EFFECTS OF NEW PIPERIDINE DERIVATIVES WITH SUBSTITUTIONS IN THE 1ST AND 4TH POSITIONS IN NALOXONE SENSITIVE ANALGESY

Background. Despite the wide arsenal of painkillers, pain relief is an urgent interdisciplinary problem that requires a search for new solutions. Purpose of the study. To establish the role of opioid receptors in the mechanism of the analgesic action of the piperidine derivatives AGV-22 and AGV-23. Material and methods. The studies were carried out on 96 white mice of both sexes weighing 30-40 g. The analgesic effect of the compounds was tested on models of thermal and chemical irritation with preliminary administration of the opioid receptor antagonist naloxone. Results. The pain reactions of mice with models of thermal and chemical stimulation in the AGV-22 / AGV-23 + naloxone and AGV-22 / AGV-23 groups were comparable. Conclusions. The mechanism of the analgesic action of the piperidine derivatives AGV-22 and AGV-23 is not associated with the activation of opioid receptors.

Antiparkinsonian activity of new N-methyl-D-aspartate receptor ligands in the arecoline hyperkinesis test

Introduction. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the population of older patients. Even though long-term combination therapy helps to cope with the main manifestations of PD. It inevitably leads to the appearance of such side effects as drowsiness, hallucinations, dyskinesia, and many others. [12]. Therefore, the search for effective antiparkinsonian drugs devoid of the above-mentioned adverse reactions remains an urgent task of modern neuropharmacology.The explored substances are derivatives of imidazole-4,5-dicarboxylic acid. These compounds belong to a fundamentally new class of N-methyl-D-aspartate ligands (NMDA) that are not channel blockers. Their pharmacological effect is realized due to interaction with the NMDA receptor recognition site, which, along with high efficiency, allows us to assume their higher safety, compared to previously existing channel blockers from the NMDA ligand group.Objective. Studing of the antiparkinsonian activity of new ligands of the glutamate NMDA-receptor complex-1,2-substituted imidazole-4,5-dicarboxylic acids on an experimental model of arecoline hyperkinesis.Materials and methods. Imidazole-dicarboxylic acid derivatives (IEM2258, IEM2248, IEM2247, and IEM1574) were injected into the lateral ventricles of the mouse brain 10 minutes before arecoline in a volume of 5 µl at doses of 0.1-0.5 µmol, then the latent period, intensity, and duration of tremor were recorded. Amantadine was used as a comparison drug.Results. Preliminary administration of the studied examined substances led to a significant decrease in the intensity and duration of arecoline tremor. The highest inhibitory activity with respect to the intensity and duration of the experimental tremor was demonstrated with the introduction of the compound IEM-2247 (at a dose of 0.1-0.5 mmol, the duration of the latent period of the tremor was 1.7-2.3 times longer than the control one, respectively, the duration of the tremor decreased by 1.5 - 2.5 times).Conclusions. The dose-dependent antiparkinsonian activity of imidazole-dicarboxylic acid derivatives is shown, indicating the prospects for the development of these substances and the further search for effective and safe antiparkinsonian agents among the compounds of this class.

ISOLYQUIRITIGENIN AFFECTS PHAGOCYTES FUNCTIONS AND INCREASES MICE SURVIVAL RATE IN STAPHYLOCOCCAL INFECTION

The results of studying the effect of isoliquiritigenin on animal survival in the model of staphylococcal infection and the function of human and animal phagocytes are presented in this article.The aim of the investigation was to study the effect of an isoliquiritigenin preliminary administration on the survival of animals against the background of staphylococcal infection, as well as on the function of phagocytes in mice and humans.Materials and methods. To assess the survival of Balb/C mice, a model of infection caused by Staphylococcus aureus J49 ATCC 25923 with the construction of Kaplan-Meier curves, was used. The effect on the phagocytes functions was studied by assessing the peptone-induced migration of phagocytes into the abdominal cavity of Balb/C mice, the absorption activity of phagocytes (neutrophils and monocytes) of human blood, as well as their production of reactive oxygen intermediates (ROIs) using а flow cytometry.Results. It was found out that a preliminary triple intraperitoneal administration of isoliquiritigenin (30 mg/kg) increases the survival rate of Balb/C mice in staphylococcal infection caused by Staphylococcus aureus J49 ATCC 25923. At the same time, isoliquiritigenin dose-dependently activates the production of reactive oxygen intermediates by human neutrophils and monocytes without statistically significantly suppressing a phagocytic activity of monocytes and neutrophils against fluoresceinisothiocyanate-labeled S. aureus J 49 ATCC 25923, as well as peptone-induced migration of phagocytes into the abdominal cavity of mice.Conclusion. Thus, a preliminary administration of isoliquiritigenin increases the survival rate of mice with staphylococcal infection and increases the production of reactive oxygen intermediates by phagocytes. The data obtained, can become the basis for further research of antibacterial and immunotropic effects of isoliquiritigenin in order to find new drugs for the treatment of staphylococcal infection.

