We have recently identified several aroylhydrazone-based molecular hybrids with antiseizure activity. We aimed to investigate the analgesic activity of these molecules further. Male ICR mice were injected intraperitoneally with the tested substances or with the vehicle only (controls). We performed hot plate tests, formalin test and maximal electroshock (MES) test and further studied the cytokine proteome in the brain. In silico analysis was performed for prediction of the physicochemical parameters and activity. The furan-substituted aroylhydrazone-based 2Hchromene hybrid showed a significant increase of the latent time as compared with the baseline values (p < .05). Both the chlorine-substituted and the methyl-substituted aroylhydrazone-based coumarin derivatives significantly decreased the first phase of the formalin test (p < .05). We also found suppression of all the cytokines which were overexpressed in the model of acute seizures (MES test) and in the formalin paw test. The in silico model predicted hydroxymethylglutaryl coenzyme A synthetase 2 (HMGCS2) enhancer activity. Further testing is needed to confirm the mechanism of the potentially beneficial effects of the tested substances and to evaluate the toxicity and efficacy of the proposed molecules.

Background: Studies have shown that the public knowledge on antibiotics is poor although many practice antibiotic self-medication. This study aimed to determine the knowledge regarding antibiotics and their use among non-academic staff members of a Sri Lankan University. Methods: This is a descriptive cross-sectional study. The participants were permanent non-academic staff members of a selected university in Sri Lanka. Consecutive sampling was done. Data were obtained using a pre-tested self-administered questionnaire administered in mother-tongue. Results: 321 individuals participated (response rate-80%); 53.9% were men; mean age was 36.8±8.8 years. 40.2% have self-medicated with antibiotics at least once during the preceding 12 months.46.4% have understood antibiotics as medicines which can act against diseases caused by all the microbes including bacteria, viruses and fungi.

To cite this article: Slavina Surcheva, Stanislav Marchev, Roman Tashev, Stilyana Belcheva & Mila Vlaskovska (2017) Action of adrenal and gonadal steroid hormones on kainic acid-evoked seizures in a rat model of epileptogenesis, Biotechnology & Biotechnological Equipment, 31:6, 1226-1230, DOI: 10.1080/13102818.2017 ABSTRACTEpilepsy is one of most reported neurological disorders after migraine, stroke and Alzheimer's disease. Empiric clinical data reveal that seizures and epilepsy more likely affect men than women. The aim of present study was to investigate the effect of steroid adrenal and gonadal hormones on the intensity, dynamics and latency of kainic acid-evoked seizure and lethality in a rat model of epileptogenesis. After surgical adrenalectomy/gonadectomy, male rats were at random assorted in groups and treated from postoperative day 1 to day 5 with corticosterone (30 mg/kg), estradiol (0.03 mg/kg), progesterone (75 mg/kg), dihydroprogesterone (75 mg/kg) and dihydrotestosterone (0.75 mg/kg). Spontaneous recurrent seizures generated by kainic acid were assessed. The treatment with corticosterone eliminated the aggravation of kainic acid-evoked seizures produced by adrenalectomy/gonadectomy. The application of corticosterone decreased the seizure intensity by 31% and prevented seizure-associated animal death. The effect of estradiol treatment was quite opposite. Estradiol treatment exacerbated the somatic and behavioural aspects of kainic acidevoked epilepsy-like syndrome. The hormone increased the intensity of kainic acid-evoked seizures by 31%, decreased the latency of clonic weak seizures by 49% and enhanced the associated lethality by 133%. The treatment with progesterone or dihydroprogesterone produced minor alterations in intensity and latency of kainic acid-evoked seizures in the operated male rats. The application of dihydrotestosterone significantly aggravated the kainic acid-evoked seizures. In summary, hormonal unbalance could play an important role for seizure susceptibility in epileptogenesis. Corticosterone has better anti-seizure activity than progesterone and testosterone has significant pro-convulsive activity.

