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12технической документации в виде фармакопейной статьи и патентов национальных и Евразийских.
2. С использованием фитоэкстрактов разработаны ряд новых лечебно-косметологических форм в виде масла, лосьонов, гелей, кремов, мазей, шампуней, красителей волос, укрепителей волос, сухих духов и ароматизаторов.
Литература
1. Велиева М.Н., Велиев П.М., Халилова Т.Ш. Разработка косметологической фармацевтической продукции на основе солодки // Современные достижения Азербайджанской Медицины. Квартальный научно-практической журнал. Баку, №4, 2011, с. 157-159.
2. Велиева М.Н., Гейдарова Р.М., Азимова Г.З., Гасанов Г.Г., Велиев П.М. Средства для ухода за кожей головы и корнями волос на основе смеси солодки голой с хной бесцветной. Евразийский Патент № 026684 от 31.05.2017
3. Велиева М.Н., Гейдарова Р.М., Мусаева А.Э., Евдаев А.Я., Велиев П.М. Средства против выпадения волос на основе лекарственных растений. Заявка на евразийский патент № 201400801/26 от 09.07.2014
4. Велиева М.Н, Мехралиева С.Дж., Мамедов Б.С. Лечебно-косметический шампунь противовы-падение волосы и себореи. Заявка на Евразийский патент 201700387 от 22.08.2017
5. Велиева М.Н., Халилова Т.Ш., Велиев П.М. Разработка лечебно-косметических средств на основе природного сырья. Природный цеолит в медицине, 2010, SWB, Borqgas; с. 254-271.
6. ГОСТ Р 17237-93. Изделия парфюмерно-косметологические. Информация для потребителя. Общие требования. М.: Изд-во стандартов, 2000, 9с.
7. Двадненко М.В., Привалова Н.М., Носо-рева М.В., Макарчук О.Н., Суховарова И.Б. Влияние косметических средств на кожу человека // Международный журнал прикладных и фундаментальных исследований. 2009, № 4, с. 99-0;
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9. Мамедова А.Э., Велиева М.Н. Лечебно-косметический эмульсионный крем. Евразийский Патент № 25061 от 30.11.2016
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INVESTIGATION OF THE POSSIBILITY OF REDUCING THE NEGATIVE INFLUENCE OF COFFEE IN COMBINATION WITH BIOLOGICALLY ACTIVE SUBSTANCES
Kompancev V.A., Kompancev D. V., Privalov I.M., Gutnova T.S.
FGBOU VO Pyatigorsk Medical and Pharmaceutical Institute -branch of the Volgograd State Medical University, Pyatigorsk, Russia
ABSTRACT
Caffeine, chemically classified as a xanthine alkaloid, is the most commonly consumed psychostimulant in the world. It helps to increase concentration, improve memory and physical performance. Caffeine, having positive inotropic and chronotropic effects, affects the cardiovascular system and the central nervous system with stimulation of motor activity. Like other chemicals, caffeine can cause an overdose. Side effects of caffeine are: tachycardia, arrhythmia, insomnia, nausea, vomiting, anxiety, agitation. Caffeine is contraindicated in glaucoma, arterial hypertension, diabetes, insomnia, atherosclerosis.
The proposed review is devoted to the urgent problem of modern pharmacy - to reduce the negative effects of caffeine, by combining it with other biologically active substances. The article gives information on possible combinations with biologically active substances, which neutralize the side effects of caffeine and enhance the overall therapeutic effect.
Keywords: caffeine, pharmacodynamics, biologically active substances, medicines, side effects
Abbreviations
BP - blood pressure
BAS - biologically active substances
GIT - Gastrointestinal tract
CNS - central nervous system
Caffeine is a natural bio-stimulator from the group of methylxanthines, which is contained in more than 60 species of plants. The most common sources of caffeine are tea leaves, coffee beans, cola nuts, cocoa pods, and coffee seeds.
Caffeine has a multistep effect on the metabolism of our body, blocking adenosine receptors, stimulating the release of dopamine, norepinephrine and glutamate, helping to mobilize intracellular calcium and inhibiting phosphodiesterase and enhancing glycogen phosphory-lase activity [1, 2].