Effects of Orally Administered Preliminary Analgesic Therapy in Diagnostic Colposcopy Patients: A Prospective Questionnaire Study

Background: Colposcopy has a key role in the diagnostic work-up and management of abnormal cervical cytology, but it might generate negative feelings of mainly anxiety and pain to the patients undergoing such examination. These feelings are interrelated, with the anxiety fueling the painful sensations. The aim of our study was to investigate the effects of preliminary administration in terms of pain and anxiety relief that the preliminary administration of paracetamol would have on patients undergoing diagnostic colposcopy. Materials & Methods: We conducted a single center prospective study which enrolled 112 patients with diagnosed or suspected cervical pathology who were examined at the Outpatient Colposcopy Clinic of Patras University Hospital, over a 7-months period. Patients were randomly assigned to one of the two groups. The interventional group received 1gr of paracetamol (acematiminofen) in pill form, 30 to 60 minutes before colposcopic assessment; the control group received no medication. At the end of consultation, all participants completed a 2-page questionnaire. Results: More patients of the interventional arm did not experience any pain at all during colposcopy compared with the control group. However, this difference was statistically not significant, probably because of the small number of patients. Moreover, there were no differences in mild and moderate pain rates between the interventional and control groups. Severe pain was only experienced by patients in the control group. Further data analysis from the first time as and for repeat colposcopy patients showed similar findings regarding pain intensity rates in the interventional and control group. When considering anxiety levels, no differences were observed between the two groups. Conclusion: The preliminary administration of low dose paracetamol in a pilot sample of colposcopy patients did not illustrate significant benefits in terms of experienced pain and anxiety levels.

If seizures left speechless: CA-P-S C-A-R-E, a proposal of a new ictal language evaluation protocol

Introduction We aimed to create standardized protocol for language examination in patients who underwent video-EEG recording and assessed its efficacy in the characterization of ictal language impairment, its ability to differentiate this from impaired awareness, and interobserver reliability in clinical practice. Methods From our database of video-EEG recordings, we selected a representative sample of 63 focal seizures with presumed language impairment. A multidisciplinary team of epileptologists, EEG technicians, and speech therapists analyzed the selected videos to highlight the critical issues of ordinary ictal language evaluation. We subsequently followed a multi-step process to develop the protocol and assess its interobserver reliability. Results A protocol based on seven tests in hierarchical succession was created, summed up in the acronym CA-P-S C-A-R-E (Closed Answers, Pro-speak question, Simple orders, Common object denomination, Audio repetition, Reading, Evoke). Following its preliminary administration for 5 months, we assessed the inter-observer reliability of 16 healthcare professionals in distinguishing between language impairment and impaired awareness among a sample of 10 seizures, finding a substantial agreement (kappa 0.61). Conclusion The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability.

Experimental Screening Study of the Antiarhythmic Activity of Empagliflosin

The antiarrhythmic activity of the type 2 sodium glucose co-transporter inhibitor Empagliflozin was studied in a model induced by calcium chloride in C57BL mice. It was found that preliminary administration of Empagliflozin at a dose of 1 mg/kg prevented CaCl2-induced ventricular arrhythmia and death during four periods of the biological half-life of the drug.

New pharmacological effects of caripazim

The effects of a proteolytic enzyme found in papaya milk juice (caripazim) on the rate of lymphatic drainage of tissues and the pharmacokinetics of cefotaxime were studied in experiments on rabbits and mice. During the study, caripazim was administered to experimental animals, and the rate of removal of Evans blue from the mesentery of mice, as well as the concentration of cefotaxime over time in the blood plasma of rabbits and the blood plasma, intestinal tissues, and livers of mice, after 1.5 and 24 h of antibiotic administration following injection of caripazim, were determined. Thus, the lymphostimulatory properties of caripazim were revealed. Its preliminary administration increased the concentration of cefotaxime in the blood plasma of rabbits in comparison with single administration of an antibiotic at all points of the study (1.5, 3, 4.5, 6, 8, 12, and 24 h). This coincides with the data from the study of the level of antibiotic in the blood plasma of mice. Administration of cefotaxime after injection of caripazim leads to an increase in its content in the intestinal tissue, after both 1.5 and 24 h, but does not affect at the accumulation of the antibiotic in the liver. The concentration ratio liver tissue / blood in mice in the main group was significantly lower than that in the control group, both 1.5 and 24 h into the experiment, which indirectly indicates a decrease in hepatic antibiotic extraction. The data obtained indicates that caripazim has the properties of an endolymphatic conductor.

