthesamevolumeofcorrespondingvehicle(p.o.)insteadof test compounds.Force differences for each rat are expressed as a percent anti-hyperalgesic activity (%AH) and calculated according to the followingformula:%AH =  dc  av − dt  ð Þ =  dc  av ð Þ  × 100 ; accordingtoTomi ć etal.(2004),wherethe dc  av denotescontrolgroupaverage  d  and  dt   denotes  d  of each rat in the test group. If the  dt   wasgreater than  dc  av , a value of 0% AH was assigned.The values for %AH were calculated after each measurement of   d (1, 2, 3, 4, and5 h after treatment)to establishthe time of peak effect.The log dose – response curves were determined at the time of peakeffect.The ED 50  (thedose thatwas expectedto result in 50 %AH)with95% con 󿬁 dence limits were estimated from corresponding log dose – response curves (Tallarida and Murray, 1986).  2.4. Isobolographic analysis The interaction between ibuprofen and etodolac with oxcarbaze-pine was evaluated by co-administration of   󿬁 xed proportions of eachdrug, and performing an isobolographic analysis (Tallarida et al.,1997). At  󿬁 rst, an ED 50  value of each drug has to be obtained from thecorresponding log dose – response curves.Inthenextstep,oxcarbazepineandibuprofenwereco-administeredat  󿬁 xed-dose fractions of the ED 50  (0.0625 ED 50 OXCARBAZEPINE +0.0625ED 50 IBUPROFEN , 0.125 ED 50 OXCARBAZEPINE +0.125 ED 50 IBUPROFEN , 0.25ED 50 OXCARBAZEPINE +0.25 ED 50 IBUPROFEN , 0.5 ED 50 OXCARBAZEPINE +0.5ED 50 IBUPROFEN ). For drug mixture, experimental ED 50  (ED 50 mix ) and itsassociated 95% con 󿬁 dence intervals were determined by linearregression analysis of the log dose – response curve and compared to atheoretical additive ED 50  (ED 50 add ) obtained from the calculation:ED 50add  =  f   × ED 50OXCARBAZEPINE  + 1 −  f  ð Þ  × ED 50IBUPROFEN ; where  f   denotes a fraction of the corresponding ED 50  in drug mixture(in our study,  f  =0.5). In this equation, ED 50 add  is the total dose, andthe variance of ED 50 add  was calculated as (Tallarida et al., 1997): VarED 50add  =  f  2 × VarED 50OXCARBAZEPINE  + 1 −  f  ð Þ 2 × VarED 50IBUPROFEN : From these variances, con 󿬁 dence intervals were calculated andresolvedaccordingtotheratiooftheindividualdruginthecombination.Supra-additivity is de 󿬁 ned as the effect of a drug combination that is 612  R.M. Stepanovi ć  -Petrovi ć   et al. / Pharmacology, Biochemistry and Behavior 97 (2011) 611 – 618  higher and statistically different (ED 50  signi 󿬁 cantly lower) than thetheoretical calculated equieffect of a drug combination with the sameproportions. When the drug combination gives an experimental ED 50 not statistically different from the theoretical calculated ED 50 , thecombination has an additive effect (Tallarida et al., 1997). Additionally,to describe a magnitude of interaction, an interaction index ( γ  ) wascalculated according to the formula (Tallarida, 2002):ED 50OXCARBAZEPINE COMBINED WITH IBUPROFEN  = ED 50OXCARBAZEPINE GIVEN ALONE + ED 50IBUPROFEN COMBINED WITH OXCARBAZEPINE  = ED 50IBUPROFEN GIVEN ALONE : An interaction index is a quantitative marker for the drugcombination that indicates the changed potency of the combination.Valuesnear1indicateadditiveinteraction;valuesmorethan1implyanantagonistic interaction and values less than 1 indicate a synergisticinteraction (Tallarida, 2002).Thesameprocedurewasfollowedforexaminingtheoxcarbazepine – etodolac combination, except that in this case we examined differentfractions of ED 50  of each drug (0.125, 0.25, 0.5 and 0.75).  