CN112336845A - Medical application of Sishen pills or extract thereof - Google Patents
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- A61K36/18—Magnoliophyta (angiosperms)
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Abstract
The invention belongs to the field of traditional Chinese medicines, and relates to a medical application of a Sishen pill or an extract thereof. Specifically, the use of any one selected from the following items (1) to (3) for preparing a medicament for sedation hypnosis, treatment or prevention of insomnia, anxiolysis, or for sleep regulation: (1) a pharmaceutical composition comprising nutmeg, fructus Psoraleae, fructus Schisandrae chinensis, fructus evodiae, fructus Jujubae, and rhizoma Zingiberis recens; (2) an extract which is an aqueous extract and/or an ethanol extract of the pharmaceutical composition of item (1); (3) a pharmaceutical preparation comprising the extract of item (2) and one or more pharmaceutically acceptable excipients. The pharmaceutical composition, the extract or the pharmaceutical preparation have good effects of tranquilizing, hypnotizing, preventing or treating insomnia or sleep control.
Description
Technical Field
The invention belongs to the field of traditional Chinese medicines, and relates to a medical application of a Sishen pill or an extract thereof. Specifically, the application is sedative hypnosis, insomnia prevention or treatment or sleep regulation.
Background
Insomnia refers to a neuropsychiatric disease that causes difficulty in falling asleep or maintaining sleep under conditions of sufficient sleep time and appropriate environment and causes daytime dysfunction, and has difficulty in falling asleep, frequent wakefulness, early awakening, and non-restorative sleep as main symptoms. Insomnia is the most common sleep disorder, the incidence rate of short-term insomnia can reach 30-50%, chronic insomnia patients in major industrial countries of the world account for at least 5-10% of the general population, 5-7% of people have or are using prescription drugs to treat insomnia, and epidemiological survey aiming at general population in China shows that 15% of people in China are troubled by chronic insomnia.
The sedative hypnotic drugs commonly used in clinic comprise benzodiazepine represented by diazepam and lorazepam
Class and non-benzodiazepines represented by zaleplon and zopiclone
And (4) class. The prior sedative hypnotic drugs commonly used at present have the problems of side effects of different degrees and medication safety. The benzodiazepine medicine has addiction after long-term useAnd dependence, and side effects such as lethargy, fine motor disorder and memory deterioration. Although the side effects of non-benzodiazepine drugs such as dysmnesia, rebound insomnia after drug withdrawal and the like are small, the non-benzodiazepine drugs can also cause daytime dysfunction such as headache, dizziness, somnolence and the like, and the long-term use of the non-benzodiazepine drugs also generates drug resistance and dependence.
The prior sedative hypnotic drugs can prolong the sleep time to a certain degree, but cannot improve the sleep quality. The normal physiological sleep of a human can be divided into Rapid Eye Movement (REM) sleep, non-rapid eye movement (NREM) sleep and NREM sleep according to the characteristics of brain electrical activity and the sleep depth, wherein the NREM sleep can be divided into four periods of I, II, III and IV, and the NREM III and IV are deep sleep periods which are main periods for recovering energy and physical strength. During overnight sleep, REM sleep accounts for about 20% -25%, NREM sleep accounts for about 75% -80%, and NREM III and IV phase account for about 13% -23%. The sleep recovery effect is closely related to the time distribution and specific gravity of each stage in the sleep process besides the total sleep time. The traditional benzodiazepine medicine can increase the period I and II of NREM sleep, and can obviously shorten or completely cancel the period IV of NREM sleep. Novel non-benzodiazepines represent the drugs zolpidem and zopiclone that also shorten the III, IV phase sleep time in REM and NREM. Disruption of normal sleep architecture prevents drug-induced sleep from achieving the same restorative effects as normal physiological sleep. The sedative hypnotic drugs currently in use increase sleep time at the expense of sleep quality, which is one of the causes of fatigue and drowsiness occurring the next day after the induction of sleep using such drugs.