The novel dipeptide ligand of TASP

Using the previously obtained first dipeptide ligand TSPO the N‑carbobenzoxy-L‑tryptophanyl-L‑isoleucine amide (GD‑23) as a basis, the new dipeptide was synthesized — the N‑phenylpropionyl–L‑tryptophanyl-L‑leucine amide (GD‑102). GD‑102 expressed anxiolytic activity in the open field test in BALB/c mice and in the elevated plus maze test in ICR mice. The minimum effective dose of GD‑102 was an order of magnitude lower than that of GD‑23. Preliminary administration of the TSPO selective antagonist, compound PK11195, completely blocked the anxiolytic activity of GD‑102, that indicated the participation of TSPO in the realization of the anxiolytic action GD‑102. The results were confirmed by molecular docking data.

HYALURONIDASE: AN EXPERIMENTAL CONFIRMATION OF THE PROPERTIES OF THE ENDOLYMPHATIC CONDUCTOR

One of the major achievements of contemporaneous pharmacology is the clinical implementation of the agents (the so called “endolymphatic conductors”) that allow for targeted delivering of antibiotic into the lymphatic system. Their use provides the basis for the lymphotropic treatment method that has been implemented into various areas of medical practice. Hyaluronidase is the most known agent used for this purpose. It has been shown that its preliminary administration before the injection of an antibiotic can improve clinical efficacy of the treatment; however, there is a need in the experimental validation of this approach to antibacterial therapy. The study was aimed at evaluation of hyaluronidase effects on the rate of lymphatic drainage of tissues and cefotaxime pharmacokinetics. We measured the time of elimination of lymphotropic Evans blue dye from the mouse mesentery when administered against the background of hyaluronidase, changes in cefotaxime levels over 24 hours in rabbit plasma and in mice plasma, gut tissues and liver at 1,5 and 24 hours after combined administration of hyaluronidase and the antibiotic. In addition, we calculated the liver to plasma ratio for the antibiotic concentrations. The data obtained shows that hyaluronidase can stimulate tissue lymphatic drainage. Its preliminary administration results in higher cefotaxime levels in rabbit and mice plasma at all time points of the study, compared to cefotaxime monotherapy, with prolongation of its systemic circulation of up to 24 hours. The use of cefotaxime after hyaluronidase leads to an increase of its levels in the mice gut tissues both at 1,5 and 24 hours, but has no effect on the antibiotic accumulation in the liver of the animals. However, the calculated liver to plasma blood ratio of cefotaxime after the administration of hyaluronidase is significantly lower than in the animals with the antibiotic monotherapy. This may indirectly indicate to a decrease in the hepatic extraction of the antibiotic when administered with hyaluronidase. The study results confirm that hyaluronidase has the properties of a lymphatic stimulator and an endolymphatic conductor for the water-soluble antibiotic cefotaxime.

Pharmacological correction of retinal ischemia/reperfusion by minoxidil

Introduction/Objective. The objective of this paper was to increase the effectiveness of pharmacological correction of retinal ischemia-reperfusion by using minoxidil. Methods. The research was carried out on 180 Wistar rats. A modification of the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 minutes. Protective effects of minoxidil at a dose 0.5 mg/kg on the model of retinal ischemia-reperfusion were estimated by the changes in the level of retinal microcirculation (laser Doppler flowmetry), electroretinogram amplitude, morphometry of retinal layers after 1 hour and 72 hours of reperfusion. Results. Minoxidil at a dose 0.5 mg/kg of rat mass improves retinal microcirculation, its electrophysiological state after 1 hour and 72 hours of reperfusion, and prevents the development of degenerative changes in the retina caused by ischemic damage to a greater extent than recombinant erythropoietin at a dose of 50 IU/kg and sildenafil at a dose of 0.5 mg/kg in monotherapy. The protective effects of minoxidil were eliminated by the preliminary administration of glibenclamide at a dose of 5 mg/kg, which indicates the presence of the preconditioning effect of minoxidil, realized through adenosine triphosphate-dependent potassium channels. Conclusion. Minoxidil at a dose of 0.5 mg/kg of rat mass protects the retina from ischemic-reperfusion injury. Protective effects of minoxidil are carried out by a preconditioning action, as evidenced by the lack of positive effects with the administration of glibenclamide.