2.5. Analysis of duration of effect of drugs and drug combinations Inordertocomparethedurationofeffectofeachdrugappliedalonewith the duration of effect produced by the same drug applied incombination, the data were expressed as the area under the curve(AUC), e.g. theareaofaseriesoftrapezoidsinwhichheightwasthepawpressure difference between non-injected and carrageenan-injectedpaw( d )andthebase,theinterval( h )betweenmeasurements(Tallaridaand Murray, 1986). Difference between AUC for control (vehicle-treated) group (AUC C ) and AUC for the each dose of drug/drugcombination (AUC D ) is calculated as  Δ AUC=AUC C − AUC D , andexpressed as the function of %AH (achieved at time of peak effect).The slope of the %AH – Δ AUC regression line ( Δ AUC= a ×%AH+ b ;where  “ a ”  denotes the slope and  “ b ”  the  y -intercept) is the relativemeasure of the durationof drug (or drug combination) effect: the drugtreatment with signi 󿬁 cantly greater slope exerts the effect of longerdurationthanthatwith lesser slope(Yakshetal., 1986).Iftheslopesof the %AH – Δ AUC regression lines for two drug treatments do not differsigni 󿬁 cantly,theequaldurationofactionisassumed.Additionally,highcorrelation coef  󿬁 cient of %AH – Δ AUC regression line indicates that theduration of the effect of drug/drug combination treatment is dose-dependent (Yaksh et al., 1986).  2.6. Statistical analysis All computations were done according to Tallarida and Murray(1986), Tallarida et al. (1997) and Tallarida (2000) using computerprograms Pharm PCS and Pharm Tools Pro. Differences betweencorresponding means were veri 󿬁 ed by using Student's  t  -test oranalysis of variance (One-Way ANOVA with repeated measures),followed by Tukey's HSD test. Test for parallelism was used tocompare the slopes of two regression lines (Tallarida and Murray,1986). The difference between theoretical ED 50  and experimentalED 50  wasexamined by Student's  t  -test. A  p  value of lessthan 0.05 wasconsidered statistically signi 󿬁 cant. 3. Results  3.1. Effects of oxcarbazepine, ibuprofen and etodolac in the paw pressuretest in carrageenan-injected rats Inthepawpressuretestinrats,oxcarbazepine(40 – 160mg/kg;p.o.),ibuprofen(10 – 120 mg/kg;p.o.)andetodolac(5 – 20mg/kg;p.o.)causedsigni 󿬁 cant dose-dependent reduction of the hyperalgesia induced bycarrageenan (Figs. 1A, B, C, 3A, and 4A). The peak effects of oxcarbazepine occurred 2 h after the administration. Maximum anti-hyperalgesic effects of ibuprofen were achieved either 2 h (120mg/kg;p.o.), or 3 h (10, 40 and 80mg/kg; p.o.) after administration. Anti-hyperalgesic effects of etodolac peaked 2 h (10 and 20mg/kg; p.o.) or3 h (5 and 15mg/kg; p.o.) after administration. The ED 50  values foroxcarbazepine and etodolac are calculated at 2 h time point and foribuprofenat3 htimepointafteradministration,andallarepresentedinTable 1.  3.2. Effects of oxcarbazepine – ibuprofen combination in the paw pressuretest in carrageenan-injected rats Oxcarbazepine – ibuprofen drug mixture administered in  󿬁 xed-dosefractionsoftheED 50 (1/16,1/8,1/4and1/2)causedsigni 󿬁 cantanddose-dependent reduction of the anti-hyperalgesia induced by carrageenanin a paw pressure test in rats (Figs. 2A and 3A). The peak effect of oxcarbazepine – ibuprofencombinationoccurredat2 h(1/4+1/4ED 50 ;p.o.), or 3 h time point after administration (1/2+1/2 ED 50 , 1/8+1/8ED 50  and 1/16+1/16 ED 50 ; p.o.) (Fig. 2A, small graph).The isobologram was constructed by connecting the ED 50  of theoxcarbazepine plotted on the abscissa with the ED 50  of ibuprofenplottedontheordinatetoobtaintheadditivityline(Fig.3B).Thus,theED 50  of oxcarbazepine (88.17 mg/kg) is shown at point (88.17,0) andthat of ibuprofen (47.07 mg/kg) is plotted at (0, 47.07); these pointsare connected by a solid theoretical line for additivity. For oxcarba-zepine – ibuprofen combination, the ED 50 mix  and the 95% con 󿬁 dencelimits(CL)ofthetotalmixtureiscalculatedbylinearregressionofthelog dose – response curve (Fig. 3A) and resolved into its componentparts according to the dosing ratio. This point is plotted in theisobologram (Fig. 3B). In this study, the components were co-administered at  󿬁 xed-dose fractions of the ED 50 : 1 = 2ED 50 OXCARBAZEPINE  + 1 = 2ED 50 IBUPROFEN  = 44 : 09 mg = kg + 23 : 54 