Research Results in Pharmacology

Pharmacokinetic parameters of a zinc complex with N‑allylimidazole

2026-07-15T17:13:43+03:00

Introduction: Zinc is an essential trace element with well-known physiological functions. Although various zinc salts are available, novel zinc complexes with organic ligands remain of pharmacological interest. Pharmacokinetic studies are essential to clarify the contribution of the zinc ion and organic ligand to their biological activity.

Materials and Methods: The pharmacokinetics of bis(N-allylimidazole) zinc diacetate (ALL) components were studied in 66 BALB/c mice. The compound was administered once intraperitoneally at 25 mg/kg. Blood, brain, liver, pancreas, kidneys, and spleen were collected at 0, 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 24 h, with 6 animals per time point. N-allylimidazole was quantified using a validated HPLC-MS/MS method, while zinc was determined by atomic absorption spectrometry.

Results and Discussion: ALL likely dissociates into N-allylimidazole and zinc under physiological conditions, resulting in distinct pharmacokinetic profiles. N-allylimidazole was detected in all tissues, including the brain. The Tmax for most tissues was 0.25 h, indicating rapid systemic distribution. The highest concentration was observed in the kidneys (Cmax 7907.58 µg/g), suggesting their involvement in ligand excretion. In the liver, N-allylimidazoleshowed prolonged retention, with a T1/2 of 14.5 h and AUC(0–24) of 11168.41 µg·h/mL. After correction for endogenous zinc, the highest zinc concentrations were detected in the liver (60.21 µg/g), pancreas (57.52 µg/g), and spleen (54.80 µg/g).

Conclusion: ALL administration resulted in rapid systemic distribution of both components. N-allylimidazole penetrated highly perfused tissues, including the brain and kidneys, whereas zincaccumulated in the liver, pancreas, and spleen. Distinct tissue distribution and elimination profiles, together with equilibrium calculations, support complete in vivo dissociation of the complex.

HAEE tetrapeptide as a promising neuroprotector: comparison with Piracetam in an experimental model of Alzheimer's disease

2026-05-26T10:49:21+03:00

Introduction: During the experiment, the effectiveness of tetrapeptide HAEE and the comparison drug Piracetam in correcting neurodegenerative disorders in Alzheimer's disease was investigated in a model of transgenic mice.

Materials and Methods: transgenic mice of the APPswe/PS1dE9 (APP/PS1) line were used in the study. The animals were injected with HAEE and Piracetam, after which behavioral tests were performed (“Open Field”, “Light‑Dark Chamber”, “Novel Object Recognition”, “Barnes Maze”). Additionally, gene expression was analyzed using real‑time PCR. The histological study included staining of brain sections with Congo red, followed by counting amyloid plaques in the cortex and hippocampus.

Results and Discussion: The administration of HAEE and Piracetam led to an improvement in cognitive performance, with both groups demonstrating memory recovery to the level of intact controls. Histological analysis showed an increase in the number of amyloid plaques in the positive control animals and a reduction in the therapeutic groups by an average of 40%. Gene expression analysis showed that HAEE and Piracetam modulate key molecular pathways associated with neuroplasticity, inflammation, and cellular survival. Changes in the expression of the Stat3, mTor, Vegfa, and Casp3 genes have been observed, reflecting the activation of compensatory neuroprotective mechanisms, as well as the relative stabilization of the pro‑inflammatory markers Il‑6 and Tnf‑a.

Conclusion: HAEE tetrapeptide at a dosage of 50 mg per 1 kg and Piracetam at a dosage of 200 mg/kg have a comprehensive positive effect on cognitive functions, molecular and morphological parameters in Alzheimer’s disease. The results obtained in the animal model confirm its high potential as a promising neuroprotective agent, comparable to or superior to classical nootropic drugs.

