Reviews on Clinical Pharmacology and Drug Therapy

The issues of chemotherapy remain the most difficult, because it is perhaps practically impossible to carry out drug therapy correctly, observing the main ethical principle of a doctor – do no harm. One of the main principles of chemotherapy is based on stopping cell replication, destroying their growth and vital activity, which is undoubtedly associated with an impact on healthy cells, the life cycle of which, depending on histological characteristics, may vary from several days to several weeks and months, which, in any case, implies an inevitable damaging effect on various organ and tissue systems. The more aggressive the chemotherapy, the more complex the combinations used, the greater the damaging consequences. Knowing the most vulnerable targets, the mechanisms of their development, it is possible to correct the most dangerous risks and prevent undesirable consequences. Accumulated experience with chemotherapy allows us to predict the most dangerous risks arising both during therapy, from chronic diseases that reduce quality of life, and after its completion, including delayed effects leading to death due to hidden, dangerous complications. Properly selected and timely complication prevention, comprehensive diagnostics of markers of pathological changes in vital organs, adjustments to therapy, and other measures are the fundamental principles of effective therapy. The main recommendations are regular visits to specialized physicians in related fields and patient compliance. Treatment for cancer patients does not end with their discharge from the hospital. Lifelong follow-up is required for patients who have completed therapy with a positive outcome.

It is reported that regulating the temperature of infected areas of the patient’s body may be important for overcoming bacterial resistance to antibiotics. However, the medical standard does not specify a target temperature value for the treatment of infectious diseases with antibiotics. At the same time, it was previously shown that an increase in temperature from 37 to 42 °C improves the rheological properties of colloidal liquids, melts lipids and/or reduces the viscosity of lipid and protein-lipid complexes of human and microbial cell membranes, in accordance with the Arrhenius law, increases the rate of chemical, biochemical reactions and the intensity of the entire cellular metabolism. The fact is that such temperature-dependent changes in the structure and function of cells facilitate and accelerate the participation of antibiotics in their metabolism and enhance the bacteriostatic effect of antimicrobials. Hyperthermia has also been found to accelerate the biological clock of microorganisms, shorten their lifespan, and accelerate population change. At the same time, hyperthermia restored the bacteriostatic effect of antibiotics that was absent and/or enhanced the bacteriostatic effect that existed under conditions of normal body temperature. The results of the first in vitro experiments and the first clinical observations of acute local suppurative inflammatory processes and chronic wounds have demonstrated the safety of local hyperthermia and its ability to enhance the antimicrobial effect of antiseptics and local antibiotics. The results showed that hyperthermia can increase the bacteriostatic activity of antibiotics by improving the rheological properties of biological fluids, reducing the density of microbial membranes, and accelerating bacterial metabolism with the inclusion of antibiotics. These data indicate the potential of therapeutic hyperthermia to maintain the effectiveness of antibiotics and other antimicrobial agents in the treatment of infections by reducing the resistance of microorganisms.

Xerostomia (dry mouth) is a common syndrome with multiple causes that tends to increase in prevalence as the population ages. The imitation of physiological saliva is a modern concept in the development of saliva replacement agents, with the gel dose form being considered optimal. This article provides a scientific rationale for the requirements and design of the pharmaceutical development of a hydrating dental gel for the symptomatic treatment of xerostomia in the context of import substitution. The information-retrieval stage of pharmaceutical development of artificial saliva is based on an understanding of the pathophysiology and etiology of xerostomia, as well as modern treatment approaches and knowledge of the composition, properties, and biological functions of human physiological saliva. The research stage of pharmaceutical development includes identifying potential molecules and compounds capable of mimicking the properties and functions of saliva, as well as formulating and improving the gel composition. An essential aspect is selecting a polymer combination with mucoadhesive properties. The search for a polymer composition includes cellulose derivatives, acrylic acid copolymers, alginates, hyaluronates, pectins, carrageenans, and fucoidans. Further expansion of structure-forming mucoadhesive polymers is possible through the use of recombinant mucins obtained by genetic engineering and plant extracts rich in polysaccharides that mimic mucin properties. Lysozyme, peroxidase, and lactoferrin, which are currently produced as bulk substances, as well as plant extracts, provide antimicrobial effects of artificial saliva. Buffering properties are maintained by potassium, sodium, and calcium bicarbonates and phosphates. Calcium lactate and fluorides impart remineralizing properties. The formulation of saliva substitutes includes organoleptic corrigents and preservatives. Selection criteria for compositions include quality parameters, biopharmaceutical performance, and antimicrobial and antioxidant characteristics of the saliva substitute. The proposed packaging for the hydrating dental gel includes 10–30 mL tubes, single-use stick packs, or strip packaging. The standardization stage involves modifying and validating analytical procedures specific to the composition, conducting stability tests, determining shelf life, and developing the process flowchart and regulatory documentation drafts. The composition and functions of salivary gland secretions serve as the foundation for defining the requirements and characteristics of the hydrating dental gel intended for pharmaceutical development. The optimal formulation is sought among combinations of mucoadhesive polymers with compounds exhibiting antimicrobial and remineralizing activity. Scientific data were analyzed and organized into a unified design framework for the pharmaceutical development of a hydrating dental gel for xerostomia therapy, comprising information-retrieval, research, and standardization stages. This design framework can be applied in research laboratories and educational institutions to train pharmaceutical industry professionals.

