CN111420062A - Synergistic agent for benzodiazepine drugs - Google Patents

Abstract

The invention provides a synergist for benzodiazepines. Based on the experimental method, the technical scheme screened the components with potential effects on benzodiazepine receptors, and explored the interaction and synergistic relationship between each component and benzodiazepines. Experiments unexpectedly found that when ribavirin, ZSTK474, lansoprazole, erythritol, bromobenzoylfuran, methimazole, niacin, and luteolin were used in combination in a specific ratio, they could effectively reduce the risk of oxidative stress including oxa. Various benzodiazepines, including diazepam, act synergistically. Based on the above beneficial findings, the present invention constructs a synergist formula with the above components, and designs a combined use scheme of the synergist and benzodiazepines. In this scheme, the two are compounded at a very low dose, and the experiment found that the neurosedative effect did not decrease significantly, but benefited from the extremely low dose, the incidence and development of adverse reactions were significantly reduced.

Description

A kind of synergist for benzodiazepines

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a synergist for benzodiazepines.

Background technique

Benzodiazepines are derivatives of a class of benzopyrene diazepines, mainly including diazepam, fluorodiazepam, clonazepam, oxazepam, chlordiazepoxide and triazolam. These drugs are benzodiazepine receptor agonists, which can cause central nervous system depression.

In the central nervous system, there are special benzodiazepine receptors mainly in the cerebral cortex. The benzodiazepine receptor is an intramembrane component of the GABAA receptor-chloride channel complex. When GABA receptors are excited, the number of chloride ion channels open increases, and the number of chloride ions entering the cell increases, resulting in hyperpolarization to inhibit postsynaptic potential and reduce the firing of some important neurons in the center, thus acting as a center. Inhibition of the nervous system. When benzodiazepines occupy benzodiazepine receptors, GABA is more likely to open chloride channels, resulting in pharmacological effects such as sedation, hypnosis, anxiolysis, anticonvulsants, and central muscle relaxation.

Benzodiazepines have good anti-anxiety effects; they act quickly and can significantly improve patients' anxiety symptoms such as fear, tension, anxiety, restlessness, agitation and irritability. As the dose increases, it can play a sedative and hypnotic effect; it has a mild sedative effect on people, and can shorten the induction sleep time, reduce the number of awakenings at night, and prolong the sleep duration. Benzodiazepines have less effect on fast-wave sleep, so dreaminess after drug withdrawal is less common than barbiturates. At the same time, benzodiazepines have anticonvulsant effects, among which diazepam and triazolam are particularly effective, and are clinically used for adjuvant treatment of tetanus, eclampsia, febrile convulsions in children and drug toxicity convulsions. Diazepam is currently the drug of choice for status epilepticus. In addition, the clinical manifestations of benzodiazepines have strong muscle relaxant and muscle tone-reducing effects, which can relieve muscle rigidity symptoms in patients with cerebral palsy.

Although it has been proved to have relatively reliable efficacy in long-term clinical application, benzodiazepines generally have certain adverse reactions. Dizziness, drowsiness, fatigue and other reactions may occur with continuous use of the therapeutic dose, and long-acting drugs are especially prone to occur; large doses occasionally cause ataxia; excessive acute poisoning can cause coma and respiratory depression; long-term use can produce a certain tolerance; Dependence and addiction can occur. In this case, the current clinical application of such drugs is very cautious. In order to overcome the adverse reactions of such drugs, reducing the dose is the most direct and effective way. However, with the reduction of the dose, the efficacy and effective time will decrease. Then, if the dose of benzodiazepines can be reduced while maintaining their efficacy levels, it is expected to overcome the problem of adverse reactions. However, such reports have not been seen in the prior art.

SUMMARY OF THE INVENTION

The present invention aims at providing a synergistic agent for benzodiazepine drugs in view of the technical defects of the prior art, so as to solve the problem of reducing benzodiazepines when alleviating adverse reactions in the prior art. The technical problem that the efficacy of the drug decreases when the dose of the drug is reduced.

Another technical problem to be solved by the present invention is how to appropriately reduce the dose of benzodiazepines on the basis of maintaining the therapeutic effect.

Another technical problem to be solved by the present invention is how to achieve synergistic effect on benzodiazepines.

