Pharmacology and Drug Toxicology

Mitochondrial dysfunction in cerebrovascular pathology as a target for pharmacological modulation: focus on benzodiazepines

I. F. Belenichev, N. V. Bukhtiyarova, O. O. Nefyodov — Wed, 17 Sep 2025 11:44:34 +0300

Mitochondrial dysfunction (MD) is recognized as one of the key pathobiochemical mechanisms in the development of cerebrovascular diseases, neurodegenerative processes and cognitive disorders. In destructive and degenerative brain diseases, there is a disruption of the mitochondrial respiratory chain, energy metabolism, and cellular ionic homeostasis, with elevated intracellular calcium levels, glutamate induced excitotoxicity, nitrosative and oxidative stress and neuronal injury. Mitochondria, which play a central role in cellular energy supply, are identified as the primary source of reactive oxygen species (ROS). The term "mitochondrial dysfunction" now encompasses a typical pathological process without strict etiological or nosological specificity.
MD is characterized by impaired respiratory chain function, reduced ATP production, excessive ROS accumulation, mitochondrial pore opening, calcium homeostasis disruption, and activation of neuronal apoptosis. These alterations lead to neuronal structural damage, decreased energy potential, impaired cognitive function, and reduced neuroplasticity. The issue is particularly relevant in the context of ischemic brain injury, trauma, chronic hypoxia, and post-hypoxic conditions.
The purpose of the study – is to analyze and summarize data from scientific literature and our own results regarding the role of MD in cerebrovascular pathology and to determine approaches to its
pharmacological correction. This article emphasizes the central role of mitochondria in pathological processes and highlights the importance of pharmacological correction of MD. It explores the mechanisms by which adaptive cellular factors such as HIF-1 and molecular chaperones Hsp70 regulate mitochondrial metabolism and contribute
to neuronal protection. Current therapeutic approaches are discussed, including the use of antioxidants, antihypoxants, energy-modulating agents, neuropeptides, and particularly peripheral benzodiazepine receptor (TSPO) modulators. Benzodiazepine derivatives such as Gidazepam®, Phenazepam®, and Cinazepam (levana) demonstrate mitoprotective properties by reducing ROS production, increasing mitochondrial membrane potential, modulating pore opening, and elevating Hsp70 levels. TSPO, located on the outer mitochondrial membrane, plays a critical role in apoptosis regulation, steroidogenesis, and cellular stress responses, making it a promising pharmacological target. The potential use of benzodiazepines in autism spectrum disorders (ASD) is also of growing interest. Thus, benzodiazepine derivatives capable of modulating TSPO and mitochondrial function may represent valuable components of combined neuroprotective strategies in cerebrovascular pathology. Further researches are needed to establish their clinical efficacy and safety in neurology, neurosurgery,
and neurocritical care

The evolution of hypnotics

A. V. Chornomydz, O. M. Oleshchuk, V.V. Chernyashova — Wed, 17 Sep 2025 12:02:41 +0300

Insomnia is one of the most prevalent medico-social problems, leading to a significant decline in quality of life, reduced work productivity, and an increased risk of somatic and psychiatric diseases.
Pharmacotherapy remains an important treatment modality, yet the history of hypnotic drugs is a continuous search for a balance between efficacy and safety.
The aim of study – to provide a comprehensive analysis of the evolution of hypnotic agents, systematize them by generation, mechanism of action, clinical advantages, and disadvantages, as well as to identify key trends and future perspectives for this pharmacological group. An analysis and systematization of scientific literature, clinical guidelines, and key studies covering the
history, pharmacology, and clinical application of sleeping medications were performed. The first generations of hypnotics (chloral hydrate, barbiturates), characterized by high efficacy but a
low safety profile and significant dependence potential, are reviewed. The benzodiazepine revolution of the 1960s is analyzed, which offered a much higher therapeutic index but did not solve the problems of long term dependence and sleep architecture disruption. The emergence of non-benzodiazepine "Z-drugs" is highlighted as an attempt to achieve greater selectivity for the α1
subunit of the GABA-A receptor. Special attention is paid to the modern era, which marks a paradigm shift from GABAergic sedation to physiological sleep modulation through fundamentally new mechanisms: agonism at melatonin receptors (the chronobiotic approach) and antagonism at orexin receptors (the "anti-arousal" approach). The practice of
off-label use of drugs from other groups (antihistamines, antidepressants, antipsychotics, gabapentinoids) is also analyzed.
Thus, the evolution of hypnotic drugs demonstrates a clear trend towards increased specificity and safety, reflecting a deeper understanding of sleep neurobiology. Modern pharmacotherapy aims for a
targeted influence on the natural regulatory mechanisms of the sleep-wake cycle with minimal risk of dependence and side effects. It is emphasized that pharmacotherapy is a component of comprehensive care, where cognitive-behavioral therapy for insomnia (CBT-I) is the gold standard for treating chronic insomnia.

