MECHANISMS OF ACTION OF LITHIUM COMPOUNDS

This review summarizes the literature data on the role of lithium compounds in modern pharmacotherapy of various diseases of the central nervous system. Attention is also paid to other therapeutic properties of lithium in atherosclerosis, cardiovascular diseases, diabetes, hematopoietic disorders, inflammation, and diseases of the urinary system. Possible ways of delivering lithium into the body have been charted, in particular, when lithium salt is combined with a sorbent (solid porous carrier). Such compounds have additional therapeutic properties. Data on the significance of lithium compounds in studies on models of diseases of the nervous system in animals are analyzed. Among these models, models of neonatal ischemia/hypoxia of the brain in vivo, neurodegenerative diseases, psychopathological states (aggressiveness, depression) and craniocerebral injury are discussed. There are researches in which the results of the lithium preparations use in clinical practice are investigated. It emphasizes the influence of genetic factors on the lithium effects. Particular attention is paid to the possibility of preventing the toxicity of lithium compounds for the body. The currently known molecular mechanisms of lithium action are discussed: inhibition of glycogen synthase kinase 3β (GSK-3β) and inositol monophosphatase 1 (IMPA1), which have key value for autophagy, oxidative stress, inflammation, mitochondrial function, induction of neurotrophic factors, apoptosis. It was concluded that the study of the molecular pathways of the functioning of lithium compounds empowers understanding both the reasons for its effectiveness in the nervous system diseases and the mechanisms of action on other body systems

Composition based on aluminum oxide and polydimethylsiloxane matrix for enhancing drug targeting

Methodological approaches developed at Research Institute of Clinical and Experimental Lymphology for a number of years allow formulating the importance of embedding active pharmaceutical ingredients (API) in the structure of porous carriers (sorbents). The composition of the carrier and API is an enteral system for prolonged dosing of pharmacological agents, which allows providing a specific pharmacological effect and safety of use. The pores of the media (sorbents) act as containers for API. This is especially important for rapidly absorbed drugs, which include, for example, lithium preparations that are used in narrow concentration limits due to their side effects. At the moment, an innovative technology for creating new medicines with an improved combination of efficiency and safety (pharmacological upgrade) has been developed and implemented. The essence of the technology is to create a composition of aluminum oxide and polydimethylsiloxane (matrix) and an active pharmacological ingredient (API). A study of two drugs based on matrix / lithium citrate and matrix / melatonin showed continued specific pharmacological activity of API, better pharmacokinetics, and better safety parameters. The matrix of aluminum oxide and polydimethylsiloxane provides an upgrade of the pharmacological properties of drugs for the dosed and safe delivery of API to the zone of their therapeutic effect

The expression of apoptosis-regulating proteins Bcl-2 and Bad in liver cells of C57Bl/6 mice under light-induced functional pinealectomy and after correction with melatonin

The presence of humans and animals under long-term continuous lighting leads to a suppression of melatonin synthesis, that is, to light-induced functional pinealectomy (LIFP), and the development of desynchronosis. To create LIFP, C57Bl/6 mice were kept under 24-hour lighting (24hL) for 14 days. The animals in the control group were kept under standard lighting conditions. In the next series of experiments, mice with LIFP received daily intragastrically either melatonin (1 mg/kg body weight in 200 μl of distilled water) or 200 μl of water as a placebo. The comparison group consisted of intact animals that received placebo under standard lighting conditions. Immunohistochemical analysis (using an indirect avidin-biotin peroxidase method) revealed the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bad in sinusoid liver cells (a heterogeneous population consisting of the endotheliocytes, Kupffer cells, Ito cells, and Pit cells) and in individual hepatocytes. The Bad expression area in the liver of LIFP mice increased 4 times against a background of the unchanged Bcl-2 expression area. Changes in the brightness (a parameter inversely proportional to the marker concentration) of Bad and Bcl-2 areas did not reach significance. Our results indicate a weakening of the antiapoptotic protection of liver cells of LIFP animals, which creates conditions for activation of the “mitochondrial branch” of apoptosis. Melatonin treatment of LIFP mice resulted in a 3.3-fold increase in Bcl-2 expression area and a 2.7 % decrease in Bcl-2 region brightness compared with the experimental untreated group. Bad protein parameters were unreliable. Thus, melatonin treatment of animals cancels the effect of LIFP, restoring the Bcl-2 expression area and increasing this protein concentration, which indicates an increase in antiapoptotic protection and creates conditions for blocking the development of the “mitochondrial branch” of apoptosis in liver cells