mg = kg ; 1 = 4ED 50 OXCARBAZEPINE  + 1 = 4ED 50 IBUPROFEN  = 22 : 04 mg = kg + 11 : 67 mg = kg ; 1 = 8ED 50 OXCARBAZEPINE  + 1 = 8ED 50 IBUPROFEN  = 11 : 02 mg = kg + 5 : 88 mg = kg and1 = 16ED 50 OXCARBAZEPINE  + 1 = 16ED 50 IBUPROFEN  = 5 : 51 mg = kg + 2 : 94 mg = kg : Thus,  󿬁 xed drug – dose ratio based on mass quantity for oxcarbaze-pine and ibuprofen was 1.9:1. The total ED 50 mix  for oxcarbazepine – ibuprofen combination is 35.71 mg/kg (Table 1), representing23.28 mg/kg oxcarbazepine plus 12.43 mg/kg ibuprofen. This point isplotted as (23.28, 12.43) on the oxcarbazepine – ibuprofen isobologram(Fig.3B);likewise,theCLforthetotaldoseisalsoresolvedintothetwocomponents. According to the formula for ED 50 add  presentedin Methods section, theoretical additive ED 50  for this combination isED 50 add =0.5×88.17+0.5×47.08=67.63 mg/kg (Table 1) (repre-senting 44.09 mg/kg oxcarbazepine plus 23.54mg/kg ibuprofen). The t  -testappliedtothepotencyratiobetweentheED 50 mix andtheED 50 add reveals a signi 󿬁 cant difference; thus, this combination presents asynergistic interaction. A graphic illustration on the isobologram(Fig. 3B) shows that the CL of these two points does not overlap.Additionally, interaction index was less than one (Table 1), con 󿬁 rmingthe synergistic interaction for oxcarbazepine – ibuprofen combination.The duration of the effects of oxcarbazepine, ibuprofen and theircombination were expressed as the slopes of the %AH – Δ AUCregression line (see Methods). The slope of %AH – Δ AUC regressionline for oxcarbazepine was signi 󿬁 cantly greater than the slopes foribuprofen and oxcarbazepine – ibuprofen combination (  p b 0.05, testforparallelism)(Table2),suggestingashorterdurationoftheeffectof ibuprofenandthedrugcombinationcomparedwithdurationofeffectof oxcarbazepine. The high correlation coef  󿬁 cients of the %AH – Δ AUCline for all three treatments indicated that the duration of the effectwas dose-dependent (Table 2). 613 R.M. Stepanovi ć  -Petrovi ć   et al. / Pharmacology, Biochemistry and Behavior 97 (2011) 611 – 618  Fig. 1.  Time course of the anti-hyperalgesic effects of oxcarbazepine (OXC) (A), ibuprofen (IBU) (B), and etodolac (ETO) (C) expressed as paw pressure differences in g ( d ) betweennon-injected and carrageenan (CAR) injected rat hind paw (bigger graphs) or as percent of anti-hyperalgesic activity (%AH) (smaller graphs). Pre-treatment  d  (plotted at verticalaxis) was obtained before induction of in 󿬂 ammation and administration of drugs. Intraplantar (i.pl.) CAR injection was given immediately after peroral (p.o.) drug (OXC or IBU orETO) administration (denoted by arrows). Each point represents the mean±SEM of paw pressure differences ( d ) (bigger graphs) or %AH (smaller graphs) obtained in 6 – 8 animals.Statistical signi 󿬁 cance (*  p b 0.05, **  p b 0.01; One-Way ANOVA with repeated measures followed by Tukey's HSD) was determined by comparison with the curve for vehicle.  Table 1 ED 50 ±SEM values (mg/kg) with 95% con 󿬁 dence limits and interaction index ( γ  ) obtained at time of peak effect after p.o. administration of oxcarbazepine, ibuprofen, etodolac andoxcarbazepine – ibuprofen and oxcarbazepine – etodolac combination in carrageenan-injected rats.Drugs/drug combination ED 50a ±SEM (con 󿬁 dence limits)  γ  b Oxcarbazepine 88.17±3.65 (73.64 – 105.57)Ibuprofen 47.07±10.27 (18.46 – 120.02)Etodolac 13.05±1.42 (8.16 – 20.87)ED 50 addc ED 50 mixd Oxcarbazepine+ibuprofen (total dose) 67.63±5.44 35.71±2.90 ⁎ 0.53(51.36 – 83.80) (25.16 – 50.70)Oxcarbazepine+etodolac (total dose) 50.54±2.35 39.08±5.90 0.77(45.09 – 56.65) (20.41 – 74.82) a ED 50 =Effective dose required to produce 50% anti-hyperalgesic activity. b γ  =ED 50 OXCARBAZEPINE COMBINED WITH IBUPROFEN/ETODOLAC /ED 50 OXCARBAZEPNIE GIVEN ALONE +ED 50 IBUPROFEN/ETODOLAC COMBINED WITH OXCARBAZEPINE /ED 50 IBUPROFEN/ETODOLAC GIVEN ALONE. Values near 