Background: Severe stress is associated with immune, neuroendocrine, cardiovascular, and other system dysfunctions and may cause various neurochemical and behavioral alterations. Stressful life events have been shown to play a role in the etiology of depression and anxiety. The search for therapeutic options in such disorders remains a relevant task of both fundamental and clinical medicine. This work investigates the stress-protective properties of molecular factors of innate immunity, specifically the iron-binding protein lactoferrin.

Aim: The work aimed to examine the antistress effect of human lactoferrin on behavioral disturbances in laboratory animals (rats) induced by chronic stress.

Methods: For stress induction, a rat model of chronic stress was used, involving daily forced swimming of laboratory animals in cold water. Locomotor activity, as well as emotional and exploratory behavior, were assessed.

RESULTS: It was shown that this stress exposure does not alter locomotor activity in rats, but increases anxiety and reduces exploratory activity, resulting in a depression-like state. Daily oral administration of human lactoferrin at a dose of 200 μg/kg body weight reduced anxiety and restored exploratory activity.

Conclusion: The findings indicate that rats subjected to chronic stress develop a depression-like state, which can be mitigated by oral administration of low doses of human lactoferrin. Thus, lactoferrin is more than just an endogenous antimicrobial and chelating compound. In addition to its anti-infective properties, lactoferrin is involved in a variety of other protective mechanisms, including its potential role as an endogenous antidepressant.

Background: A clinical observation of the results of treatment with recombinant granulocyte colony-stimulating factor (G-CSF) in patients with idiopathic neutropenia, a condition characterized by infertility and miscarriage, demonstrated spontaneous pregnancy in patients with a history of infertility. These results served as the basis for the use of G-CSF in refractory endometrial syndrome.

Aim: The work aimed to investigate the effect of G-CSF on the expression of the vascular endothelial growth factor (VEGF) gene and the transcription factor HOXA10 in primary cultures of human endometrial cells.

Methods: The study included eight female patients who were examined before enrolling in assisted reproductive technology programs. Endometrial aspiration biopsy was performed on days 5–10 of the menstrual cycle. The samples were cultured for 72 hours in DMEM supplemented with various concentrations of G-CSF (1 and 100 mg/mL). The expression of VEGF and HOXA10 genes was assessed using real-time polymerase chain reaction, and VEGF concentration in the culture medium was determined by enzyme-linked immunosorbent assay. Statistical analysis was performed using one-way ANOVA followed by Tukey’s test.

Results: A dose-dependent stimulatory effect of G-CSF on VEGF [F(2, 21) = 31.55; p < 0.001] and HOXA10 [F(2, 21) = 14.31; p < 0.001] gene expression was established. Upregulation was observed already at 1 mg/mL, whereas significant differences were achieved at 100 mg/mL. A significant increase in VEGF concentration in the culture medium was also detected in response to G-CSF [F(2, 21) = 109.4; p < 0.001]. The stimulatory effect was observed in all examined endometrial samples.

Conclusion: G-CSF exerts pleiotropic effects by stimulating VEGF and HOXA10 expression in endometrial cells in vitro. These mechanisms may underlie endometrial regeneration and improved receptivity, which are of particular relevance for treating patients with refractory endometrium and recurrent implantation failure in assisted reproductive technology programs

Background: The development of modern cancer therapies and new chemotherapeutic agents is ongoing. Heterocyclic compounds attract particular interest as promising therapeutic agents in the field of antitumor drug synthesis. A method for synthesizing spiro-linked pharmacophore fragments has recently been developed, resulting in spiro-linked barbiturates and oxindoles, a fundamentally new class of spirocyclic cycloadducts with expected antitumor activity. To assess the potential side effects of these novel compounds, it is crucial to evaluate their impact at the tissue and cellular levels, particularly on the liver and kidneys, as well as on macrophages, a critical component of the hepatic and renal mononuclear phagocyte system. Hepato- and nephrotoxicity are well-known adverse effects of many cytotoxic agents.

Aim: The work aimed to assess the response of the hepatic and renal macrophage pool to novel spiro-linked heterocyclic compounds in rats.

Methods: Male Wistar rats were divided into three groups. Animals in the control group received a single intraperitoneal injection of 1 mL of 0.9% sodium chloride solution. The other two groups received a single intraperitoneal injection of 1 mL of either a spiro-linked barbiturate (Compound 1; EG I) or a spiro-linked oxindole (Compound 2; EG II) at a dose of 12 mg/kg body weight. Animals were euthanized 2, 4, and 8 weeks after dosing. Tissue sections (5 µm thick) were prepared using standard histological techniques and stained with hematoxylin and eosin. Macrophages were detected immunocytochemically using anti-CD68 antibodies.

Results: Morphological analysis of the liver revealed endotheliitis in both experimental groups. Morphometric evaluation of the Kupffer cell pool demonstrated a significant increase in their number in EG I and EG II at all time points. Morphological analysis of the kidneys showed increased glomerular cellularity in both experimental groups, along with mild diffuse focal lymphomonocytic infiltration of the interstitium, which was more pronounced in EG II. The number of macrophages significantly increased in both experimental groups at 2 and 4 weeks, returning to control levels in EG I by week 8. In EG II, it remained significantly elevated compared with both the control and EG I groups.

Conclusion: Morphological examination indicated that the liver was the most sensitive to a single dose of the tested compounds. Reactive changes in the hepatic macrophage pool were observed in both experimental groups at all time points. The kidneys also responded to both compounds, with more pronounced changes in macrophage numbers in EG II. The macrophage pool response to the administered compounds in the examined organs was identical, with the spiro-linked oxindole showing a slightly greater toxic effect.