Pharmacophore modeling of selective interaction of ligands with cytochrome P450 isoforms

M. Ya. Golovenko — Wed, 17 Sep 2025 13:09:49 +0300

Cytochrome P450 (CYP) enzymes are essential players in drug metabolism and exhibit pronounced selectivity toward specific substrates and inhibitors. This selectivity arises from structural differences in
the active sites of various CYP isoforms.
The aim of the study - to establish the reasons for the selective interaction of substrates and inhibitors with different CYP isoforms by identifying the structural and functional features of the active site of
enzymes that cause differences in their specificity.
In this study, pharmacophore modeling approaches were applied to identify key molecular interactions governing ligand selectivity across CYP isoforms. Pharmacophore models were constructed
based on the spatial and electronic features of known substrates and inhibitors. The analysis revealed critical pharmacophoric elements responsible for isoform-specific binding.
The models obtained can be used to predict metabolic pathways, guide the design of selective inhibitors, and support early-stage drug development and screening.

Evaluation of the efficacy of liposomal forms of quercetin in LPS-induced model of acute respiratory distress syndrome

Z. S. Suvorova — Wed, 17 Sep 2025 13:17:00 +0300

Acute respiratory distress syndrome (ARDS) is a severe and often fatal complication of various critical conditions, including bacterial and viral infections (such as COVID-19), sepsis, trauma, and aspiration. It is characterized by diffuse alveolar damage, cytokine overproduction, endothelial dysfunction, microthrom bosis, and alveolar-capillary barrier disruption, leading to life-threatening respiratory failure. Despite intensive care and supportive therapy, there is a persistent need for effective pharmacological agents that can reduce inflammation and protect lung tissues. Quercetin, a plant-derived flavonoid with proven antioxidant, anti-inflammatory, and endothelial-protective properties, is considered a promising candi date. Its liposomal form enhances bioavailability and targeted delivery. The combination of quercetin withzinc(II), a trace element with immunomodulatory and antiviral activity, may further potentiate its therapeutic effects.
The aim of the study is to evaluate the therapeutic potential of the liposomal form of quercetin and its liposomal composition with zinc in an LPS-induced model of acute respiratory distress syndrome
(so-called "fatal" ARDS) in animals by analyzing survival, clinical presentation, and morphological condition of lung tissue in laboratory animals. An LPS-based ARDS model in mice was used, supplemented with muramyl dipeptide and Freund's adjuvant. Survival, clinical condition, and histopathological changes in the lungs and myocardium were evaluated. Test samples were administered intravenously. Statistical analysis of the quantitative results was performed using Student’s t-test.
In the model of "fatal" acute respiratory distress syndrome (ARDS) induced by the combined administration of LPS, MDP, and Freund’s adjuvant, a high mortality rate (up to 71%) was recorded, along with a marked deterioration in overall clinical condition and pronounced destructive-inflammatory morphological changes in the lungs and heart. Intravenous administration of liposomal forms of quercetin led to a statistically significant increase in survival rates, improvement in the animals’ clinical condition, and a reduction in the severity of organ morphological damage. A positive effect was observed on survival dynamics, attenuation of inflammatory and dystrophic changes in lung tissue, preservation of myocardial histological architecture, and reduction of pulmonary hypertension manifestations.
The results obtained indicate the therapeutic potential of liposomal quercetin formulations as a treatment option for ARDS, particularly in the context of intensive care of inflammatory lung injury.