To achieve the above technical purpose, the present invention adopts the following technical solutions:

A synergist for benzodiazepines, the synergist comprises the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythritol 5 parts, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, and 1 part of luteolin; the weight ratio of the synergist and the benzodiazepines is 0.2:1.

Preferably, the synergist also includes 0.2 parts by weight of chrysin.

Preferably, the synergistic agent further includes 0.4 parts by weight of nosaccharide.

Preferably, the synergist also includes 0.7 parts by weight of PR-957.

Preferably, the synergist also includes 0.05 parts by weight of calcium dobesilate.

Preferably, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, 5 parts of erythritol, 0.2 parts of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, 1 part of luteolin, 0.2 part of chrysin, 0.4 part of nostoc polysaccharide, 0.7 part of PR-957, and 0.05 part of calcium dobesilate.

Preferably, the benzodiazepines are selected from one or several of the following components: diazepam, flurazepam, chlordiazepoxide, oxazepam, clonazepam, lorazepam , alprazolam, estazolam, triazolam, midazolam, zolpidem.

Preferably, the benzodiazepines are oxazepam; the daily doses of the synergist and oxazepam are 0.2 mg and 1 mg, respectively.

In the above technical solutions, ribavirin was originally used for viral pneumonia and bronchitis caused by respiratory syncytial virus, and skin herpes virus infection; ZSTK474 is a PI3K inhibitor, which can inhibit type I P13K subtype, and is currently mainly used for tumor Treatment; Lansoprazole can inhibit the secretion of basal gastric acid and the secretion of gastric acid in a stimulated state, so as to play a therapeutic role in gastric ulcer, duodenal ulcer, reflux esophagitis and other gastrointestinal diseases; erythritol is a A 4-carbon sugar alcohol, which is mainly used in the food industry as a sweetener at present, and has not yet been found to have neuromodulatory or sedative effects; Therefore, it reduces the concentration of uric acid in the blood, and it is mainly used for ventilation treatment before H; Conjugation of amino acid, thereby restoring the function of suppressor T cells to normal; niacin belongs to vitamin B3, which is converted into nicotinamide in the body, and is contained in the coenzyme molecule of dehydrogenase. It is a component of NAD and NADP and has a reversible Hydrogenation and dehydrogenation properties, so it plays the role of transferring hydrogen in the redox process; luteolin is a natural flavonoid compound with anti-inflammatory, anti-allergic, uric acid-lowering and other pharmacological activities. Clinically, it is mainly used for inflammation, tumor and other diseases treatment.

It can be seen that the components in the synergist of the present invention do not have a sedative effect or a central nervous system inhibitory effect within the current cognitive range, and they do not show a synergistic effect with each other, and are even used for treatment separately. different diseases. The unexpected discovery of the present invention, after the above-mentioned components are combined in a specific ratio, can play a synergistic effect on a variety of benzodiazepines including oxazepam, so that it can be achieved at a very low dose. Conventional curative effect, thereby reducing the dosage of benzodiazepines on the premise of ensuring sedative effects, has positive significance for relieving the addiction and adverse effects of benzodiazepines. It has been verified by experiments that the compound scheme of the synergist of the present invention and the benzodiazepines has definitely reduced the incidence of adverse reactions, and since the consumption of the synergist itself is relatively low, the content of each component is significant. less than their respective therapeutic doses, and thus not cause a metabolic burden.

The invention provides a synergist for benzodiazepines. The technical scheme screened the components with potential effects on benzodiazepine receptors based on experimental methods, and explored the interaction and synergistic relationship between each component and benzodiazepines. The experiment unexpectedly found that when ribavirin, ZSTK474, lansoprazole, erythritol, bromobenzoylfuran, methimazole, niacin, and luteolin were used in combination in a specific ratio, they could effectively reduce the risk of oxidative stress including oxa. Various benzodiazepines, including diazepam, act synergistically. Based on the above beneficial findings, the present invention constructs a formula of a synergist with the above components, and designs a combined use scheme of the synergist and benzodiazepines. In this scheme, the two are compounded at a very low dose. The experiment found that the neurosedative effect did not decrease significantly, but benefited from the extremely low dosage, the incidence and development of adverse reactions were significantly reduced.

Description of drawings

FIG. 1 is a graph showing the experimental results of a sleep-promoting experiment in a specific embodiment of the present invention.