Efficacy and side effects of different regimens of experimental postmenopausal osteoporosis therapy with zoledronic acid and their correction by combination with resveratrol

2026-05-15T09:58:03+03:00

Introduction: As an age-associated metabolic disease of the skeleton, osteoporosis (OP) causes a significant medical and socio-economic burden. One of the challenges in clinical practice is the adverse effects of widely used bisphosphonates. Therefore, the search for preventive pharmacotherapeutic strategies is needed.

Materials and Methods: Sixty female Wistar rats randomized into 6 equal groups were used to study the effects of a single and prolonged intravenous administration of zoledronic acid (ZA) without and in combination with an endothelioprotective dose of resveratrol (2 mg/kg intraperitoneally daily), compared with sham-operated and osteoporotic animals. X-ray densitometry and histological methods were used.

Results and Discussion: Already at 4 weeks after bilateral ovariectomy (OVx), the typical signs of osteoporotic lesions comparable with OP in humans are present. A single administration of ZA following 4 weeks of OP had a significant corrective effect on bone structure and the fatty component of bone marrow. After a second dose of ZA at 8 weeks after OVx, signs of bone damage were detected by week 12. The addition of 4 weeks of resveratrol therapy after the second dose of ZA (until 12 weeks after OVx) leads to switching of bone marrow precursors to osteoblastic differentiation, reducing the adipocytic component; cytoprotective action on osteocytes with their switching to a synthetic phenotype, reducing the potential activation of osteoclasts and blocking periosteocytic osteolysis; and protection of bone vessels via the endothelioprotective properties of resveratrol.

Conclusion: An endothelioprotective dose of resveratrol exerts multitarget cell- and endothelium-dependent mechanisms of protective action when combined with prolonged zoledronic acid therapy, preventing its adverse effects.

Toxicity and bioresorption of magnetite and manganese-zinc ferrite nanoparticles with oleic acid-based and amino-silica coatings

2026-05-14T10:54:37+03:00

Introduction: The prospects for using magnetic hyperthermia in cancer therapy are largely determined by the properties of the magnetic nanoparticles (MNPs), including heating efficiency, biosafety, and bioresorption capacity. In this study, we performed a comparative in vivo assessment of the toxicity and bioresorption of Fe3O4- and Zn0.2Mn0.8Fe2O4-based MNPs stabilized with oleic acid/sodium oleate (OA) or amino-functionalized silicon dioxide (SiO2–NH2).

Materials and Methods: Four types of MNPs were synthesized: Fe3O4@OA, Zn0.2Mn0.8Fe2O4@OA, Fe3O4@SiO2–NH2 and Zn0.2Mn0.8Fe2O4@SiO2–NH2. The particles were characterized using DLS, TEM and vibrating sample magnetometry. Acute toxicity was evaluated in BALB/c mice after a single intraperitoneal or intramuscular administration. Biosafety and bioresorption after intramuscular administration were assessed on days 2, 14, and 90, using hematological and biochemical blood tests, histological examination, sample magnetization, and total iron content in tissues.

Results and Discussion: After intraperitoneal administration, the LD50 values were 904 mg/kg for Fe3O4@OA, 1145 mg/kg for Zn0.2Mn0.8Fe2O4@OA, and 2955 mg/kg for Zn0.2Mn0.8Fe2O4@SiO2–NH2, whereas the LD50 for Fe3O4@SiO2–NH2 was not reached. After intramuscular administration at a dose of 1020 mg/kg, neither deaths nor pronounced systemic toxicity was observed. By day 90, MNPs with an oleic acid/sodium oleate-based coating showed a decrease in magnetic signal and total iron content at the injection site, whereas SiO2–NH2-coated nanoparticles remained in muscle tissue.

Conclusion: The study showed that the chemical nature of the coating is one of the main factors determining the toxicity and bioresorption of Fe3O4 and Zn0.2Mn0.8Fe2O4 MNPs. Particles with a SiO2–NH2 coating were characterized by lower acute toxicity after intraperitoneal administration compared with MNPs coated with oleic acid/sodium oleate. After intramuscular administration at a dose of 1020 mg/kg, neither mortality nor pronounced signs of systemic toxicity were detected for any type of MNPs. It was also shown that the coating type affects the possibility and rate of bioresorption: after intramuscular administration at a dose of 256 mg/kg, MNPs with a SiO2–NH2 coating remained at the injection site for 90 days, whereas the oleic acid/sodium oleate-based coating promoted bioresorption.