Electrocardiographic analysis of cardiac effects of anticonvulsant doses of digoxin and its combinations with sodium valproate and carbamazepine in rats

V. V. Tsyvunin, S. Yu. Shtrygol’, D. V. Shtrygol’ — Wed, 17 Sep 2025 13:27:24 +0300

Treatment of drug-resistant epilepsy is a complex problem, one of the ways to solve which may be the use of adjuvants that enhance the effects of antiepileptic drugs (AEDs). Such adjuvants include digoxin in subcardiotonic doses. Clinically, positive experience of its use is accumulating, a number of mechanisms have been investigated in the experiment and the most effective combinations with classical AEDs have been identified. The question arises about the effect of anticonvulsant doses of digoxin on the heart. The aim of the study – to determine the effect of digoxin in an anticonvulsant dose per se and in combination with sodium valproate and carbamazepine on the ECG in rats. The experiments were conducted using albino male rats, in which ECG was recorded under thiopental
induced anesthesia. Animals of group 1 at the beginning of the experiment served as vehicle control (baseline ECG was recorded), after which digoxin 0.57 mg/kg was administered intraperitoneally (i.p.) and after 25–30 min its effect on electrophysiological parameters of cardiac function was determined. For this purpose, animals of group 2 were administered sodium valproate 215 mg/kg i.p., anesthesia was given 20–25 min later, ECG was recorded 5 min after its onset (intrinsic effect of valproate), digoxin was administered and after another 25–30 min ECG was recorded again (effect of the combination). In rats of group 3, the electrocardiographic effects of carbamazepine 28.6 mg/kg intragastrically and its combination with digoxin were determined according to a similar protocol. The indicated doses were calculated from effective anticonvulsant doses for mice (digoxin 0.8 mg/kg, sodium valproate 300 mg/kg, carbamazepine 40 mg/kg) using the species stability coefficient. ECG was recorded in the II standard lead on the ЕСІТ03М2 device with needle electrodes. Standard ECG parameters were measured, and the systolic index (SI) was determined as the ratio of the QT interval to the RR cardiac cycle duration (QT/RR, %). It was established that digoxin in an anticonvulsant dose does not cause dangerous ECG abnormalities in rats anesthetized with thiopental sodium: its effect is limited to moderate bradycardia within the species norm of heart rate (HR) – a decrease on 12% (p < 0.05) and a tendency to increase in the PQ interval by 4 ms (8%), the QT interval by 4 ms (5%). Sodium valproate does not cause changes in ECG parameters, and when used against the background of digoxin, the decrease in heart rate is 14% (p < 0.05), the PQ interval increases by an average of 8 ms (16%, p < 0.05), the QT interval – by 6 ms (8%, p < 0.05). Carbamazepine also does not affect ECG parameters, and when combined with digoxin, the heart rate is reduced insignificantly by 9%, the PQ intervals tend to increase by 5 ms (10%) and QT by 5 ms (7%). SI with the combined use of digoxin and carbamazepine significantly decreases by 3.7% (p < 0.05), which indicates an increase in cardiac contractile function. Thus, no dangerous effects of digoxin in an anticonvulsant dose of 0.57 mg/kg on the ECG of rats were detected, only moderate bradycardia occurs. When combining digoxin with sodium valproate, more pronounced bradycardia is observed than under the influence of digoxin per se, a significant slowdown of atrioventricular conduction and prolongation of the QT interval, which requires electrocardiographic monitoring. When combining digoxin with carbamazepine, significant bradycardia and prolongation of the PQ and QT intervals are not observed.