FIG. 2 is a graph showing the experimental results of an anxiolytic experiment in a specific embodiment of the present invention.

Fig. 3 is a statistical structure diagram of adverse reactions in a specific embodiment of the present invention.

Detailed ways

Specific embodiments of the present invention will be described in detail below. In order to avoid unnecessary details, well-known structures or functions will not be described in detail in the following embodiments. The language of approximation used in the following examples can be used for quantitative expressions, showing that some variation in quantity is permissible without changing the basic function. Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Example 1

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, and 1 part of luteolin; the benzodiazepine drug is oxazepam, and the synergist is oxazepam. The daily doses of Shazepam are 0.2 mg and 1 mg, respectively.

Example 2

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, 1 part of luteolin, and 0.2 part of chrysin; the benzodiazepines are oxazepam, and the synergistic The daily doses of the synergist and oxazepam were 0.2 mg and 1 mg, respectively.

Example 3

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, 1 part of luteolin, and 0.4 part of nostice polysaccharide; the benzodiazepines are oxazepam, the The daily doses of the synergist and oxazepam were 0.2 mg and 1 mg, respectively.

Example 4

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of nicotinic acid, 1 part of luteolin, and 0.7 part of PR-9577; The daily doses of the synergist and oxazepam were 0.2 mg and 1 mg, respectively.

Example 5

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, 1 part of luteolin, 0.05 part of calcium dobesilate: the benzodiazepine drug is oxazepam , the daily doses of the synergist and oxazepam were 0.2 mg and 1 mg, respectively.

Example 6

A synergist for benzodiazepines, the synergist is composed of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, and erythrose 5 parts of alcohol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of niacin, 1 part of luteolin, 0.2 part of chrysin, 0.4 part of nostoc polysaccharide, 0.7 part of PR-9577, calcium dobesilate 0.05 part; the benzodiazepines are oxadipam, and the daily doses of the synergist and oxazepam are 0.2 mg and 1 mg, respectively.

Comparative Example 1

Oxazepam at a daily dose of 1 mg.

Comparative Example 2

A composition, consisting of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, 5 parts of erythritol, 0.2 parts of bromobenzofuran, 0.5 parts of methimazole part, 0.8 part of niacin, 1 part of luteolin; the daily dose of the composition is 0.2 mg.

Comparative Example 3

A composition, consisting of the following components by weight: 6 parts of ribavirin, 2 parts of ZSTK474, 3 parts of lansoprazole, 5 parts of erythritol, 0.2 parts of bromobenzofuran, 0.5 parts of methimazole part, 0.8 part of niacin, 1 part of luteolin, 0.2 part of chrysin, 0.4 part of nostoc polysaccharide, 0.7 part of PR-9577, and 0.05 part of calcium dobesilate; the daily dose of the composition is 0.2 mg.

Comparative Example 4

Ribavirin was used in combination with oxazepam at daily doses of 0.065 mg and 1 mg, respectively.

Comparative Example 5

ZSTK474 is used in combination with oxazepam at daily doses of 0.022 mg and 1 mg, respectively.

Comparative Example 6

Lansoprazole was used in combination with oxazepam at doses of 0.032 mg and 1 mg per II, respectively.

Comparative Example 7

Erythritol was used in combination with oxazepam at daily doses of 0.054 mg and 1 mg, respectively.

Comparative Example 8

Bromobenzofuran was used in combination with oxazepam at daily doses of 0.0022 mg and 1 mg, respectively.

Comparative Example 9

The daily doses of methimazole and oxazepam were 0.0054 mg and 1 mg, respectively.

Comparative Example 10

Niacin was administered in combination with oxazepam at daily doses of 0.0086 mg and 1 mg, respectively.

Comparative Example 11

Luteolin was used in combination with oxazepam at daily doses of 0.011 mg and 1 mg, respectively.

Comparative Example 12

Oxazepam at a daily dose of 15 mg.

sleep-promoting experiment

Experimental animals: ICR mice, weighing 18-22 g, grade 1. The animal room was kept at constant temperature and humidity (temperature 22°C±3°C, humidity 50%±10%), controlled by 12h circadian rhythm (8:00-20:00). Cages (440mm × 270mm × 178mm), 12 to 15 per cage, with unlimited water. Before the experiment, the animals were acclimated in the animal room for 7 days.