Evaluation of the anxiolytic properties of benzimidazole-2-thioethanones, 2-alkylthio- and 2-alkylsulfonylbenzimidazoles

2026-05-06T23:11:52+03:00

Introduction: Fabomotizole is an anxyolytic drug produced in Russia, a 2-mercaptobenzimidazole derivative. The pleiotropic effects of the benzimidazole scaffold, combined with proven neuropsychotropic properties, make fabomotizole a promising target for the synthesis of its analogs to obtain new derivatives with pronounced biological activity.

Materials and Methods: The study involved 125 white outbred male mice, randomly divided into 25 experimental groups (n=5). Twenty-one derivatives of benzimidazole-2-thioethanone, 2-alkylthio-, and 2-alkylsulfonylbenzimidazole were studied. The screening dose was calculated at the level of 1/100 of LD₅₀, determined in silico by the consensus ADMET prediction. The behavioral patterns of the animals were assessed in vivo in Light/Dark Box and Open Field in comparison with etifoxine (50 mg/kg), fabomotizole (20 mg/kg), and phenazepam (0.01 mg/kg). In the final stage, the studied structures were optimized using quantum chemistry methods for subsequent analysis of the structure-activity relationship.

Results and Discussion: The most active derivatives of 2-mercaptobenzimidazole were derivatives of 5-unsubstituted-2-mercaptobenzimidazole: ZH-2, ZH-3, ZH-4, and ZH-41. Among all the studied compounds, a decrease in anxiolytic effect was observed in sequence: 5-unsubstituted – 5-chloro-substituted – 5-methoxy-substituted 2-mercaptobenzimidazoles. A study of the mercaptobenzimidazole fragment using molecular mechanics and quantum chemistry methods revealed that the addition of a substituent to the benzene ring leads to a redistribution of the electron density of cyclic structures.

Conclusion: The synthesis of new molecules with a putative anxiolytic effect based on 2-mercaptobenzimidazole is a promising direction in medicinal chemistry. The most active compounds are those without a substituent at position 5 of the benzimidazole ring.

The novel AMPA glutamate receptor antagonist zampaxidol attenuates binge eating potentiated by foot-shock stress

2026-04-01T17:57:46+03:00

Introduction: Binge eating is linked to the brain reward system, modulated by glutamatergic projections affecting the mesolimbic dopamine pathway. This study explored AMPA receptor antagonists' effects on binge eating and stress-induced feeding behavior. The aim was to investigate the effects of the GluA1 AMPA receptor antagonist zampaxidol (IEM-2131) and the reference compound IEM-1460 in a binge eating model, and to demonstrate zampaxidol's antagonistic activity at AMPA receptors.

Materials and Methods: vivo experiments were performed on 42 adult male Wistar rats (250–300 g) divided into three groups (n = 14): intact control, IEM-1460 (3 mg/kg, i.p.), and zampaxidol (1 mg/kg, i.p.). In vitro experiments were conducted on 16 isolated Danio rerio neurons. Foot shock was used as stress. Antagonists' effects on kainic acid-induced ionic currents were examined via patch clamp.

Results and Discussion: Zampaxidol and IEM-1460 reduced mean chocolate mixture consumption to 11.5 ± 1.6 g and 10.0 ± 0.9 g, respectively, significantly lower than in the no-intervention group (15.9 ± 0.5 g) and the foot-shock-only group (18.6 ± 0.9 g). Both compounds produced a pronounced blocking effect on AMPA receptors. Zampaxidol's IC50 was 0.65 ± 0.27 μM.