The insomnia seriously affects the physical and mental health and the life quality of patients, and simultaneously causes heavy burden to the society, and the conventional sedative hypnotic can change the sleep time but cannot increase the sleep depth and improve the sleep quality, so that the sedative hypnotic has a sleep structure regulation effect, can increase the sleep depth of the insomnia patients and has great significance in research and development of novel sedative hypnotic for improving the sleep quality.
The four-god pill is originally seen in Chen Shi's prescription for infantile pox eruption, which is recorded by Chen Wenzhong, and consists of two god pills (nutmeg and fructus psoraleae) and schisandra chinensis powder (schisandra chinensis and fructus evodiae), the two prescriptions are combined, and the pill has excellent effects of warming and invigorating spleen and kidney, and strengthening intestine and relieving diarrhea, and is highly popular with doctors of all ages. Has definite clinical curative effect on treating colitis, irritable bowel syndrome, allergic colitis and other diseases. In a mouse acute and chronic colitis model induced by dextran sulfate sodium, the administration of a Sishen pill of 2.25 g/kg/day by intragastric administration can obviously improve the colon tissue inflammatory injury and the mouse disease activity index, and the mechanism is mainly related to the inhibition of Th17 reaction and the promotion of Th17 generation; in a rat ulcerative colitis model constructed by using a 2.4.6-trinitrobenzenesulfonic acid-ethanol method, the Sishen Wan can also improve the general state of a model rat, relieve pathological injury of colon and NO level in tissues and lower the concentration of TNF-alpha in serum, and the research shows that the treatment effect of the Sishen Wan can be related to immune regulation and inhibition of oxidative stress reaction. In the research of the irritable bowel syndrome, the Sishen pill can reduce the diarrhea index of a spleen-kidney-yang deficiency type irritable bowel syndrome model rat, reduce the intestinal sensitivity, improve the abnormal structure of intestinal flora of a model group rat, and prompt that the Sishen pill can play a role in treating the irritable bowel syndrome by regulating the intestinal flora. The sedative-hypnotic effect and the sleep structure regulation effect of the four-god pill are not reported.
Disclosure of Invention
Through intensive research and creative work, the inventor surprisingly finds that the Sishen pill can inhibit spontaneous activity of a mouse, prolong the disappearance time of righting reflex of the mouse and shorten the disappearance latency of the righting reflex in cooperation with the sodium pentobarbital; has excellent sedative hypnotic activity. Furthermore, electroencephalogram analysis shows that the four-god pill can increase normal sleep time, adjust sleep structures, increase slow wave sleep time and fragment number, has a unique sleep regulation and control effect, and can improve sleep quality by enhancing slow wave sleep while increasing sleep time. Has the potential of being applied to sedation hypnosis, treating or preventing insomnia or used for sleep regulation. The following invention is thus provided:
one aspect of the present invention relates to the use of any one selected from the following items (1) to (3) for the preparation of a medicament for sedation hypnosis, treatment or prevention of insomnia, anxiolysis, or for sleep regulation:
(1) a pharmaceutical composition comprising nutmeg, fructus Psoraleae, fructus Schisandrae chinensis, fructus evodiae, fructus Jujubae, and rhizoma Zingiberis recens;
(2) an extract which is an aqueous extract and/or an ethanol extract of the pharmaceutical composition of item (1);
(3) a pharmaceutical preparation comprising the extract of item (2) and one or more pharmaceutically acceptable excipients.
