RU2674337C1 - Remedy for seasonal desynchronosis correction - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to pharmaceutical industry, and namely to means for correcting seasonal desynchronosis. Means for correcting seasonal desynchronosis, which is a dry extract of the aerial part of the Meadowsweet, with 3–5 % moisture content and a lithium concentration of 90 mcg/g, obtained by a three-stage extraction with 20 % ethyl alcohol at a ratio of raw material and extractant 1:2, followed by drying at a temperature of not more than 40 °C and further dispersing.

EFFECT: above means is effective for correcting seasonal desynchronosis.

1 cl, 3 tbl

Description

The invention relates to clinical pharmacology and relates to means for the correction of seasonal desynchronosis.

In the human body, a huge number of physiological processes are subordinated to circadian rhythms. As a result of violation of the rhythms of the body, a state of desynchronosis occurs. Violation of daily biorhythms (desynchronosis) can occur under the influence of a variety of factors. Such factors may include: a sharp change in the duration of the light period, a sharp change in atmospheric pressure or temperature, transmediated flights, shift work methods, and the use of psychotropic drugs that affect the natural structure of biological rhythms of the body [1, 2]. The development of desynchronosis is accompanied by malaise, chronic fatigue, sleep disturbance, the occurrence of various diseases, or an exacerbation of existing ones [1]. Thus, the problem of desynchronosis correction deserves special attention.

An important role in the mechanisms of synchronization (coordination) of circadian (circadian) rhythms is played by lithium compounds. The rhythm-modulating (returning biorhythm consistency) properties of lithium salts using lithium oxybutyrate as an example were studied in detail at the Siberian State Medical University by Professor T.A. Zamoshchina [3]. However, the official lithium salts (lithium carbonate and lithium oxybutyrate) are not widely available and are subject and quantitatively registered in all medical institutions [14].

The means of chronobiological correction (options) and the method of chronobiological correction [4] are patented, consisting of two herbal complexes - morning tonic and evening, which has a calming effect. The morning complex includes: spirulina, eleutherococcus roots, rhizomes and roots of leuzea and angelica, Siberian fir needles, nettle and raspberry leaves, as well as a number of vitamins. It is known that during therapy with spirulina and eleutherococcus, sleep disturbances, development of anxiety and increased irritability are observed [5]. In addition, these components are not recommended for children under 12 years of age [5]. It was shown that in another component - angelica - there are substances harmful to the body and it is necessary to use means based on it in moderation and with caution [5]. All together indicates a disadvantage of this complex as a means of chronobiological correction.

Known drug "Melaxen", which includes the active component - melatonin (a synthetic analogue of the pineal gland hormone). Due to its sedative and adaptogenic properties, “Melaxen” normalizes physiological sleep, and also corrects the functioning of biological rhythms [5]. However, he has a number of side effects: headache, nausea, vomiting, diarrhea, morning drowsiness, the occurrence of allergic reactions, swelling. This remedy has a number of contraindications: severe renal impairment, diabetes mellitus, renal failure, leukemia, pregnancy, lactation.

Known tool for the correction of desynchronism of the rhythm of sleep-wakefulness [6], which is a dry extract of Repeshka hairy (Agrimonia pilosa Ledeb.). However, there are several features that distinguish favorably the extract of Labasnica vulgaris from the extract of the hairy Repeshka. Firstly, the lithium content in Labaznik extract is 10 times higher than that in Repeshka extract. Secondly, the hairy Repeshka extract is intended for the correction of only one rhythm - sleep-wakefulness, while the Labasnica vulgaris extract is applicable for the correction of at least two rhythms - behavioral activity and body temperature. It is known that in humans and animals, the rhythm of sleep-wakefulness (measured by behavioral activity) and the rhythm of body temperature are associated with the activity of two different but functionally related circadian oscillators [7]. Obviously, the rhythm-modulating effect of the hairy Repeshka extract is associated with an effect only on the oscillator that controls behavioral activity, and the effect of the Labasnica vulgaris extract extends to the oscillator that regulates body temperature.

Currently, there is known evidence that the lithium concentrator — Labasnica vulgaris — is used as a drug with nootropic and adaptogenic activity [7], and is part of the collection of medicinal plants with antioxidant effects [8]. Of all the existing tools, which are based on Lubaznica vulgaris, at the moment there is not a single tool aimed at correcting mismatched biological rhythms.