Antimicrobial activity of antiseptics Miramistin and Octenisept against gram-negative bacteria

S. Yu. Shtrygol', T. A. Bukhtiarova, O. O. Matiyko — Wed, 17 Sep 2025 13:38:31 +0300

Injuries of various origins are a serious problem in medical practice, as they are often complicated by infections. The frequency of complications associated with contamination of the wound surface increases significantly in combat conditions. Colonization of the wound surface with antibiotic-resistant strains of microorganisms leads to a long stay of the patient in the hospital and requires increased costs for the treatment. To prevent infection of skin and soft tissue injuries, local antimicrobial agents are used – antiseptics. Their rational use can play an important role in the prevention of wound colonization and formation of biofilms on the wound surface. Among antiseptic agents, the quaternary ammonium compounds Octenisept and Miramistin deserve attention. Due to the long-term use of drugs in medical practice, the sensitivity of microorganisms may change over time. An assessment of the ability of drugs to prevent the formation of biofilms that contribute to the chronicity of the inflammatory process is relevant.
The aim of the study is to assess the sensitivity of planktonic cells and biofilms of gram-negative bacteria P. aeruginosa, A. baumanii, and K. pneumoniae to the action of Miramistin and Octenisept.
The study was conducted in vitro using bacteria isolated from patients with purulent-inflammatory processes. The study of antibacterial activity was carried out on planktonic cells and biofilms, with the
determination of the minimum inhibitory concentration (MIC) and biofilm biomass under the influence of drugs in subinhibitory concentrations. According to the results of the experiments, all clinical isolates of P. aeruginosa and A. baumanii show moderate sensitivity to the action of Miramistin (MIC in the range from 18.5 μg/ml to 150.0 μg/ml). The most pronounced effect is observed against A. baumanii (from 0.78 μg/ml to 50.0 μg/ml). Clinical strains of Gram-negative bacteria showed marked sensitivity to the action of Octenisept, inhibition of bacterial growth was observed at dilutions from (1:2) to (>1:4096), depending on the test strain. The antibiofilm effect of Miramistin and Octenisept against P. aeruginosa and K. pneumoniae is recorded already at the initial stages of biofilm formation, which is due to impaired adhesion to the substrate. The effect of Octenisept against A. baumanii is most pronounced at the later stages of biofilm formation (16–24 hours). Thus, the antiseptic agents Miramistin and Octenisept are active against planktonic cells and biofilms formed by gram-negative bacteria, which are relevant in combat conditions. Their use in inhibitory concentrations can prevent colonization of the wound surface in injuries of various origins and chronicity of the inflammatory process.

The determination of micro and macroelement composition of flowers and leaves of potato (Solanum tuberosum)

Y. P. Shevchenko — Wed, 17 Sep 2025 00:00:00 +0300

The aim of the study was to carry out a comparative research of micro- and microelement composition of potato (Solanum tuberosum) flowers and leaves by X-ray fluorescence analysis (XRF).
The materials for the study were samples of potato flowers and leaves collected under natural growth conditions. A modern X-ray fluorescence spectrometer was used for the study, which allows for high accuracy to identify and quantify elemental composition of biological materials. The results of the study showed that both potato flowers and leaves contain significant concentrations of macronutrients such as potassium (K), calcium (Ca) and chlorine (Cl), as well as important trace elements for plants – iron (Fe), copper (Cu), manganese (Mn) and zinc (Zn). At the same time, differences in the distribution
of elements between flowers and leaves were observed, which may be due to the different physiological functions of these plant organs. X-ray fluorescence analysis allowed to characterise in detail elemental composition of potato flowers and leaves, revealing differences in the concentrations of micro- and macroelements between these organs. The data obtained can be taken into account in the following pharmacological studies of this raw material.

Alexander Viktorovich Stefanov On the 75th anniversary of his birth

Wed, 17 Sep 2025 14:20:02 +0300

We remember and honor Alexander Viktorovich Stefanov, a talented scientist in the field of physiology, biochemistry, pharmacology, an outstanding organizer in the field of healthcare in Ukraine, a remarkable person who left behind many good deeds. We will remember him!