In one or more embodiments of the invention, the use, wherein,
the pharmaceutical composition comprises: 1-3 parts of nutmeg, 3-5 parts of fructus psoraleae, 1-3 parts of schisandra chinensis, 0.5-1.5 parts of fructus evodiae, 1-3 parts of Chinese date and 1-3 parts of ginger;
preferably, the pharmaceutical composition comprises: 1.5-2.5 parts of nutmeg, 3.5-4.5 parts of fructus psoraleae, 1.5-2.5 parts of schisandra chinensis, 0.6-1.4 parts of fructus evodiae, 1.5-2.5 parts of Chinese date and 1.5-2.5 parts of ginger;
preferably, the pharmaceutical composition comprises: 1.8-2.2 parts of nutmeg, 3.8-4.2 parts of fructus psoraleae, 1.8-2.2 parts of schisandra chinensis, 0.8-1.2 parts of fructus evodiae, 1.8-2.2 parts of Chinese date and 1.8-2.2 parts of ginger;
preferably, the pharmaceutical composition comprises: 2 parts of nutmeg, 4 parts of fructus psoraleae, 2 parts of schisandra chinensis, 1 part of fructus evodiae, 2 parts of Chinese date and 2 parts of ginger;
preferably, the pharmaceutical composition is composed of nutmeg, fructus psoraleae, fructus schizandrae, fructus evodiae, fructus jujubae and ginger.
In one or more embodiments of the invention, the use, wherein the extract is prepared by a preparation method comprising the following steps:
1) extracting the medicinal composition with 50% -90% ethanol (preferably 60% -80% or 65% -75% ethanol, more preferably 70% ethanol) to obtain ethanol extract and residue;
2) extracting the residue with water to obtain water extract;
3) combining the alcohol extract and the water extract to obtain the extract.
In one or more embodiments of the invention, the use is described, wherein in step 1) is reflux extraction;
preferably, the extraction time is 0.5-5 hours, 0.5-2 hours or 0.5-1.5 hours;
preferably, the amount of water is 2-20 times, 2-15 times, 8-12 times or 10 times;
preferably, the aqueous extract is a thick paste obtained after concentration.
In one or more embodiments of the invention, the use is described, wherein in step 2) is decoction;
preferably, the extraction time is 1 hour;
preferably, the amount of ethanol is 2-20 times, 2-15 times, 8-12 times or 10 times;
preferably, the alcohol extract is a thick paste obtained after concentration.
In one or more embodiments of the invention, the use, wherein the pharmaceutical preparation consists of the extract of item (2) as the only pharmaceutically effective ingredient, and one or more pharmaceutically acceptable excipients.
In one or more embodiments of the invention, the use, wherein the unit dose of the pharmaceutical preparation is 20g to 400g, 50g to 300g, 80g to 250g, 100g to 200g, 120g to 180g, 130g to 160g, 110g, 120g, 130g, 140g, 150g, 160g, 170g, 180g, 190g or 200g, calculated on the weight of the pharmaceutical composition used to prepare the extract. Without being bound by theory, the high dose of 22.18g/Kg in example 2, the specific surface area of human and mouse is 9.1, the body weight of adult is 60Kg, and the daily dose is about 146 g.
In one or more embodiments of the invention, the use, wherein the sleep modulation is to increase sleep time and sleep depth, increase the number of slow wave sleep segments, and/or extend the duration of slow wave sleep segments.
In the experiments of the present invention, the sedative-hypnotic effect of the pharmaceutical composition (extract) was demonstrated by the results of the prolongation of the flip reflex time in fig. 1. The results in fig. 5 and 6 prove that the medicinal composition (extract) has influence on the sleep structure and shows the sleep regulation and control effect.
Another aspect of the present invention relates to a pharmaceutical formulation comprising an extract according to any of the present invention, one or more pharmaceutically acceptable excipients, and at least one compound for sedative-hypnotic activity;
preferably, the compound is selected from benzodiazepines
Compounds of the class and non-benzodiazepines
A compound of the class;
preferably, the benzodiazepine
The compound is diazepam or lorazepam;
preferably, the non-benzodiazepine
The compound is zaleplon or zopiclone.
Another aspect of the invention relates to a combination drug product comprising a first drug product and a second drug product packaged separately, wherein,
the first pharmaceutical product comprises a pharmaceutical formulation according to any of the present invention;
the second drug product comprises at least one compound for sedation and hypnosis, and one or more pharmaceutically acceptable excipients;
preferably, the compound is selected from benzodiazepines
Compounds of the class and non-benzodiazepines
A compound of the class;
preferably, the benzodiazepine
The compound is diazepam or lorazepam;
preferably, the non-benzodiazepine
The compound is zaleplon or zopiclone.