Experimental method: ICR mice were randomly divided into groups according to body weight, with 100 mice in each group; the doses of Examples 1 to 6 and Comparative Examples 1 to 12 were converted into the mouse dosage according to the ratio of 1:0.0026 (that is, using Examples 1 to 6 and The doses of Comparative Examples 1 to 12 were multiplied by 0.0026 to obtain the daily dose of mice), and the synergist and oxazepam were administered by intragastric administration at the same time. After administration, observe whether the mice fall asleep and record the sleep-onset latency, calculate the average sleep-onset latency of mice in each experimental group, and evaluate the relative value of the average sleep-onset latency of each experimental group by taking the average sleep-onset latency of the blank control group as 100%. The criterion for falling asleep was: place the mouse with its back down on a warm bottom, and fall asleep when the righting reflex disappears for ≥ 5 min, and not fall asleep when it is less than 5 min. The sleep latency was calculated as the time from administration to 1 min after the disappearance of the righting reflex, and the sleep time was calculated as the disappearance of the righting reflex for 1 min to the recovery of the righting reflex.

The experimental results are shown in Figure 1. The experimental results showed that after administration of the drugs of Comparative Examples 4 to 11, the average sleep latency of experimental animals was basically the same as that of Comparative Example 1. It can be seen that the combination of ribavirin, ZSTK474, lansoprazole, erythritol , brombenzoyl benzofuran, methimazole, niacin, luteolin and other ingredients when used alone with oxazepam, did not play a synergistic effect, and oxazepam still maintained its dosage conditions. level of efficacy. After the drugs of Comparative Examples 2 and 3 were administered, the average sleep-onset latency of the experimental animals was basically the same as that of the blank control group, indicating that only the synergist of the present invention or its improved formula was applied without oxazepam. No sleep-promoting effect; this shows that the synergist of the present invention only has a synergistic effect on oxazepam, and itself has no sedative effect. Comparing Comparative Examples 1, 4 to 11 with Examples 1 to 6, it was found that although the content of oxadipam in each group was the same, since Examples 1 to 6 adopted the complete synergistic formulation of the present invention, the The sleep-promoting effect of Xazepam is significantly enhanced, and its average sleep-onset latency is even basically the same as that of Comparative Example 12, while the content of oxazepam in Examples 1 to 6 is only 1/1 of the content of Oxazepam in Comparative Example 12. 15. This fully proves that the synergist of the present invention can make low-dose oxazepam exert the curative effect of conventional dose. In addition, it is worth noting that when components such as chrysin, nostice polysaccharide, PR-957, calcium dobesilate are added on the basis of the basic formula of the synergist of the present invention, although there is no synergistic effect on it However, when the above-mentioned 4 components were added simultaneously in a specific ratio (i.e., Example 6), the synergistic effect was further increased, and the sleep-promoting effect was obtained. further improvement.

Anxiety Experiment

Rats weighing 180-200 grams were taken and housed individually in hanging wire cages, and the animal room was maintained at a constant temperature (21±2°C) and humidity (50±10%). The room is lit 12 hours a day (lights on at 6 am). Rats had free access to food and water during the study period. Conduct behavioral research between 6 and 13. The test apparatus consisted of an opaque plexiglass open area (106 cm long x 92 cm wide x 50 cm high) containing a cylindrical plating chamber (14 cm long, 10 cm diameter) which was longitudinally adjacent to an inner wall with the open end 40 cm from the corner. The open area was illuminated with 60 watt incandescent bulbs, and the lighting was adjusted with an adjustable transformer so that the brightness at the entrance to the cylinder was 231ux. Rats are accustomed to the handling by stroking the surface of the back for approximately 1 minute per day for 5-6 consecutive days prior to testing. To elicit an exploratory behavioral test in this unfamiliar environment, each rat was placed inside a cylinder and then safely reached the bottom. In the adjacent room, 10 trained observers evaluated their behaviors through video monitors for 15 minutes, and evaluated whether the experimental rats were anxious one by one. 100 rats were randomly selected from each experimental group. For the same experimental group, each observer The proportion of anxious individuals in the total number of the experimental group is given respectively, and the average value is taken as the incidence of anxiety state in the experimental group.