A new technical task is to search for medicines of the natural complex of macro- and microelements in the form of water and alcohol extracts from plant materials, in which lithium is accumulated, which has chronobiological activity aimed at correcting seasonal desynchronosis.

The problem is solved by using an aqueous-alcoholic extract of the herb Labaznika vulvifolia (Filipendula ulmaria) of the Rosaceae family as a chronobiological agent aimed at correcting seasonal disorders of the circadian rhythms of the body (desynchronosis).

Obtaining Labasnica vulgaris extract was carried out by the method of repercolation (multiple extraction). The raw material for the preparation was the crushed grass of Labasnica vulgaris collected in the flowering phase, with a particle size of 3-5 mm and a moisture content of 13-15%. As extractant, 20% ethyl alcohol was used. The choice of extractant was due to the high water solubility of organic and inorganic lithium salts [6]. In addition, a 20% concentration of ethyl alcohol has a bactericidal effect necessary for the technical implementation of the extraction process.

The extraction was carried out by the method of stepwise three-fold extraction of raw materials at room temperature. The ratio of raw material to extractant was 1: 2; at each stage, extraction was carried out after 24 hours.

The obtained extracts were combined and freed from mechanical impurities. Next, the liquid extract was dried at a temperature of not more than 30-40 ° C and dispersed. Dry extract of Lubaznik vulvaria is a hygroscopic (moisture-absorbing) powder of dark brown color, bitter-mucous taste, with a pronounced smell. The moisture content in the extract was 3-5%, the lithium concentration was 90 mg / kg.

Solstices cause seasonal changes in geophysical parameters (changes in the ratio of light and dark periods of the day, the intensity of light radiation, temperature). It is known that when the rhythms of illumination change, the endogenous rhythm of animals (including humans) begins to adapt to new external conditions. However, switching to new temporary pointers does not occur immediately. In humans, for example, such an adaptation can last from 1 to 3 weeks. In the process of restructuring the temporal structure of the body, the norms of daily curves, phases, periods, and amplitudes of fluctuations in the indicators of a person's health and his physiological processes begin to change. At the same time, some rhythms are tuned to the endogenous oscillator and become near-daily, while others continue to fluctuate in the diurnal mode. Thus, external desynchronization can provoke the appearance of internal [9]. There is evidence that in areas where winter days are too short and summer days are too long, and there are significant changes in the amount of daylight at different times of the year (the Arctic), some people develop seasonal affective disorders [10].

Based on the foregoing, the chronobiological activity of the water-alcohol extract of Lubaznica vulgaris was investigated in vivo using a model of natural disturbance of biological rhythms during the winter and summer solstices when keeping animals in natural light. The studies were carried out on rats of Wistar male mice weighing 200-300 g. Using a probe, Lubaznika vulvifolia extract in suspension was injected into the animal’s stomach for 9 days. The dose of the injected water-alcohol extract of Lubaznica vulgaris was calculated by the lithium content, which corresponded to the lithium content of 10 mg / kg of the official lithium salt of oxybutyrate and it was 7 g / kg. As control substances, purified water and an extract of Lubaznik vulgaris (Filipendula vulgaris) in an equivalent dosage, as well as a synthetic organic salt, lithium oxybutyrate, at a dose of 10 mg / kg, were used.

The rhythm-modulating activity of the Labasnica vulgaris extract was evaluated on days 7–9 of chronic administration by its effect on the rhythmic organization of the behavioral activity and body temperature of rats under conditions of pronounced desynchronosis. It is known that these two rhythms reflect the activity of two different oscillators in the human body and mammals, including rodents [11].

During the winter and summer solstices, the biological rhythms of small rodents are released from the control of the light-dark cycle and become arrhythmic or free-flowing, i.e. are tuned to the regime of an endogenous oscillator, the period of activity of which is individual and varies within 20–28 hours [11].

To assess the behavioral activity of rats, the “open field” method was used, and horizontal, vertical, and mink components were recorded over 5 minutes every 4 hours for three consecutive days.

Statistical processing of chronobiological data was carried out by the methods of one-way analysis of variance and cosinor analysis [12, 13].