In the present invention, the term "sedative-hypnotic" is a pharmacological concept, meaning that drugs calm the mood of a person at small doses and induce similar physiological sleep at large doses.
Advantageous effects of the invention
The pharmaceutical composition, the extract, the pharmaceutical preparation or the combined pharmaceutical product has good effects of tranquilizing, hypnotizing, preventing or treating insomnia or sleep regulation.
Drawings
FIG. 1A is the effect of Sishen Wan extract on sleep latency in mice. Note: n 10, p <0.05, p <0.01, p < 0.001, compared to the solvent control.
FIG. 1B: effect of the bolus extract on sleep duration in mice. Note: n 10, p <0.05, p <0.01, p < 0.001, compared to the solvent control.
FIG. 2A: effect of bolus extract on number of cross-check in mice. Note: n 10, p < 0.001, compared to the blank control.
FIG. 2B: the effect of the Sishen Wan extract on the number of times the mouse stands. Note: n 10, p < 0.001, compared to the blank control.
FIG. 3A: the influence of the Sishen pill extract on the sleep latency of a mouse PCPA insomnia model. Note: n-10, p <0.05, p <0.01, p < 0.001, compared to the solvent control; compared with the PCPA model group, the # p is less than 0.05, the # p is less than 0.01, and the # p is less than 0.001;
FIG. 3B: influence of the Sishen Wan extract on sleep duration of a mouse PCPA insomnia model. Note: n-10, p <0.05, p <0.01, p < 0.001, compared to the solvent control; compared with the PCPA model group, the # p is less than 0.05, the # p is less than 0.01, and the # p is less than 0.001; compared to the diazepam group, $ p <0.05, $ $ p < 0.01.
FIG. 4: the effect of the Sishen pill extract on the sleep and wake time of rats. Note: n is 3, PS: out-of-phase sleep, SWS: and (5) slow wave sleep. P <0.05, p <0.01 compared to control.
FIG. 5A: effect of the bolus extract on the mean time to sleep segments in rats. Note: n is 3, PS: out-of-phase sleep, SWS: and (5) slow wave sleep. P <0.05 compared to control.
FIG. 5B: effect of the bolus extract on the number of sleep segments in rats. Note: n is 3, DZ: diazepam, SSW: four-god pill, PS: out-of-phase sleep, SWS: and (5) slow wave sleep. P <0.05, p <0.01, p < 0.001, compared to the control group. Compared with diazepam group, # p <0.05, # p <0.01, # p < 0.001.
FIG. 6A: the effect of the four-god pill on the total number of sleep-wake transitions in rats. Note: n-3, p <0.05 compared to control.
FIG. 6B: the influence of the four-god pill on the conversion frequency of the sleep-wake stages of the rat. Note: n is 3, W is Wake, clear-headed; s: slow wave sleep, Slow wave sleep; a: active wake, Active awake. P <0.05 compared to control.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1: preparation method of the Chinese medicinal composition ethanol extract
(1) Heating (boiling) 10 times (per gram of medicinal material by adding 1ml of ethanol) and 70% of ethanol (by weight ratio) for reflux extraction for 2 hours, filtering, and concentrating the filtrate to obtain a thick paste for later use;
(2) decocting the residue with 10 times of water for 2 times (each time for 1 hr), filtering, and concentrating the filtrate to obtain soft extract;
(3) mixing the water extract of step (2) with the alcohol extract of step (1), and mixing to obtain extract containing 1.26g crude drug per ml; for use in the following examples.
Example 2: sedative-hypnotic effect of Sishen pill extract
1. The influence of the Sishen pill extract and sodium pentobarbital on the mouse orthotropic reflex.
Experimental animals: ICR mice, male, SPF grade, 22-25g, purchased from Schbefu (Beijing) laboratory animals, Inc.
And (3) testing a sample: the prepared Sishen Wan extract is prepared by weighing corresponding mass of extract according to the extraction rate and the dosage of medicinal materials, and adding physiological saline to prepare suspension for gastric lavage.