After testing each rat, the plexiglass chamber and cylinder were cleaned with 1.0% glacial acetic acid to prevent olfactory cues from affecting the behavior of subsequently tested rats. The doses of Examples 1 to 6 and Comparative Examples 1 to 12 are converted into the dosage of mice according to the ratio of 1:0.0026 (that is, the doses of Examples 1 to 6 and Comparative Examples 1 to 12 are multiplied by 0.0026 respectively to obtain the mouse dosage. The daily dose), the synergist and oxadipam were administered by intragastric administration at the same time; the administration time was 20-60 minutes before the behavioral test, and all the drugs were administered by intragastric administration.

The experimental results are shown in Figure 2. The experimental results showed that on the basis of low-dose oxazepam, ribavirin, ZSTK474, lansoprazole, erythritol, bromobenzofuran, methimazole, niacin, luteolin were introduced respectively. and other components will not play a synergistic effect (Comparative Examples 1, 4-11). Simply giving the synergist did not show any sedative effect (blank control, comparative examples 2 and 3). On the basis of low-dose oxazepam, the synergistic agent of the present invention can be given, which can play a significant synergistic effect (Examples 1-6, Comparative Example 12). On the basis of the synergist of the present invention, only when the characteristic doses of chrysin, nostoc polysaccharide, PR-957 and calcium dobesilate are introduced, the synergistic effect can be improved (Examples 1-6). The above experimental results and the sleep-promoting experimental results show similar directivity, thereby proving that the present invention has a synergistic effect on the sedative efficacy of oxazepam.

Adverse Reaction Statistics

For the animals used in the above sleep-promoting experiments and anti-anxiety experiments, the doses in the experiments were continued to be administered for 10 months, and the incidence of adverse reactions during this process was calculated.

The experimental results are shown in Figure 3. The experimental results show that under the conditions of long-term administration of low-dose oxazepam (Examples 1 to 6, Comparative Examples 1, and Comparative Examples 4 to 11), compared with those without oxazepam (blank control, Comparative Example 2). , Comparative Example 3) The incidence of adverse reactions is almost the same, and there are basically no adverse reactions cases, which is in sharp contrast with the incidence of adverse reactions brought about by the conventional dose of oxazepam (Comparative Example 12). This shows that the dosage reduction scheme of the present invention is indeed effective for alleviating adverse reactions, and the problem of adverse reactions is basically overcome under the dosage conditions.

The embodiments of the present invention have been described in detail above, but the above contents are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the scope of the application of the present invention shall be included within the protection scope of the present invention.

Claims (8)

1. A synergistic agent for benzodiazepine drugs is characterized by comprising the following components in parts by weight: 6 parts of ribavirin, 4742 parts of ZSTK, 3 parts of lansoprazole, 5 parts of erythritol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of nicotinic acid and 1 part of luteolin; the weight ratio of the synergistic agent to the benzodiazepine drug is 0.2: 1.

2. The synergist for benzodiazepine drug of claim 1, further comprising 0.2 weight part of chrysin.

3. The synergistic agent for benzodiazepines drugs according to claim 1, which further comprises 0.4 parts by weight of nostoc flagelliforme polysaccharide.

4. The synergist for benzodiazepine drug of claim 1, further comprising 0.7 weight part of PR-957.

5. The synergist for benzodiazepine drug of claim 1, which further comprises 0.05 weight part of calcium dobesilate.

6. The synergistic agent for benzodiazepines drugs according to claim 1, which is characterized by comprising the following components in parts by weight: 6 parts of ribavirin, 4742 parts of ZSTK, 3 parts of lansoprazole, 5 parts of erythritol, 0.2 part of bromobenzoyl benzofuran, 0.5 part of methimazole, 0.8 part of nicotinic acid, 1 part of luteolin, 0.2 part of chrysin, 0.4 part of hairy moss polysaccharide, PR-9570.7 parts and 0.05 part of calcium dobesilate.

7. The synergistic agent for benzodiazepine drugs as claimed in claim 1, wherein said benzodiazepine drug is selected from one or several of the following components: diazepam, flurazepam, chlordiazepoxide, oxazepam, clonazepam, lorazepam, alprazolam, estazolam, triazolam, midazolam, zolpidem.

8. The synergistic agent for benzodiazepines drugs of claim 1, wherein said benzodiazepine drug is oxazepam; the daily doses of the synergistic agent and the oxazepam are 0.2mg and 1mg respectively.

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