Materials and methods. This conceptual review was carried out using a set of retrospective, perspective and transversal studies studying the mechanisms of interaction of the analyte with various classes of biologically active substances, the potentials for potentiating the therapeutic effect, minimizing side effects, and the possibility of creating new drugs based on it.
An electronic search was conducted in the following specialized information databases: It-medical, Pub-med, Medsite (medical records and e-books), INFORMA healthcare, Scientific Electronic Library e-library.ru, Excerpta Medica Database (EMBASE), VINITI RAS, PsyclNFO since its inception of these databases until July 1, 2018.
The search included publications in any language. Search terms were "caffeine", "interaction", "pharmacodynamics", "biologically active substances", "drugs", "side effects" in the title, annotations and keywords. In the reference lists of all found articles, searches were performed to find previously unidentified literature of a given topic.
More than 800 relevant sources were reviewed, and 15 potentially acceptable articles were selected and analyzed in detail by the results of a manual search of reference lists.
Results and discussion. All potential effects of caffeine at the cellular level are determined by three mechanisms of action: antagonism of adenosine receptors, especially in the central nervous system; mobilization of intracellular calcium storage; phosphodiester-ase inhibition.
Consider the main aspects of the effects of caffeine on the central nervous system. According to most researchers, caffeine affects cognitive functions, stimulates mental activity, activates mental and physical performance, enhances attention concentration, wakefulness, reduces reaction time [3, 4]. In low concentrations, it stimulates locomotor activity; in high doses, caffeine causes an anxiogen-like effect [5].
For the excitation of the nervous system of the weak type, small doses of caffeine are enough; for a strong type, higher doses are necessary. Analeptic activity and influence on the spinal cord within the framework of a given problem should not be considered,
since This effect is expressed in large doses and has limited use [6].
Caffeine in a certain range of concentrations is used as a coadjuvant to potentiate the analgesic effect.
At the same time, the development of tolerance to caffeine, which is partial and reversible, is possible [7].
Based on the foregoing, caffeine is used to stimulate mental activity, with fatigue, migraine, and hypotension. It is a component of many combined drugs. For example, the use of caffeine as an additive reduces the amount of acetaminophen by 40%, with the same therapeutic effect [8]. Therefore, combinations of caffeine with other drugs are not only a proven way to increase the effectiveness of therapy, but also help to reduce the negative impact on the body of the entire drug as a whole.
Before considering the possible options for combining caffeine, we will focus on the side effects of its use.
Caffeine has several effects on the cardiovascular system. High doses of a substance primarily induce antagonism of adenosine and phosphodiesterase inhibition, which manifests itself in positive inotropic and chronotropic effects, and a subsequent increase in heart rate, and an improvement in conductivity [9, 10].
This causes the direct pacing effect of caffeine. Parallel stimulation of caffeine sodium-potassium-ATPase increases the negative membrane potential of the cell, which leads to an increased risk of ventricular arrhythmias. Caffeine in high concentrations causes supraventricular and ventricular ectopic strokes, atrial fibrillation, this causes flutter and arrhythmia [11].В ряде исследований указано на то, что высокие дозы кофеина и низкие уровни эстрогенов могут действовать синергически, оказывая сосудосуживающее действие на коронарные артерии.
Caffeine therapy causes tachycardia (its peripheral action prevails), sometimes reflex bradycardia is possible, therefore it is advisable to combine the use of caffeine simultaneously with anti-hypoxic and anti-is-chemic compounds (glycine, taurine, ginkgo biloba extract). It is necessary to include in the caffeine-containing preparations salts of potassium and magnesium, the ions of which contribute to the normalization of the work of the myocardium. With coronary artery disease, myocardial infarction and stroke, the therapeutic effect of caffeine is minimal. A number of studies have argued that regular consumption of caffeinated beverages reduces the risk of mortality from cardiovascular diseases in elderly patients [12].