The experimental method comprises the following steps: after the mice are purchased, the mice are adaptively raised for one week, and are randomly divided into 4 groups according to the body weight, wherein each group comprises 10 mice, namely a solvent control group (vehicle, normal saline), a four-god pill low dose group (recorded by the mass of crude drugs, 5.55g/kg), a four-god pill medium dose group (recorded by the mass of crude drugs, 11.09g/kg) and a four-god pill high dose group (recorded by the mass of crude drugs, 22.18 g/kg). The administration method is as follows:
(1) different dosage groups of the four-god pill are respectively administrated with corresponding medicine (20ml/kg) by single intragastric administration, and a solvent control group is administrated with equal volume of normal saline by intragastric administration.
(2) After 40min of gavage, four groups were intraperitoneally injected with pentobarbital sodium (42mg/kg, 5ml/kg), mice were placed in an independent space at about 25 ℃, and the time of administration was recorded.
(3) Observing the sleep state of the mouse, recording the disappearance time of the righting reflex, namely keeping the mouse in a supine position for 60 seconds without recovering, and allowing the mouse to sleep; and recording the recovery time of the righting reflex of the mouse, namely that the mice can recover autonomously within 60 seconds, and judging that the sleep is finished if the mice are continuously turned three times.
(4) Respectively calculating sleep latency and sleep time, wherein the sleep latency is righting reflex disappearance time-administration time, and the sleep time is righting reflex recovery time-righting reflex disappearance time.
The experimental results are as follows: see fig. 1A-1B.
The results in FIG. 1A show that single intragastric administration of the medium-dose tetrastigma pill (11.09g/kg) and the high-dose tetrastigma pill (22.18g/kg) can shorten the sleep latency period induced by pentobarbital sodium, and the differences are significant (p is less than 0.01) compared with the solvent control group.
The results in fig. 1B show that the duration of pentobarbital sodium-induced sleep can be significantly prolonged by the administration of high, medium and low doses of the four-drug pill for a single gavage, with statistical differences (p < 0.001).
The pentobarbital sodium synergistic hypnosis experiment is a classic experiment for verifying the sedative hypnotic effect of a medicament, and the fact that the extract plus the pentobarbital sodium is superior to the pentobarbital sodium used alone can indicate that the extract has the sedative hypnotic effect, and the righting reflex disappearance time of a mouse can be prolonged when the extract and the pentobarbital sodium are synergistically acted.
The result shows that the four-god pill extract has obvious sedative hypnotic effect.
2 Central inhibition of Sishen pill extract
Experimental animals: ICR mice, male, SPF grade, 22-25g, purchased from Schbefu (Beijing) laboratory animals, Inc.
And (3) testing a sample: the prepared Sishen Wan extract is prepared by weighing corresponding mass of extract according to the extraction rate and the dosage of medicinal materials, and adding physiological saline to prepare suspension for gastric lavage. The diazepam is converted into a mouse administration dosage according to a clinical dosage, and the corresponding solid mass is weighed to prepare a normal saline solution for intraperitoneal injection.
An experimental instrument: open field experimental box.
The experimental method comprises the following steps: after the mice are purchased, the mice are adaptively raised for one week, and are randomly divided into 3 groups according to the body weight, wherein each group comprises 10 mice, namely a solvent control group (vehicle, normal saline), a positive control group (diazepam, 3mg/kg) and a four-god pill high-dose group (22.18g/kg of crude drug mass). The treatment method comprises the following steps:
(1) the positive control group and the four-god pill high-dose group are respectively administered with corresponding drugs (20ml/kg) by single intragastric gavage, and the solvent control group is administered with equal volume of normal saline by intragastric gavage.
(2) After 40min of gastric lavage, the mouse is placed into one of 4 corner squares of an open box facing the wall, the open box is a black wooden box, the bottom paint of the box is divided into 3 white lines in length and breadth, so that 16 squares with equal size are formed, the mouse freely explores the environment for 5min, and the movement of the mouse for 5min is observed.