Conclusions: The findings highlight the essential role of GluA1 AMPA receptors in food addiction. IEM-1460 (3 mg/kg, i.p.) and zampaxidol (1 mg/kg, i.p.) demonstrated high efficacy in a rat binge eating model potentiated by foot-shock stress. AMPA receptor antagonists may be useful for treating psychogenic stress-induced binge eating.

The antiplatelet-antithrombotic effect and antioxidant activity of the Phlojodicarpus sibiricus extract

2026-04-01T10:21:13+03:00

Introduction: Cardiovascular disease and ischemic stroke remain the leading causes of death and disability worldwide. Phlojodicarpus sibiricus has a wide range of pharmacological properties due to its content of coumarins. The aim of this study was to determine the antiplatelet effect and antioxidant activity of Phlojodicarpus sibiricus extract (P. sibiricus).

Material and Methods: A dry ethanol extract of P. sibiricus was used in the experiments. The antiplatelet activity of P. sibiricus was assessed using in vitro test. The effect of the extract on haemostasis was evaluated in models of blood coagulation and chemically induced vascular thrombosis. The experiments were conducted on 86 Wistar rats weighing 180-220 g, divided into groups: Group 1 – Vehicle, groups 2-4 – rats receiving P. sibiricus at doses of 50, 100, and 200 mg/kg, respectively; groups 5-6 – rats treated with aspirin (30 mg/kg) and heparin (200 U/kg), respectively. The antioxidant activity of the extract was assessed in vitro using the DPPH assay and the Fe²⁺ binding model.

Results: P. sibiricus demonstrated antiplatelet activity (in concentration 50 – 200 µg/mL) in vitro. Administration of P. sibiricus to rats at doses of 50, 100 and 200 mg/kg increased the duration of bleeding by 2 times and suppressed thrombus formation by 52.6% compared to the control.

Conclusion: P. sibiricus exerts an antiplatelet effect at doses of 50–200 mg/kg due to the combined antiplatelet and antioxidant effects of coumarins.

Evaluation of cardiotoxicity of a new antitumor compound, anthrafuran, a derivative of anthracycline antibiotics

2026-03-27T17:57:49+03:00

Introduction: Anthracyclines and anthracenedione derivatives are a group of anticancer drugs that are widely used in clinical practice. Their application is frequently limited by cardiotoxic effects. The aim of this study was to evaluate the cardiotoxicity of the new anthracenedione derivative Anthrafuran (AF) in comparison with Doxorubicin (Dox) and Mitoxantrone (MT).

Materials and Methods: The study was conducted on 50 adult female Wistar rats. AF, MT, and Dox were administered in therapeutic doses and regimens for this animal species (AF: 20 mg/kg x 3/48 per os; MT: 1 mg/kg x 3/96 i.v.; Dox: 2.5 mg/kg x 3/72 i.v.). Electrocardiographic (ECG) parameters and heart weight index were determined; histological evaluation of the myocardium was performed on days 1 and 30 post-treatment.

Results: Dox intravenous injections in therapeutic doses caused a pronounced cardiotoxic effect. The signs of cardiac decompensation manifested as a significant decrease in heart rate (HR) (Dox 486±6, control 522±12.8), prolongation of the QT interval (Dox 0.06±0.002, control 0.048±0.001), an increase in weight index of the heart (Dox 0.41±0.03, control 0.36±0.006), and myocardial damage. Although the cardiotoxicity of MT was less pronounced, it nevertheless negatively affected both ECG parameters (HR 465±15, QT 0.056±0.002) and the structure of the heart muscle. The use of AF did not cause any pathological changes and had no effect on the heart weight index or ECG parameters (HR 498±7.3, QT 0.052±0.003, weight index of the heart 0.35±0.009).

Conclusion: Unlike Dox (2.5 mg/kg x 3/72 i.v.) and MT (1 mg/kg x 3/96 i.v.), the new anthracenedione derivative AF (20 mg/kg x 3/48 per os) in therapeutic doses does not possess cardiotoxic properties, supporting its potential for clinical study.