During the winter solstice in the intact group of rats in the spectrum of rhythms of behavioral activity was completely absent any rhythm. However, in the spectrum of body temperature rhythms, two harmonics were determined - 12 h and 25 h, whose acrophases (the time of maximum severity of the parameter) were in the morning, which indicated the daily type of activity of animals and the adjustment of the temperature rhythm to a freely flowing, i.e. on the endogenous oscillator mode (Table 1). Thus, in the intact group of rats during the winter solstice, internal (between the temperature and behavioral rhythms) and external (between physiological rhythms and the external light-dark cycle) desynchronosis were expressed.

In the control group of animals treated with purified water, desynchronosis was also expressed. However, a 24-h rhythm appeared in the spectrum of body temperature rhythms (Table 1), which can be associated with a 24-h cycle of administration of purified water to animals [11], since the action of the food (or drinking) regimen that captures the rhythms is fascinating [11].

In the group of animals treated with lithium oxybutyrate injections, an increase in the sensitivity of rhythms to the 24 h external injection cycle was observed in the spectrum of rhythms of motor activity, as evidenced by the appearance of a pronounced 24 h harmonic (Table 1). The rhythms of the temperature index maintained a free current state, as indicated by the presence of 12 h and 25 h harmonics. Thus, during the winter solstice of lithium, oxybutyrate helped to restore 24 hours of the rhythm of behavioral activity lost during the solstice (see intact and control groups of rats, Table 1) and the freely current rhythm of body temperature.

In the experimental group of rats treated with Lubaznica vulgaris extract, motor activity acquired a rhythmic character, as evidenced by the appearance of 10 hours and 20 hours of components in the spectra of the rhythms of this indicator, with a domination of 10 hours of rhythm. However, the appearance of three statistically significant harmonics in the temperature spectrum of rhythms was observed — 14 hours, 24 hours, and 25 hours (Table 1). The appearance of a 25-h rhythm testified to the beginning of the restructuring of the temperature rhythm into a freely current state. Thus, the extract of Labasnica vulgaris during the winter solstice facilitated the restructuring of the rhythms of behavioral activity and body temperature in a free current state.

During the summer solstice, in the intact group of rats, rhythm was completely absent in the spectra of rhythms of motor activity and body temperature (Table 2). In animals, internal and external desynchronosis was observed.

In the control group of rats receiving Lubaznik vulgaris extract, the appearance of a number of statistically significant harmonics was observed in the spectrum of rhythms of behavioral activity (Table 2). The presence of such an abundance of harmonics indicates a complete lack of synchronization of individual harmonics. Nevertheless, the total motor activity in this group acquired a rhythmic character compared with the intact group. In the spectrum of rhythms of body temperature, statistically significant rhythms in the control group were not observed.

Thus, the common Labasnik extract was more of an external synchronizer than an internal one. Perhaps a certain contribution to this process was made by the oral administration procedure itself, and Labasnik common extract increased sensitivity to this external cycle even more.

In the experimental group of rats receiving Lubaznica vulgaris extract, motor activity acquired a rhythmic character, compared with the intact group of animals, as evidenced by the appearance of many near-daily and daily harmonics. Compared with the control group of rats receiving Labaznika vulgaris extract, the rhythm spectrum of the same indicator in the experimental group narrowed almost by half.

The appearance of rhythmics was also observed in the temperature spectrum of rhythms, as indicated by the presence of 20 h and 21 h harmonics. If we compare the 21-h periods of the rhythms of motor activity and body temperature in the group of rats receiving the Lubaznika vulgaris extract, we see that the acrophase of 21 h of the body temperature rhythm occurred earlier than the acrophase of 21 h of the rhythm of motor activity, which should be observed according to the literature [3 , eleven].

Thus, during the summer solstice, the Labasnica vulgaris extract accelerated the restructuring of both rhythms to a freely current mode and facilitated internal synchronization between the rhythms.

After the rhythmic modulating properties of Lubaznica vulvaris were proved, using the method of flame photometry, the total lithium content in the organism of rats treated with Lubaznika vulgaris extract, Lactobacillus vulgaris extract and a synthetic organic salt, lithium oxybutyrate, was determined (Table 3).

Compared to intact rats, a significant increase in the cation content in the body was observed in the groups of animals treated with Labasnik extract of polyvalent and lithium oxybutyrate compared with intact rats (Table 3). Obviously, this was the reason for the pronounced rhythm-modulating effects in these groups, since rhythm-modulating properties are not known for other inorganic and organic components of the Lubaznik common and Labaznik common extracts (flavonoids, catechins, coumarins, tannins, metal cations and anions) [15, 16].

