Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 22-28 ◽  
Author(s):  
Jarogniew J. Luszczki ◽  
Mirosław Zagaja ◽  
Barbara Miziak ◽  
Maria W. Kondrat-Wrobel ◽  
Katarzyna Zaluska ◽  
...  
Keyword(s):  
Dose Response ◽  
Treatment Plan ◽  
Linear Regression Analysis ◽  
Fixed Ratio ◽  
Maximal Electroshock ◽  
Type I ◽  
Additive Interaction ◽  
Pharmacoresistant Epilepsy ◽  
Isobolographic Analysis ◽  
Chimney Test

Background/Aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice. Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs. Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction. Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy.

scholarly journals Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

2016 ◽  
Vol 24 (2) ◽  
pp. 87-94 ◽  
Author(s):  
Mirosław Zagaja ◽  
Barbara Miziak ◽  
Katarzyna Załuska ◽  
Paweł Marzęda ◽  
Bartłomiej Drop ◽  
...  
Keyword(s):  
Fixed Ratio ◽  
Maximal Electroshock ◽  
Type I ◽  
Additive Interaction ◽  
Pharmacodynamic Interaction ◽  
Pharmacoresistant Epilepsy ◽  
Total Brain ◽  
Clonic Seizures ◽  
Additive Interactions ◽  
Chimney Test

Summary Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world. Aim. To determine the interaction profile for the combination of retigabine (RTG) and oxcarbazepine (OXC) in both, the model of tonic-clonic seizures, the maximal electroshock (MES)-induced seizure model and chimney test (motor performance) in adult male albino Swiss mice. Methods. Isobolographic analysis (type I) was applied to characterize interactions for the combination of RTG with OXC with respect to its anticonvulsant and acute side (neurotoxic) effects, as determined in the MES and chimney tests, respectively. Results. The combination of RTG with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in the MES test in mice. Similarly, the combination of RTG with OXC at the fixed-ratio of 1:1 produced additive interaction with a tendency towards sub-additivity in the chimney test in mice. Measurement of total brain concentrations of both AEDs revealed that RTG did not affect total brain concentrations of OXC and inversely, OXC had no impact on RTG’s total brain concentrations, confirming pharmacodynamic interaction between the drugs. Conclusions. The additive pharmacodynamic interactions in both the MES and chimney tests in mice were observed for the combination of RTG with OXC.

scholarly journals Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis

2020 ◽  
Vol 72 (5) ◽  
pp. 1288-1296 ◽  
Author(s):  
Jarogniew J. Łuszczki ◽  
Maria Kondrat-Wróbel ◽  
Mirosław Zagaja ◽  
Sławomir Karwan ◽  
Hubert Bojar ◽  
...  
Keyword(s):  
Seizure Activity ◽  
Fixed Ratio ◽  
Mechanisms Of Action ◽  
Clinical Settings ◽  
Maximal Electroshock ◽  
Type I ◽  
Pharmacodynamic Interaction ◽  
Isobolographic Analysis ◽  
Mes Test ◽  
Patients With Epilepsy

Abstract Background Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians’ experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug–drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice. Materials and methods The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1. Results The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. Conclusion The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.

An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac

2018 ◽  
Vol 29 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Eric Boakye-Gyasi ◽  
Ella Anle Kasanga ◽  
Elvis Ofori Ameyaw ◽  
Wonder Kofi Mensah Abotsi ◽  
Robert Peter Biney ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Aqueous Extract ◽  
Dose Response ◽  
Formalin Test ◽  
Fixed Ratio ◽  
Test Dose ◽  
Response Curves ◽  
Isobolographic Analysis ◽  
Aerial Parts