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Despite the plethora of anti-epileptic drugs (AEDs) available, in one third of patients with epilepsy the seizure control remains poor. Due to the similarity between the mechanisms of epileptogenesis and neuropathic pain, some AEDs have an indication for pain treatment. All of them, however, show adverse effects. There has been a recent strengthening of the specific regulatory restrictions for some AEDs, due to the recognised risk of fetal harm. The aim of the present study is to investigate the anti-convulsive and analgesic activity of newly synthesised hydrazide-hydrazone derivatives bearing 2Hchromene and coumarin scaffold in ICR mice. Male ICR mice were used (8 per group). Maximal electroshock (MES) test was applied to study anti-convulsive activity. Two tests were used to assess analgesic activity, i.e. the hot plate test and the formalin test. Antiseizure activity has been observed for p-chlorphenyl, 2-furyl and p-methoxyphenyl substituted derivatives of coumarin-hydrazide/hydrazones (4a, 4c) (ED50 99.71mg/kg, 81.29 mg/kg respectively, MES test), and for p-chlorphenyl and 2-furyl substituted derivatives of 2H-chromene based hydrazide/hydrazone (8a, 8b) (ED50 87.63 mg/kg and 12.51 mg/kg, respectively, MES test). During the hot plate test, 8b significantly increased the latency time when compared to the control group (median values 53.5 vs. 25 sec, p<0.05). During the first phase of the formalin test, 4a and 4c significantly shortened the licking time (median values 15 and 25 sec, respectively) when compared to the control group (51 sec, p<0.05). The investigated substances did not demonstrate anti-nociceptive effects during the second phase of the formalin test. The results from this study indicate that 4a, 4c and 8b possess anti-nociceptive and anti-convulsive effects. The connection between the chemical structure of the investigated compounds and the observed is to be elucidated by ongoing studies. These studies will also reveal certain molecular mechanisms of action.

Pharmacovigilance activities are of vital importance for ensuring effective and safe medicinal products. In order to clarify to which extent marketing authorisation holders (MAHs) meet the requirements of the Law and the Directives related to this activities, we conducted a systematic search among the procedures submitted to the Bulgarian Drug Agency (BDA) related to the implementation of the decisions of the Pharmacovigilance Committee and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for a period of 6 years. The results of the study showed significant discrepancies between regulatory requirements and the behavior of the MAH at the national level. This could be a serious problem, as inadequate or late implementations of the PRAC (Pharmacovigilance Risk Assessment Committee)/CMDh/EC recommendations can lead to untimely informing of healthcare professionals and patients about potential safety concerns and risks related to the use of medicinal products.

Background: Accumulating evidence points towards serotonin (5-hydroxytryptamine; 5-HT), melatonin and their metabolites as modulators or markers of a wide range of physiological processes. Literature remains however scarce about their metabolism and usual plasma levels. We developed an analytical method to determine plasma concentrations of 5-HT and 8 of its metabolites: melatonin (Mel), N-acetylserotonin (NAS), 6-hydroxymelatonin (6-OH Mel), 5-methoxytryptamine (5-MT), 5-hydroxyindole-acetic acid (5-HIAA), 5-methoxyindole-acetic acid (5-MIAA), 5-hydroxytryptophol (5-HTP), 5-methoxytryptophol (5-MTP). This work aimed at validating the method and determining physiological ranges for these metabolites in plasma. Methods: Free 5-HT and its 8 metabolites were measured in plasma with a newly developed LC-MS/MS assay. To determine reference plasma concentration ranges, these analytes were measured in 98 healthy subjects (aged 18-70 years, 44 males). Most blood samples (n= 92) were collected between 8h30 and 10 AM to limit the impact of circadian variations, after 24h of abstinence from serotonin rich foods. The study was approved by the local ethics committee and informed consent was obtained according to GCP/ICH requirements. Results: The assay was found linear on calibration curves (0.25 to 400'000 pg/ml) for all analytes with sensitivity (0.25 to 390 pg/ml) depending on the analyte. Intra-and inter-run coefficients of variation were acceptable (0.5% to 22.7%) and no carryover was observed. Free 5-MT, 5-HTP and 5-MTP remained below the quantification limit. Geometric mean values (CV%) were determined for the remaining metabolites (pg/ml): 5-HT: 31829 pg/ml (54%); Mel: 7.4 (110%), NAS: 6.8 (77%), 6-OH-Mel: 0.5 (101%), 5-HIAA: 6018 (28%); 5-MIAA: 55.3 (48%). Significant circadian variations were observed among 21 volunteers monitored over 24h. Conclusions: We developed and validated a robust method for measuring serotonin and 8 metabolites in human plasma. Usual ranges for plasma levels were determined in 98 healthy volunteers. These results afford valuable biomarkers of physiological and pathological serotonin production.

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