The effect of caffeine on blood pressure depends on its baseline. If we have a normal baseline blood pressure, then caffeine either does not change it, or does not significantly increase it. If the drug is introduced on the background of hypotension, pressure normalizes.
In this regard, the combination of caffeine with plant adaptogens, which are used for hypotension, seems to be promising, which allows to slightly reduce the dose of caffeine and, consequently, the severity of adverse reactions.
Caffeine stimulates the body's metabolic processes, increasing glycogenolysis, causing hyperglyce-
mia (these effects are negative for people with diabetes). At the same time, plant adaptogens enhance gly-colysis, promote early activation of aerobic oxidation processes, and increase the conjugacy of oxidation and phosphorylation. This allows the use of plant adaptagens (primarily aralia) in patients with diabetes mellitus, which smooths out the severity of hypergly-cemia when using caffeine [1, 13].
Caffeine increases lipolysis, reducing the body's dependence on the use of glycogen, stimulating the activity of hormone-sensitive lipase and inhibiting the activity of glycogen phosphorylase.
High concentrations of free fatty acids in the blood for a long time have a toxic effect on the beta cells of the pancreas, inhibiting the secretion of insulin. At the same time, cells of other organs are involved - cardio-myocytes, hepatocytes, initiating damage and chronic dysfunction. It is possible to reduce the severity of li-polysis caused by caffeine by combining caffeine with other agents. High doses of caffeine release adrenaline from the adrenal medulla, causing oxidative stress. Adding vitamin E, phytoadaptogens, selenium, helps to increase stress resistance and inhibits the processes of peroxidation.
Caffeine reduces the effectiveness of the action of vitamins B, PP, thereby decreasing the content of iron, potassium, zinc, calcium in the body.
It is possible to correct this by the addition of missing vitamins and elements.
When considering the use of caffeine at the same time as vitamins, macro- and microelements, it is necessary to consider not only the variants of their compatibility (both pharmaceutical and pharmacological), but also compatibility with the used excipients.
The absorbability of the active substance is significantly influenced not only by its physicochemical properties (molecular size, solubility, stability, degree of ionization, ability to chelate and complexation, etc.), but also the created dosage form (for example, disintegration of tablets, presence of different nature of excipients) and others.
The combination of drugs often alters the absorption of substances in the gastrointestinal tract (GIT). When considering possible combinations of caffeine with various compounds, it is necessary to consider their compatibility in the process of absorption. A frequent reason for the decrease in absorption is the direct interaction of drugs in the intestinal lumen as a result of the occurrence of inactive chelate formations, or com-plexones. Chelating agents include orally administered drugs that release calcium and magnesium ions. These drugs easily form complexones with cardiac glycosides, indirect anticoagulants, sulfonamides, phenylbutazone and salicylates.
There is no evidence in the literature that compounds containing calcium and magnesium reduce the absorption of caffeine. In this regard, we consider it necessary to correct violations of the electrolyte composition caused by caffeine by introducing into the caffeine tablets calcium and magnesium compounds (for example, magnesium asparaginate).
In our opinion, a promising combination of caffeine with magnesium, which will allow to level side
effects and increase therapeutic. It is known that one of the most important effects of magnesium is the inhibition of excitation processes in the cerebral cortex (which should be considered as particularly valuable in the treatment of caffeine). Magnesium is involved in many metabolic reactions of energy exchange, such as the formation, accumulation, transfer and utilization of energy, free radicals and their oxidation products. Therefore, this element largely determines the normal functioning of the nervous system and is very important for the functioning of the central nervous system (CNS). Magnesium is a universal regulator of biochemical and physiological processes in the body, existing as a cofactor for more than 300 enzymes, including and is part of numerous enzymes of the nervous and glial tissues of glutamine synthetase, glutamine-cysteine synthetase, and cholinesterase. Currently, medicine uses a number of drugs based on magnesium ion. These include magnesium sulfate, magnerot, magne B6, mag-nesol, asparkam, cardiomagnyl, magnesium citrate, etc. Magne B6 is a preparation based on a complex of magnesium and vitamin B6 (pyridoxine).