The experimental results are as follows: see fig. 2A and 2B.
The results show that the standing times of the mice in the administration group are obviously reduced compared with the solvent control group, and the difference has statistical significance (p is less than 0.001). The number of cross-lattice times is reduced, and the difference is not statistically significant.
The results show that the Sishen Wan extract has a central inhibition effect.
Example 3: insomnia intervention effect of Sishen pill extract on PCPA model
Experimental animals: ICR mice, male, SPF grade, 22-25g, purchased from Schbefu (Beijing) laboratory animals, Inc.
And (3) testing a sample: the prepared Sishen Wan extract is prepared by weighing corresponding mass of extract according to the extraction rate and the dosage of medicinal materials, and adding physiological saline to prepare suspension for gastric lavage. The diazepam is converted into a mouse administration dosage according to a clinical dosage, and the corresponding solid mass is weighed to prepare a normal saline solution for intraperitoneal injection.
The experimental method comprises the following steps: after the mice are purchased, the mice are adaptively raised for one week, and are randomly divided into 6 groups according to the body weight, wherein each group comprises 10 mice, namely a solvent control group (vehicle, normal saline), a positive control group (diazepam 3mg/kg, i.p.), a PCPA model group (400mg/kg, i.p.), a four-god pill high dose group (recorded as crude drug dose, 5.55g/kg), a four-god pill medium dose group (recorded as crude drug dose, 2.775g/kg) and a four-god pill low dose group (recorded as crude drug dose, 1.39 g/kg). The administration method is as follows:
(1) except for the solvent control group, mice in each group were injected with PCPA (400mg/kg, 10ml/kg) intraperitoneally for molding, and were continuously administered for three days, and after 12 hours from the last administration, 6 groups were subjected to the following pentobarbital sodium synergistic hypnotic experiment.
(2) Different dosage groups of the four-god pill are respectively administrated with corresponding medicine (20ml/kg) by single intragastric administration, and a solvent control group is administrated with equal volume of normal saline by intragastric administration. After each group was gavaged for 40min, pentobarbital sodium (42mg/kg, 5ml/kg) was intraperitoneally injected, and the mice were placed in an independent space at about 25 ℃ and the time of administration was recorded.
(3) Observing the sleep state of the mouse, recording the disappearance time of the righting reflex, namely keeping the mouse in a supine position for 60 seconds without recovering, and allowing the mouse to sleep; and recording the recovery time of the righting reflex of the mouse, namely that the mice can recover autonomously within 60 seconds, and judging that the sleep is finished if the mice are continuously turned three times. Respectively calculating sleep latency and sleep time, wherein the sleep latency is righting reflex disappearance time-administration time, and the sleep time is righting reflex recovery time-righting reflex disappearance time.
The experimental results are as follows: see fig. 3A-3B.
The results of the experiment on inducing insomnia by PCPA show that the sleep latency (time to fall asleep) of mice in the PCPA model group is remarkably prolonged (figure 3A) and the sleep duration is remarkably shortened (figure 3B) compared with the solvent control group. The positive drug diazepam and the four-god pills with various doses can obviously shorten the sleep latency of a model mouse by single administration, and have equivalent effect. The positive drug diazepam and each dose of the four-god pills can obviously prolong the sleep duration of a model mouse, wherein the single intragastric administration effect of the high dose of the four-god pills is strongest and is superior to that of the positive drug diazepam.
The result shows that the Sishen pill extract can improve the mouse insomnia caused by PCPA and has more remarkable advantage in the aspect of prolonging the sleep time.
Example 4: sleep regulation effect of Sishen pill extract
Experimental animals: SD rats, male, SPF grade, 200-250 g, purchased from Schbefu (Beijing) laboratory animals, Inc.
An experimental instrument: DSI wireless physiological signal acquisition system (Dataquest A.R.T.4.31), HD-S21 type small animal wireless physiological signal telemetering implant, and NeuroCore 3.1.1 electroencephalogram analysis software.