Silver containing sorbents: Physicochemical and biological properties

New silver containing sorbents, based on mineral carriers, such as alumina and silica systems with a meso- and macro- porous structure, have a higher mechanical resistance and, hydrophilic and hydrophobic chemical composition of the surface. These sorbents are easy to find and relatively inexpensive, compared to their known equivalents. They are furthermore characterised by high specific surface and simple preparation, whilst the addition of silver considerably increases their antiseptic activity. The results of research of the physical, chemical and biological properties of the developed substances, as well as bio-comparability of sorbents with biological tissues, are presented in this paper. The modified material acts simultaneously as the carrier for active substances to the area of therapeutic application and as a sorbent used to remove toxic agents from such areas. This approach led us to modify the sorbent, and prolong the delivery of substances such as silver, as an effective antibacterial and antimycotic agent

The effect of silver-containing sorbent on red blood cells during hemosorption: an <i>in vitro</i> study

The aim of the study was to investigate the influence of the original porous silver–containing sorbent on the morphofunctional parameters of red blood cells during in vitro hemoperfusion. Material and methods. Donor blood was perfused through glass columns filled with a sorbent based on porous aluminum oxide, polydimethylsiloxane and silver nanoclusters and a sorbent without silver. The effect of a silver-containing sorbent on the change in morphofunctional parameters of red blood cells after perfusion through sorbents was determined by scanning flow cytometry. Results and their discussion. Due to the uniformity of the distribution of silver (0.1 %) over the sorbent granules, the parameters of the porous structure – the specific surface area and pore volume – practically do not change compared to the sorbent without silver. Morphological parameters of original donor blood and after hemoperfusion are within the norm. The functional parameters are also normal, although the introduction of silver in to the sorbent slightly increases the number of active band 3 (B3) proteins on erythrocyte membranes, both in comparison with the donor red cell mass as a control and in comparison with the sorbent without silver. There is also an increase in the ultimate extensibility of the erythrocyte membrane compared to the original blood (2.2 times) and the sorbent without silver (1.4 times). Conclusions. A sorbent modified with silver and a sorbent without silver does not have a damaging toxic effect on the morphofunctional parameters of blood under perfusion conditions. The mechanisms affecting the indicators of the ultimate extensibility of the erythrocyte membrane after blood perfusion through a silver-containing sorbent require further research

Estimation of acute toxicity of a drug based on the complex of lithium citrate, polymethylsiloxane, aluminum oxide

Research Institute of Clinical and Experimental Lymphology has developed an innovative drug based on a complex of lithium citrate, polymethylsiloxane and aluminum oxide (LOAP). Lithium-based drugs are effective in treating bipolar disorders. However, the toxic effects of lithium cause a “narrow therapeutic window”, which limits its clinical use. The creation of the drug LOAP was aimed at creating a prolonged form with a slow release of lithium to reduce toxic properties and use lithium citrate as an active pharmacological agent. At the moment, the lithium complex has no analogues. The purpose of the study was to study the parameters of acute toxicity of the LOAP. Material and methods. When studying acute toxicity, drugs were administered once intragastrically to mice and rats at doses of 12000, 10000, and 5000 mg/kg. Results. A single administration of drugs intragastrically through a probe in the maximum possible doses to mice and rats did not cause the death of animals and did not cause a locally irritating effect on the gastric mucosa. LOAP can be assigned to hazard class 4 (GOST 12.1.007-76)

STUDYING THE POSSIBLE MUTAGENIC PROPERTIES OF NEW MEDICINE ON THE BASIS OF COMPLEX LITHIUM CITRATE, ALUMINUM OXIDE AND POLYMETHILSILOXANE