In our opinion, the creation of sublingual caffeine-containing tablets opens up certain prospects. A number of facts can be presented in favor of this proposal, incl. and the fact that caffeine is well absorbed from the mouth. The thin epithelial layer of the oral mucosa, which is well vascularized, and the physicochemical properties of caffeine itself contributes to absorption. Considering this method of administration, it is possible to offer a combination of caffeine with glycine, which is widely used in medicine as tablets for resorption in the oral cavity (glycine tablets "Biotic" 100 mg each).
Another problem that is quite acute when taking caffeine is an increase in the secretory activity of the stomach and, as a result, the development of heartburn in the consumer. However, the joint use with generally accepted caffeine antacids is not possible, because "Classic" antacid agents can enhance the motility of the stomach and form complexes, so their effect on the absorption of many drugs is almost unpredictable. Some drugs, such as Almagel, on the surface of the mucous membrane form a layer that complicates the absorption of drugs. In this regard, it is possible to recommend the use of caffeine simultaneously with glycine, which has a mild antacid effect and is devoid of the many side effects of antacids. In order to reduce the negative effect of caffeine on the gastrointestinal tract, it is possible to consider the use of caffeine with vegetable astringents, such as calamus rhizome. In addition, it is proposed to focus on bismuth nitrate mainly, which is able to protect the gastric mucosa from irritation with hydrochloric acid and further destruction by proteolytic enzymes. This compound is widely used in gastroenterology in the form of combined means "Vikalin" and "Vikair".
In the case of the use of caffeine in asthenia, it is considered expedient to combine it with phy-toadaptagens, which, as is well known, possess a complex of valuable properties that increase the resistance and non-specific resistance of an organism to adverse effects.
Adaptogens are especially highly effective for heavy physical exertion and overwork. As with the intake of caffeine, during the first hour after administration, an unstable ergogenic effect occurs, completely disappearing after a few hours and requiring repeated use of the drug. Thus, they have similar pharmacokinetic parameters, primarily the rate of onset of the effect and its duration [14].
It is necessary to cite another fact in favor of the combination of caffeine with adaptogens - this is a significant increase in attention and memory, those effects for the sake of which people often resort to caffeine-containing drinks.
When choosing a dose of adaptagen in combination with caffeine, it is advisable to use the course method with small doses. The supercompensation phase is achieved gradually, an individual dose adjustment is required 2-3 times. The shock method with large dosages with a combination of caffeine with an adaptogen should not be used, in our opinion.
When taking adaptagenov may increase blood pressure, potassium levels in the blood, nervous excitability. These side effects, as in the case of caffeine, are valuable and positive (increased blood pressure, activation of the central nervous system). And the increase in potassium in the blood will allow to correct the violation of electrolyte metabolism caused by therapy with caffeine.
Separately, it is necessary to consider the possibility of a combination of caffeine with pantokrin. The complex of biologically active substances of pantokrin has a pronounced stimulating effect on the activity of the nervous and cardiovascular systems. In addition, pantocrine has a large number of micronutrients needed by the person. Introduction of pantocrin allows to compensate for the violation of the microelement composition, which provokes the use of caffeine. The fact that it increases the body's pespecific reactivity also testifies to the use of pantocrine.
Achievements of molecular biology and fundamental neurochemistry made it possible to obtain unique data on the role of taurine and the mechanisms of its action. Taurine stabilizes cell membranes, modulates calcium transfer, and is capable of conjugating to xenobiotics, retinoic acid and bile salts. Taurine protects membranes either by detoxifying destructive compounds or by directly preventing changes in permeability. Taurine is used for epilepsy, ischemia, obesity, diabetes, hypertension and neurodegeneration in the elderly. Taurine in combination with caffeine is able to speed up metabolism, increase concentration, increase mental activity and prevent drowsiness [15].