Thus, it was proved that the extract of Labasnica vulgaris with a high lithium content had a pronounced rhythmic modulating effect on both behavioral and temperature rhythms, reflecting the activity of two different oscillators. During the winter and summer solstices, the Labasnica vulgaris extract accelerated the rebuilding of rhythms of behavioral activity and body temperature into a free-flowing state and smoothed the state of seasonal desynchronosis in the rhythmostasis of animals.

INFORMATION SOURCES

1. Rapoport S.I. Chronomedicine, circadian rhythms. Who needs this? // Clinical medicine. - 2012. - T. 90. - No. 8. - S. 73-75.

2. Volobuev A.N. Circadian biophysics and chronomedicine / A.N. Volobuev, V.F. Pyatin, N.P. Romnachuk // Health and education in the XXI century. - 2016. - T. 18. - No. 5. - S. 97-100.

3. Zamoshchina T.A. Chronobiological basis of the neurotropic effects of lithium salts: Diss. Doct. biol. sciences / T.A. Zamoshchina. - Tomsk, 1997 .-- S. 286.

4. Patent No. 2317822 of the Russian Federation // E.P. Volikov, T.G. Gorokhovskaya, Yu.Yu. Gichev. Means of chronobiological correction (options) and a method of chronobiological correction.

5. The Register of Medicinal Products of Russia. Encyclopedia of medicines and pharmaceutical products [Electronic resource]. - 2000-2017. - URL: https://www.rlsnet.ru (accessed 08.23.2017).

6. Patent No. 2493866 of the Russian Federation // E.A. Krasnov, A.I. Yatsenkov, T.A. Zamoshchina, E.V. Ivanova Means for correcting sleep-wake rhythm desynchronosis.

7. Patent No. 2311193 of the Russian Federation // Aksienko S.G. and others. A tool with nootropic and adaptogenic activity.

8. Patent No. 2613171 of the Russian Federation // I.V. Shilova, I.A. Samylina, N.I. Suslov Collection of medicinal plants antioxidant action.

9. Hildebrandt G. Chronobiology and chronomedicine / G. Hildebrandt, M. Moser, M. Lechofer // M .: Arnebia. - 2006 .-- S. 24, 28, 29.

10. Khaustova EA Seasonal affective disorder: diagnosis and therapy / E.A. Khaustova // International Neurological Journal. - 2012 .-- S. 188-192.

11. Ashoff, Yu. Free-flowing and captured circadian rhythms / Yu. Ashoff // Biological rhythms / Ed. Yu. Ashoff. - M .: Mir, - 1984. - T. 1. - S. 54-69.

12. Koryagina Yu.V. CosinorEllipse 2006 No. 20066611345 / Yu.V. Koryagina, S.V. Nopin // Computer Software ... (Offic. Bull.). - 2006. - No. 3 (56). - S. 42.

13. Lyubishchev A.A. Analysis of variance in biology // M .: ed. Mosk. University, 1986. - S. 200.

14. Decree of the Government of the Russian Federation of 1998 No. 681 “On the establishment of a list of narcotic drugs, psychotropic substances and their precursors to be controlled in the Russian Federation” [Electronic resource]. - 1990-2017. - URL: http://base.garant.ru (accessed 09.09.17).

15. Zamoshchina T.A. Experimental evaluation of the chronobiological activity of the aqueous extract of the aerial part of the Repeynichnosa / T.A. Zamoshchina, E.A. Krasnov, V.I. Otmakhov et al. // Experimental and Clinical Pharmacology. - 2016 .-- S. 3-6.

16. Gorbacheva A.V. Lubaznik vistifolia in phytotherapy of inflammatory processes / A.V. Gorbacheva, S.G. Aksienko, V.G. Pashinsky. - Tomsk, 2005 .-- S. 35-52.

Claims (1)

Means for the correction of seasonal desynchronosis, which is a dry extract of the aerial part of Lubaznica vulgaris with 3-5% moisture content and a lithium concentration of 90 μg / g, obtained by three-stage extraction with 20% ethyl alcohol with a ratio of raw material and extractant 1: 2, followed by drying at a temperature not more than 40 ° C and further dispersion.