Aim of the study was to investigate the possible mutagenic properties of a new drug based on a lithium-containing substance – a complex of lithium citrate, polymethylsiloxane and aluminum oxide. Material and methods. Methods for testing mutagenicity using chromosomal aberrations in the bone marrow cells of CBA mice and somatic recombination in Drosophila melanogaster were used. Results. It was shown that a single intragastric administration of drug at a dose of 5000 mg/kg and a fivefold course of administration at a dose of 400 mg/kg to CBA mice did not increase the level of cytogenetic disorders in bone marrow cells. The study of the lithium complex drug in a somatic mosaicism test revealed that the preparation at a dose of 2000 mg/kg does not increase the frequency of mutations in Drosophila melanogaster. Conclusion. A single intragastric administration of the studied drug at a dose of 5000 mg/kg and its course administration (400 mg/kg × 5) do not increase the level of cytogenetic disorders in the bone marrow cells of CBA mice. In the somatic recombination (mosaicism) test system on D. melanogaster, no increase in the appearance of mutant setae and spots on the body and head was observed when using yellow and singed markers. The results of the study indicate that the studied drug does not have mutagenic properties

Whole organisms or pure compounds? entourage effect versus drug specificity

As the therapeutic use of sacred plants and fungi becomes increasingly accepted by Western medicine, a tug of war has been taking place between those who advocate the traditional consumption of whole organisms and those who defend exclusively the utilization of purified compounds. The attempt to reduce organisms to single active principles is challenged by the sheer complexity of traditional medicine. Ayahuasca, for example, is a concoction of at least two plant species containing multiple psychoactive substances with complex interactions. Similarly, cannabis contains dozens of psychoactive substances whose specific combinations in different strains correspond to different types of therapeutic and cognitive effects. The “entourage effect” refers to the synergistic effects of the multiple compounds present in whole organisms, which may potentiate clinical efficacy while attenuating side effects. In opposition to this view, mainstream pharmacology is adamant about the need to use purified substances, presumably more specific and safe. In this chapter, I will review the evidence on both sides to discuss the scientific, economic, and political implications of this controversy. The evidence indicates that it is time to embrace the therapeutic complexity of psychedelics.2019-07-3

EFFECTS OF THE LITHIUM – CONTAINING SORBENT ON TERMS OF BEHAVIORAL REACTIONS UNDER CHRONIC ALCOHOL INTOXICATION MODEL

Lithium preparations are widely used for stabilize mood in case of bipolar affective disorder. Currently neuroprotective and neuroregenerative effects of lithium are of interest as in case of acute brain injury, also in chronic neurodegenerative diseases such as dementia, alcoholism, Alzheimer disease, etc. [1–5]. In clinical practice use of lithium preparations is limited due to difficult adjustment of drug dosage, necessity of monitoring its concentration in blood, side effects development as a result of accumulation of lithium in a body. For the purpose of improvement of pharmacologic properties lithium is combined with other agents (for example modifying sorbent) thus it can produce longer-term and more harmless (less side reactions) effect in the long view. Lithium immobilization on sorption basis will allow to use sorbent as detoxicant and carrying agent of drugs to body. The purpose of the work is studying the effect of the lithium – containing sorbent on terms of behavioral reactions under chronic alcohol intoxication model.Materials and methods. During the work we used nonlinear mice – males, which weight 25–30 g (180 animals). Chronic alcohol intoxication was precipitated via 40% proof spirit injections (oral supplementation in quantity of 3 g/kg during 2 weeks), additionally mice drunk 5% proof spirit from drinking bowl. Each experimental group consisted of 10 animals. Study drugs were inserted inside while ethanol injecting. Control animals were inserted 0,9% salin solution. Emotional state of animals was assessed through forced swim test, short – term memory assessment was performed through conditioned passive avoidance reflex. Effect of chronic alcohol intoxication on the parameters of conditioned reflex activity was measured every 7 days.Results. It was found that the investigated lithium-containing sorbent increases: the number of mice are trained passive avoidance reflex, remembering percent of electric shock animals compared to the negative control , and – the duration of the latent time of immobility in comparison with the negative control.Conclusion. The proposed formulation of lithium (immobilized on a sorbent ) has a complex neurotropic action, showing antitoxic properties against a background of long-term administration of ethanol