Despite the apparent contradictions of the joint use of the psychostimulant caffeine with neurotransmitter acid of the inhibitory type of action of glycine, this combination deserves special attention. Glycine is the main inhibitory neurotransmitter for fast synapses in the spinal cord, has a neurotransmitter effect, eliminates the symptoms of excessive arousal and normalizes the processes of inhibition, has a neuroprotective effect with increased excitability of the central nervous system. The main indications of the joint use of caffeine with glycine is neurasthenia and neurosis. This allows
us to consider the combination of caffeine with glycine appropriate.
Ginkgo biloba contains a rich complex of biologically active substances (BAS): flavonol and flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, superoxide dismutase ascorbic acid and cate-chin. Studies on the pharmacological activity of ginkgo biloba extract have shown that, similar to caffeine, flavone glycosides contained in ginkgo biloba, which are the main active ingredient, have the ability to inhibit the enzyme phosphodiesterase, which leads to a decrease in arteriole tone and an increase in blood flow. A number of studies emphasize that flavonoid glycosides can reduce damage to endothelial cells due to free radical oxidation, thereby reducing the progression of atherosclerosis. The other side of the action of a BAS extract of ginkgo biloba is associated with improved cerebral circulation due to: increased blood flow, suppression of the action of platelet activating factor, changes in the metabolism of the neuron. Ginkgo biloba is considered as an inexpensive option for the prevention of cognitive decline in elderly patients.
Moreover, the high efficacy of Ginkgo biloba preparations is combined with the safety of their use. Combined use with caffeine will allow to obtain a more pronounced therapeutic effect with lower concentrations of the components.
Since caffeine activates adrenaline rush, it can trigger the development of oxidative stress. In this regard, it is advisable to combine with caffeine such an-tioxidant compounds as selenium and vitamin E.
Selenium blocks the action of free radicals, protecting the contents of the cell from destruction. This not only improves the functioning of tissues and organs, but is also an excellent prevention of aging of the body, cardiovascular and oncological diseases.
Vitamin E is widely used as an antioxidant and is closely related to the trace element selenium. The intake of these two components is strictly proportional, 25 ^g of selenium should be in every 200 units of tocopherol, which ensures maximum effectiveness of the latter.
Promising in our opinion is the combination of caffeine with the general tonic drug -apilak. Apilak -royal jelly which contains an extensive complex of biologically active substances, including components such as vitamins (C, B12, B8, B6, B5, B2, B1, H, ino-sitol, folic acid), mineral elements (potassium, sodium, calcium, magnesium, phosphorus, iron), 23 amino acids, among which there are essential amino acids: va-line, tryptophan, histidine, methionine.
Similarly to caffeine, it is indicated for arterial hypotension, recommended for asthenic conditions, physical overload, during the period of social adaptation. The rich composition of BAS apilak not only replenishes the caffeine's reduced effectiveness of the action of vitamins B, PP, but also replenishes the mineral and amino acid pool in the body. This allows us to consider this combination as expedient for creating a drug that has a general strengthening effect, stimulating the work of the whole organism, helping to get rid of constant fatigue and drowsiness.
Conclusion of the article. A number of approaches have been proposed for correcting possible side effects associated with prolonged use of caffeine. When selecting possible compounds for combinations, the scientific validity and feasibility of their use, as well as their pharmacological compatibility, were taken into account.
A special place was given to phytoadaptogens, since they have unique properties that are not only similar in pharmacological effects to caffeine, but also complement and, in some cases, correct its negative effects.
Thus, based on the analysis, we can recommend the following concepts for the combined use of caffeine:
1. Use with electrolytes and trace elements in order to compensate for the deficiency caused by caffeine therapy (iron, potassium, zinc, calcium).
2. Use with phytoadaptogens (Aralia, Rhodiola,
etc.)
3. Use with pantokrin - an adaptogen of animal origin and a source of trace elements.
4. Use with neurotransmitter amino acids: glycine and taurine.
5. Application with ginkgo biloba extract
6. Use with antioxidants: selenium and vitamin E.
7. Use with bismuth nitrate and airway in order to reduce the negative effect of hydrochloric acid on the walls of the stomach.
8. Application with apilak.
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