And (3) testing a sample: the prepared Sishen Wan extract is prepared by weighing corresponding mass of extract according to the extraction rate and the dosage of medicinal materials, and adding physiological saline to prepare suspension for gastric lavage. The diazepam is converted into a rat administration dosage according to a clinical dosage, and the corresponding solid mass is weighed to prepare a normal saline solution for intraperitoneal injection.
The experimental method comprises the following steps:
(1) implant surgery
Animals were acclimatized for one week after purchase and anesthetized by intraperitoneal injection of 10% chloral hydrate at 3 ml/kg. Skin preparation in head and neck operation area, and skin disinfection with iodophor and alcohol cotton ball after shaving. The rat is placed on a brain stereotaxic apparatus operating table in a prone position, the position of the adapter is adjusted, and the head of the rat is fixed. The skin of the head was incised longitudinally with an incision length of 2cm, the skull exposed, and the periosteum scraped off. Finding a bregma point, marking the positions of 2mm at the left and right of the bregma point by using a scalpel, drilling a hole by using a skull drill, stripping a wire sheath at the front end of the implanted sub-wire to expose a metal guide wire, bending the metal guide wire, placing the metal guide wire under the skull without penetrating through a dura mater, and recording the brain electrical activity. The main body part of the implant is placed under the skin of the back of a rat. After the operation, the wound was sutured, the rat was placed in a warm environment until awakened, and the antibiotic was intraperitoneally injected for one week continuously after the operation.
(2) Drug delivery and signal acquisition
Rats recover one week after surgery, and are randomly divided into 3 groups according to body weight, wherein each group comprises 3 animals, namely a solvent control group (normal saline), a positive control group (diazepam 3mg/kg, i.p.), and a four-god pill (5.55 g/kg in crude drug dose). After administration, each group was returned to the original feeding cage, and after 30min, the starter was opened to collect the electroencephalogram signals for 3 hours.
(3) Electroencephalographic analysis
The electroencephalogram signals are subjected to sleep scoring by using a Rodent sleep scoring module (Rodent sleep scoring module) which is defaulted by Neurosphere 3.1.1 electroencephalogram analysis software, 10s is taken as a unit, and the original signals are classified according to electroencephalogram characteristics, namely waking, active waking, slow wave sleep and out-of-phase sleep.
The experimental results are as follows: see fig. 4, 5A-5B, and 6A-6B.
FIG. 4 shows that the Sishen Wan extract can significantly increase the slow wave sleep time (p < 0.01) and decrease the waking time (p < 0.05) of rats. The results show that the four-god pill can increase the sleep time and the sleep depth of the rat.
Fig. 5A shows that the bolus extract significantly extended the average duration of the slow wave sleep segment and shortened the average duration of the wake segment. In the statistical results of fig. 5B for the number of fragments, the bolus of the four drugs simultaneously increased the number of fragments active for wakefulness, wakefulness and slow wave sleep with significant differences compared to the control group and the diazepam group. The results show that the two drugs have different characteristics of regulating the sleep structure and can possibly play a role by different mechanisms.
Fig. 6A shows that the bolus extract has a tendency to increase the total number of interconversions between sleep and wake stages. Fig. 6B shows that the bolus extract significantly increased the interconversion between wakefulness and slow wave sleep, which is absent from diazepam.
The result shows that the Sishen pill extract can increase the sleep time and the sleep depth of rats in the electroencephalogram layer, increase the number of slow wave sleep segments, prolong the duration of the slow wave sleep segments and have the sleep regulation and control effect.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (10)
1. Use of any one selected from the following items (1) to (3) for the preparation of a medicament for sedation hypnosis, treatment or prevention of insomnia, anxiolysis, or for sleep regulation:
(1) a pharmaceutical composition comprising nutmeg, fructus Psoraleae, fructus Schisandrae chinensis, fructus evodiae, fructus Jujubae, and rhizoma Zingiberis recens;
(2) an extract which is an aqueous extract and/or an ethanol extract of the pharmaceutical composition of item (1);
(3) a pharmaceutical preparation comprising the extract of item (2) and one or more pharmaceutically acceptable excipients.
