Katarzyna Świąder

Traxoprodil augments the antidepressant-like activity of agomelatine but not of mianserin or tianeptine in the forced swim test in mice

BACKGROUND The main objective of our study was to evaluate the influence of traxoprodil on the activity of the atypical antidepressant drugs (agomelatine, mianserin, tianeptine). METHODS The forced swim test (FST) in mice was used to determine the antidepressant-like activity of the tested agents. Drugs levels in brain tissue were assessed by a high performance liquid chromatography method. RESULTS Concurrent intraperitoneal administration of per se ineffective doses of traxoprodil (10mg/kg) and agomelatine (20mg/kg) shortened the immobility time of animals in the FST. The observed effect was associated with elevated brain levels of traxoprodil. Similar interaction was not detected for traxoprodil and mianserin (10mg/kg) or tianeptine (15mg/kg). CONCLUSION Traxoprodil-agomelatine interaction is pharmacokinetic in nature. A combination of these agents has a potential to become an interesting strategy in the treatment of depression.

Chronic treatment with caffeine and its withdrawal modify the antidepressant-like activity of selective serotonin reuptake inhibitors in the forced swim and tail suspension tests in mice. Effects on Comt, Slc6a15 and Adora1 gene expression

&NA; Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5 mg/kg, twice daily for 14 days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5 mg/kg) and escitalopram (2 mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14‐day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant‐like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems. HighlightsCaffeine was administered for 14 days and on day 15th it was withdrawn.Ineffective doses of fluoxetine or escitalopram (FLX/ESC) were administered on day 15th.FLX/ESC given together with caffeine displayed antidepressant‐like activity.Caffeine and FLX/ESC modified Adora1 and Slc6a15 mRNA level in the cerebral cortex.Caffeine withdrawal after its chronic intake may change activity of FLX/ESC.

Comparison of physicochemical properties of suppositories containing starch hydrolysates

The purpose of this work was to determine the effect of starch hydrolysates (SH) on the physicochemical properties of suppositories. The study was conducted with suppositories with acetaminophen (AAP) a typical antipyretic analgesic, as model drug on lipophilic (cocoa butter) and hydrophilic base (polyethylene glycol 1500 + 400). The suppositories with and without the addition of SH were examined for physicochemical tests according to European Pharmacopoeia 8th edition (Ph. Eur.): the uniformity of mass of single-dose preparation test, the softening time determination of lipophilic suppositories test, the disintegration of suppositories test, and dissolution test with flow-through apparatus. The results confirm the possibility of using starch hydrolysates as a cheap and safe addition to modify physicochemical properties of suppositories.

The influence of selective A1 and A2A receptor antagonists on the antidepressant-like activity of moclobemide, venlafaxine and bupropion in mice

The main goal of our study was to investigate whether a selective antagonism of the adenosine A1 or A2A receptors is able to enhance the antidepressant activity of commonly prescribed drugs.

Protective action of nicotinic acid benzylamide in a variety of chemically-induced seizures in mice

PURPOSE The study aims to assess the anticonvulsant effects offered by benzylamide nicotinic acid (Nic-BZA) in many animal models of chemically-induced seizures (i.e., pentylenetetrazole [PTZ], pilocarpine [PILO], bicuculline [BIC], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], kainic acid [KA], and N-methyl-d-aspartic acid [NMDA]). Additionally, it analyses side effects of administering Nic-BZA in the form of loss of co-ordination and memory impairment as evaluated in the rotarod and passive avoidance tests, respectively. RESULTS Antiseizure activity of Nic-BZA was reported in numerous models of chemically-induced seizures and its ED50 value was 37.1mg/kg for PTZ, 53.0mg/kg for AMPA, 81.4mg/kg for BIC, 86.3mg/kg for KA, and 182.6mg/kg for PILO. Moreover, Nic-BZA was totally ineffective (in dosages of up to 200mg/kg) in mice challenged with NMDA-induced seizures. The evaluation of the side effects present shortly after dosing in the rotarod test has revealed neurotoxicity of Nic-BZA with experimentally determined TD50 value of 188.5mg/kg. Protective index (PI) assessment analysis for Nic-BZA has disclosed a substantial difference between the dosage resulting in acute impairment of co-ordination and the dosage resulting in anticonvulsant effect in various chemically evoked seizures, remaining practically ineffective (in dosages of up to 200mg/kg) in mice subjected to the NMDA-induced seizure test. Additionally, Nic-BZA (in dosages of up to 100mg/kg) did not impair long-term memory in mice. CONCLUSIONS Summing up, Nic-BZA has a wide anticonvulsant effect in different experimental epilepsy models.

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

PURPOSE The aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice. METHODS Electroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence. RESULTS Cimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals. CONCLUSIONS Based on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.