Zsolt Gáll, Szabolcs Koncz, Orsolya Gáll and Melinda Kolcsár
Objective: This study evaluated the anticonvulsant action of lacosamide (LCS), a novel drug that was recently approved for the treatment of partial or secondarily generalized seizures, using an animal model of generalized epilepsy induced by repetitive pentylenetetrazole (PTZ) administration in rats. The main goal was to evaluate the behavioral pattern of lacosamide action by classifying seizures according to a modi Racine-scale. Furthermore, the reproducibility of the win-PTZ kindling model of epilepsy, a recently described variant of the standard PTZ-kindling model, was also assessed.
Methods: Adult male Wistar rats (n=16) were divided into two groups and underwent the win-PTZ-kindling protocol in two independent trials. After finishing the kindling procedure, all animals, which presented stage 5 seizures were tested for the anticonvulsant action of lacosamide at three different doses (3, 10, and 30 mg/kg).
Results: The maximal severity of seizures decreased and the latency to stage 3-5 seizures increased when the animals were treated with lacosamide at a single dose of 10 mg/kg compared to saline pretreatment (p < 0.05), both parameter reflecting an anticonvulsant action of the drug. Unfortunately, the number of stage 3-5 seizures also increased, but not significantly. The win-PTZ kindling model showed an adequate reproducibility between different trials, however, the number of fully kindled rats was lower than previously reported.
Conclusions: Lacosamide showed a convincing anticonvulsant action in the win-PTZ kindling model of epilepsy by preventing the generalization of seizures. The win-PTZ kindling model was proved to be useful for studying epileptogenesis and the anticonvulsant action of drugs.
Dan Andonie, Zsolt Gáll, Paul Bosa, Maria Titica Dogaru and Szende Vancea
An uncomplicated, sensitive liquid chromatography linked to mass spectrometry (LC/MS) for evaluation of carbamazepine and carbamazepine-10,11-epoxide (its metabolite) in human plasma, human saliva, rat plasma, and rabbit plasma was developed. Analyses were conducted on a Zorbax SB-C18, 100 mm × 3 mm ID, 3.5 μm column, at a column temperature of 40 ºC. The mobile phase was comprised of 0.1% formic acid in water and methanol in a 35 : 65 (v/v) ratio, with a flow rate of 0.4 mL/min. Lacosamide was utilized as internal standard. Under these chromatographic conditions, the retention times of lacosamide, carbamazepine-10,11-epoxide, and carbamazepine were 1.4 min, 1.6 min, and 2.2 min, respectively. The quantification of the analytes was performed using multiple reaction monitoring, with the use of a triple quadrupole mass spectrometer with electrospray positive ionization. The monitored ions were m/z 194 derived from m/z 237 for carbamazepine, m/z 180 derived from m/z 253 for carbamazepine-10,11-epoxide, and m/z 108 derived from m/z 251 for lacosamide. The samples were prepared by protein precipitation from 0.2 mL of plasma/saliva using 0.6 mL of internal standard solution in methanol. Calibration curves were constructed over the ranges 1.1–17.6 µg/mL and 0.23–5.47 µg/mL for carbamazepine and carbamazepine-epoxide, respectively. The coefficients of determination obtained by using a weighted (1/x) linear regression were greater than 0.994. The reported LC-MS/MS method was applied to preclinical pharmacokinetic studies and therapeutic drug monitoring.
Kolcsár Melinda, Gáll Zsolt, Bába László-István and Kun Imre Zoltán
The relationship between antidepressants (AD) and metabolic syndrome (MS) can be approached from many perspectives. We can start from the mutuality of depression and MS: depression often causes MS and vice versa; however, the two diseases aggravate each other. Altered glucocorticoid secretion - among others - may be a common etiological factor for depression and MS. Enhanced glucocorticoid production leads both to sleep disorders and insulin resistance, and several antidepressants cause obesity and insulin resistance. In addition, sympathetic nervous system activity increases in depression, together with the elevated production of counter-insulin hormones such as catecholamines (adrenaline) and glucocorticoids. From the components of MS, body weight changes can be most easily followed by the patient. The obesogenic mechanisms of AD drugs are different. The H1-receptor blocking agents have the most important weight gaining effect, followed by the 5-HT2c-receptor blocking and/or down-regulating ADs. The fattening effect of mirtazapine, paroxetine, and tricyclic antidepressants are based on such central mechanisms. Blocking of alpha1-receptors contributes to the obesogenic effects of certain drugs by inducing sedation: this has been confirmed in case of imipramine, amitriptyline, and doxepin. Fluoxetine behaves differently depending on the dose and duration of treatment: while at the usual doses it induces weight loss at the beginning of therapy, its initial anorexigenic effects reverses during prolonged use; while its activation effect at high doses is favorable in bulimia. The selective noradrenaline reuptake inhibitor reboxetine reduces appetite, similarly to bupropion, which inhibits dopamine reuptake as well. We highlight the effect of fluoxetine on direct adipogenicity, mentioning its preadipocyteadipocyte transformation-reducing and adipocyte proliferation-inhibiting activity, as well as its ability to enhance fat cell autophagy.
László-István Bába, Zsolt Gáll, István Lóránt Bíró, Tibor Mezei, Imre Zoltán Kun and Melinda Kolcsár
This study aims to investigate the effects of chronic fluoxetine (FLX) treatment on preadipocyte factor-1 (Pref-1) expression in subcutaneous, visceral and brown adipose tissues, and on the size of vacuoles in a dipocytes obtained from the perirenal regions in rats. Twenty-eight Wistar rats were treated with FLX at two different doses and fourteen animals received vehicle. After 40 days of treatment, the subcutaneous, perirenal and interscapular adipose tissues were collected. Pref-1 expression was examined using an immunohistochemical method and the vacuolar area was measured in stained sections. In the low dose FLX group, the size of vacuoles increased both in male and female animals. The high dose of FLX also induced a significant increase of vacuole size, but only in male animals. Neither of the two doses of FLX has significantly affected the Pref-1 expression in any type of adipose tissue.