1 indicate additive interaction, values more than 1 imply an antagonistic interaction and values less than 1 indicate a synergistic interaction (Tallarida, 2002). c ED 50 add =Theoretical additive ED 50  for drug mixture. d ED 50 mix =Experimental ED 50  for drug mixture. ⁎  p b 0.05 between ED 50 add  and ED 50 mix  ( t  -test), indicates a synergistic interaction (Tallarida et al., 1997).614  R.M. Stepanovi ć  -Petrovi ć   et al. / Pharmacology, Biochemistry and Behavior 97 (2011) 611 – 618   3.3. Effects of oxcarbazepine – etodolac combination in the paw pressuretest in carrageenan-injected rats Oxcarbazepine – etodolac drug mixture administered in  󿬁 xed-dosefractions of the ED 50  (3/4, 1/2, 1/4 and 1/8) caused signi 󿬁 cant and dose-dependentreductionofthehyperalgesiainducedbycarrageenaninapawpressure test in rats (Figs. 2B and 4A). The peak effect of oxcarbazepine – etodolac combination occurred at 1h (3/4+3/4 ED 50 ; p.o.), or 2h afteradministration (1/2+1/2 ED 50 , 1/4+1/4 ED 50  and 1/8+1/8 ED 50 ; p.o.)(Fig. 2B, small graph).The isobolographic analysis for mixture of oxcarbazepine withetodolac was performed as described in details for the mixture withibuprofen. Fixed drug – dose ratio based on mass quantity for oxcarba-zepine and etodolac was 6.76:1. The total ED 50 mix  for oxcarbazepine – etodolaccombinationis 39.08 mg/kg(Table1),representing34.04mg/ kg oxcarbazepine plus 5.04mg/kg etodolac. The theoretical additiveED 50  for this combination is 50.54 mg/kg (Table 1), representing44.02mg/kg oxcarbazepine plus 6.52 mg/kg etodolac. Despite theinteraction index value less than one (Table 1), the  t  -test applied tothepotencyratiobetweentheED 50 mix andtheED 50add hasnotrevealeda signi 󿬁 cant difference, indicating an additive interaction, as shown inthe corresponding isobologram (Fig. 4B).The duration of the effects of oxcarbazepine, etodolac and theircombination were also expressed as the slopes of the %AH – Δ AUCregression line (see Methods). There is signi 󿬁 cant difference betweenthe slopes for oxcarbazepine and etodolac (  p b 0.05, test for parallel-ism) but no difference between the slopes for oxcarbazepine andoxcarbazepine – etodolac combination (  p N 0.05, test for parallelism)(Table 2), indicating a shorter duration of effects of etodolac andlongerdurationoftheeffectsproducedbyoxcarbazepinealoneandincombination with etodolac. A relatively high correlation coef  󿬁 cientsof the %AH – Δ AUC lines for both treatments indicated that theduration of the effect was dose-dependent (Table 2). 4. Discussion In this examination we used isobolographic analysis to character-ize the nature of the interaction of oxcarbazepine with ibuprofen or Fig. 2.  Time course of the anti-hyperalgesic effect of oxcarbazepine – ibuprofen (OXC+IBU) (A), and oxcarbazepine – etodolac (OXC+ETO) (B) combination, expressed as pawpressure differences in g ( d ) between non-injected and carrageenan (CAR) injected rat hind paw (bigger graphs) or as percent of anti-hyperalgesic activity (%AH) (smaller graphs).Pre-treatment  d  (plotted at vertical axis) was obtained before induction of in 󿬂 ammation and administration of drug combinations. Intraplantar (i.pl.) CAR injection was givenimmediately after peroral (p.o.) drug combination administration (denoted by arrows). Each point represents the mean±SEM of paw pressure differences ( d ) (bigger graphs) or %AH (smaller graphs) obtained in 6 – 8 animals. Statistical signi 󿬁 cance (*  p b 0.05, **  p b 0.01; One-Way ANOVA with repeated measures followed by Tukey's HSD test) was determinedby comparison with the curve for vehicle.615 R.M. Stepanovi ć  -Petrovi ć   et al. / Pharmacology, Biochemistry and Behavior 97 (2011) 611 – 618
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SAVE OUR EARTH

We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

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