2. The use according to claim 1, wherein,
the pharmaceutical composition comprises: 1-3 parts of nutmeg, 3-5 parts of fructus psoraleae, 1-3 parts of schisandra chinensis, 0.5-1.5 parts of fructus evodiae, 1-3 parts of Chinese date and 1-3 parts of ginger;
preferably, the pharmaceutical composition comprises: 1.5-2.5 parts of nutmeg, 3.5-4.5 parts of fructus psoraleae, 1.5-2.5 parts of schisandra chinensis, 0.6-1.4 parts of fructus evodiae, 1.5-2.5 parts of Chinese date and 1.5-2.5 parts of ginger;
preferably, the pharmaceutical composition comprises: 1.8-2.2 parts of nutmeg, 3.8-4.2 parts of fructus psoraleae, 1.8-2.2 parts of schisandra chinensis, 0.8-1.2 parts of fructus evodiae, 1.8-2.2 parts of Chinese date and 1.8-2.2 parts of ginger;
preferably, the pharmaceutical composition comprises: 2 parts of nutmeg, 4 parts of fructus psoraleae, 2 parts of schisandra chinensis, 1 part of fructus evodiae, 2 parts of Chinese date and 2 parts of ginger;
preferably, the pharmaceutical composition is composed of nutmeg, fructus psoraleae, fructus schizandrae, fructus evodiae, fructus jujubae and ginger.
3. The use according to any one of claims 1 to 2, wherein the extract is obtained by a preparation method comprising the steps of:
1) extracting the medicinal composition with 60-80% ethanol (preferably 70% ethanol) to obtain ethanol extract and residue;
2) extracting the residue with water to obtain water extract;
3) combining the alcohol extract and the water extract to obtain the extract.
4. The use according to claim 3, wherein in step 1) is reflux extraction;
preferably, the extraction time is 0.5-5 hours, 0.5-2 hours, or 0.2-1.5 hours;
preferably, the amount of water is 2-20 times, 2-15 times, 8-12 times or 10 times;
preferably, the aqueous extract is a thick paste obtained after concentration.
5. The use according to claim 3 or 4, wherein in step 2) is decoction;
preferably, the extraction time is 1 hour;
preferably, the amount of ethanol is 2-20 times, 2-15 times, 8-12 times or 10 times;
preferably, the alcohol extract is a thick paste obtained after concentration.
6. The use according to any one of claims 1 to 5, wherein the pharmaceutical preparation consists of the extract of item (2) as the sole active ingredient, together with one or more pharmaceutically acceptable adjuvants.
7. Use according to any one of claims 1 to 6, wherein the unit dose of the pharmaceutical preparation is 80g to 250g, 100g to 200g, 120g to 180g or 130g to 160g, calculated on the weight of the pharmaceutical composition used for preparing the extract.
8. The use of any one of claims 1 to 7, wherein the sleep management is to increase sleep time and depth, increase number of slow wave sleep segments, and/or extend duration of slow wave sleep segments.
9. A pharmaceutical formulation comprising the extract as set forth in (2) of any one of claims 1 to 8, one or more pharmaceutically acceptable excipients, and at least one compound for sedative-hypnotic activity;
preferably, the compound is selected from benzodiazepines
Compounds of the class and non-benzodiazepines
A compound of the class;
preferably, the benzodiazepine
The compound is diazepam or lorazepam;
preferably, the non-benzodiazepine
The compound is zaleplon or zopiclone.
10. A combination drug product comprising a first drug product and a second drug product packaged separately, wherein,
the first pharmaceutical product comprises the pharmaceutical formulation of any one of claims 1 to 8, item (3);
the second drug product comprises at least one compound for sedation and hypnosis, and one or more pharmaceutically acceptable excipients;
preferably, the compound is selected from benzodiazepines
Compounds of the class and non-benzodiazepines
A compound of the class;
preferably, the benzodiazepine
The compound is diazepam or lorazepam;
preferably, the non-benzodiazepine
The compound is zaleplon or zopiclone.
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