Synthesis and ophthalmic hypotensive effect of new potential benzimidazole-based Rho-kinase-2 inhibitors

2026-03-21T14:44:44+03:00

Introduction: Based on the chemical structures of known Rho-kinase-2 inhibitors, 18 benzimidazole derivatives were synthesized and studied for their ophthalmic hypotensive activity in animals with normal intraocular pressure. The dependence of the pharmacological effect on the chemical structure of the compounds was analyzed. The effect of the most active compounds on Rho-kinase-2 activity was assessed.

Materials and Methods: Ophthalmic hypotensive activity was assessed by measuring intraocular pressure with a TonoVet veterinary tonometer in 120 mongrel rats (6 in each group) before and after instillation of reference drug solutions (timolol and melatonin) and 18 test substances. The effect of the test compounds on Rho-kinase activity was assessed using an in vitro enzyme-linked immunosorbent assay spectrophotometrically.

Results: The most active compounds among the new benzimidazole derivatives after a single instillation at a concentration of 0.4% were compound 7a (1-(4-fluorobenzyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine hydrochloride), which reduced intraocular pressure in normotensive animals by 28.21%, exceeding the effect of the reference drug timolol(26.84%), but inferior to melatonin (30.95%), and compound 1d (1-(1-(2-(azepan-1-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-3-(3-trifluoromethyl)phenyl)urea hydrochloride), which reduced ophthalmotonus by 23.96%, slightly inferior to timolol. The test compounds do not affect intraocular pressure dynamics in the contralateral eye and, therefore, do not have a systemic effect, unlike the reference drugs. It was also found that compounds 7a and 1d at a concentration of 1*10-4 mol/L inhibit Rho-kinase-2 by 26.72% and 18.11%, respectively.

Conclusion: The most active compounds, 7a and 1d, were identified as Rho kinase-2 inhibitors that exhibit ocular hypotensive effects in normotensive animals in vivo.

Synthesis, characterization and biological and immunological evaluation of heterocyclic 4‑aminoantipyrine derivatives

2026-03-12T23:54:11+03:00

Introduction: Impairment of the erectile component of the copulatory cycle represents a significant clinical and social problem, substantially reducing the quality of life in men. The highest incidence of this pathology is observed in male patients over 50 years of age, which is associated with an age-related decrease in gonadal hormonal function. In the present paper, the results of experimental studies evaluating the efficacy of co-administration of Siberian fir polyprenols and Panax ginseng in a model of copulatory function impairment caused by androgen deficiency are demonstrated.

Materials and Methods: The focus of the study was a herbal preparation being a pharmaceutical composition of Siberian fir polyprenols and Panax ginseng. The experiment was conducted in 26 sexually mature category-I male SD rats (Sprague Dawley with body weight of 250-300 g and aged 12 weeks). Siberian fir polyprenols were administered at a dose of 23 mg/kg combined with Panax ginseng at a dose of 1.5 ml/kg. The treatment course duration was 7 days. Tribestan (Sofarma, Bulgaria) at a dose of 70 mg/kg was used as a reference drug. Reduction in copulatory activity caused by androgen deficiency was modeled by administering synestrol to male rats. The level of copulatory activity was assessed by the paired sexual behavior test.

Results and Discussion: The results of experimental studies showed that the administration of synestrol to male rats led to the suppression of their copulatory activity. The groups of animals receiving Siberian fir polyprenols and Panax ginseng against the background of synestrol administration exhibited a statistically significant increase in the number of animals with rising copulatory activity (the number of mating attempts increased, and cases of ejaculation were reported). The pharmacological activity of the reference drug Tribestan was manifested at the level of tendencies.

Conclusion: The present paper demonstrates that Siberian fir polyprenols (dosed at 23 mg/kg) in combination with Panax ginseng tincture (dosed at 1.5 ml/kg) prove effective in stimulating the copulatory activity of male rats under conditions of androgen deficiency.