AbstractBackground:Geraniin, a dehydroellagitannin, is a major component of the aqueous extract of the aerial parts ofPhyllanthus muellerianus(Kuntze) Exell. (Euphorbiaceae). SeveralPhyllanthusspecies are traditionally used for painful disorders. The anti-nociceptive effects of the aqueous extract of the aerial parts ofP. muellerianusand of geraniin have been scientifically established. The aim of the paper is to determine whether a combination of geraniin and diclofenac or geraniin and morphine leads to better anti-nociceptive effects.Methods:The nature of the interactions of morphine and diclofenac with geraniin was evaluated by undertaking the isobolographic analysis. Mice were treated with geraniin (3–30 mg/kg), morphine (1–10 mg/kg), and diclofenac (10–100 mg/kg) to obtain the ED50values of the agents in the formalin test. Dose-response curves were then obtained and analyzed after the co-administration of geraniin with morphine or diclofenac in fixed ratio (1:1) combinations based on specific fractions (1/2, 1/4, and 1/8) of their respective ED50values for the formalin test.Results:Geraniin was less potent than morphine but more potent than diclofenac in the formalin-induced nociception. The isobolographic analysis of geraniin/morphine (G/M) and geraniin/diclofenac combinations (G/D) at different fractions revealed the potentiation of their anti-nociceptive effects. The degrees of potentiation, which were calculated as interaction indices, showed synergism for both combinations in both phase I (G/M: 0.040, G/D: 0.017) and phase II (G/M: 0.004, G/D: 0.002) of the formalin test.Conclusions:The present study demonstrates synergism for the co-administration of geraniin with both morphine and diclofenac.

scholarly journals Additive interaction of levetiracetam with lamotrigine in the mouse 6 Hz psychomotor seizure model – an isobolographic analysis

2015 ◽  
Vol 26 (1) ◽  
pp. 82-87
Keyword(s):  
Dose Response ◽  
Seizure Activity ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Additive Interaction ◽  
Isobolographic Analysis ◽  
Psychomotor Seizure ◽  
Seizure Model ◽  
A Current ◽  
Anticonvulsant Effects

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with lamotrigine (LTG – a second-generation antiepileptic drug), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to characterize the consequent anticonvulsant interactions between the drug combinations. Results indicated that LEV administered singly was associated with a DRRC that was parallel to that for LTG. With isobolography for parallel DRRCs, the combination of LEV with LTG at three fixed-ratios of 1:3, 1:1 and 3:1 exerted additive interaction. LEV combined with LTG exerted additive interaction in the mouse 6 Hz psychomotor seizure model.

Hormonal characterization and classification of breast cyst fluid in gross cystic mastopathy

1994 ◽  
Vol 1 (2) ◽  
pp. 49-55 ◽  
Author(s):  
I Számel ◽  
B Budai ◽  
K Daubner ◽  
J Kralovánszky ◽  
Sz Ottó ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Sex Steroids ◽  
Linear Regression Analysis ◽  
Cyst Fluid ◽  
Type I ◽  
Breast Cyst Fluid ◽  
Breast Cyst ◽  
Apocrine Metaplasia ◽  
Endocrine Parameters

ABSTRACT Gross cystic disease (GCD) of the breast may be associated with a higher risk for the development of breast cancer. High levels of sex steroids, steroid hormone precursors, prolactin and cations have been found in breast cyst fluid (BCF) by several investigators. Accordingly, endocrine parameters and the cationic composition of BCF may be considered as useful characteristics to follow patients bearing macrocysts. In this study we have investigated the concentrations of estradiol (E2), progesterone, testosterone, dehydroepiandrosterone (DHA) and DHA-3-sulfate (DHA-S), prolactin, potassium (K+) and sodium (Na+) in BCF aspirated from 99 women. The mean age of the patients was 49.8 years (range 32-58). The hormone levels were measured by RIA methods; K+ and Na+ were determined by flame photometry. Estradiol, progesterone, testosterone, DHA, DHA-S, prolactin and K+ showed significant accumulation in the BCF compared with their respective serum values. The K+/Na+ ratio proved to be useful in dividing cysts into type I (≥1), type II (<1 but ≥0.1) and type III (<0.1) subgroups. For type I BCF, higher DHA, DHA-S and prolactin concentrations were detected. Linear regression analysis established a highly significant (P<0.001) correlation between the concentrations of E2 and DHA-S (r=0.686), and also between testosterone and DHA-S (r=0.711). These findings indicate that type I BCF might be a marker for 'active' GCD of the breast, and suggest that it may be associated with an increased breast cancer risk, since this group of patients is supposed to have cysts with apocrine metaplasia. It is suggested therefore that when BCF is aspirated, sex steroids, steroid precursors and cations should be routinely measured, and women with type I cysts should be regularly examined.

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