CN114272381A - Application of M-type cholinergic receptor agonist and medicine for relieving polydipsia symptoms - Google Patents
Application of M-type cholinergic receptor agonist and medicine for relieving polydipsia symptoms Download PDFInfo
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Abstract
The invention relates to application of an M-type cholinergic receptor agonist and a medicine for relieving polydipsia symptoms. The research finds that the M-type cholinergic receptor agonist can relieve the symptoms of polydipsia, such as polydipsia caused by diabetes insipidus and polydipsia caused by psychotropic drugs. After standard, scientific and rigorous tests and pharmacological experiments are carried out, the application of the M-type cholinergic receptor stimulant in preparing the medicine for relieving the polydipsia symptoms is provided. The research combines a mental disease treatment drug and an M-type cholinergic receptor agonist into a new drug, can relieve polydipsia symptoms, diabetes insipidus and the like caused by using the mental disease treatment drug while treating the mental disease, relieves the symptoms of polydipsia and diuresis of a patient, and reduces the risk of kidney injury.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of an M-type cholinergic receptor agonist and a medicine for relieving polydipsia symptoms.
Background
Diabetes Insipidus (DI) is a group of clinical syndromes in which Arginine Vasopressin (AVP), also known as antidiuretic hormone (ADH), is deficient to varying degrees due to hypothalamic-neurohypophyseal lesions, or the kidney is deficient in sensitivity to AVP due to multiple lesions, resulting in dysfunction of the tubules to reabsorb water. The former is Central Diabetes Insipidus (CDI) and the latter is renal diabetes insipidus (NDI), which is clinically characterized by polyuria, polydipsia, low specific gravity urine or hyposmosis. Among them, Central Diabetes Insipidus (CDI) is a clinical syndrome that occurs after decreased vasopressin (AVP, also known as antidiuretic hormone) secretion, mainly due to neuronal damage in the hypothalamus and pituitary. The inability to concentrate urine, due to the decreased reabsorption of urine by the tubules and collecting ducts due to the deficiency of antidiuretic hormones, leads to the discharge of large amounts of dilute urine with compensatory thirst, a heterogeneous disease characterized by polyuria and polydipsia.
Over the last several decades, the treatment of central diabetes insipidus has not changed significantly, and desmopressin (dDAVP) and a deficiency in replacement free water remain the cornerstones of treatment. Oral administration of dDAVP has replaced nasal dDAVP as a more reliable way to treat chronic central diabetes insipidus. In most cases of diabetes insipidus, osmotically regulated thirst is complete and intake of fluid accurately compensates for kidney water loss. Thus, patients often develop anemia even before treatment with desmopressin. Desmopressin therapy is primarily aimed at relieving the symptoms of polyuria, nocturia and related thirst. However, in situations where the patient does not have access to water, such as in fasting or intraoperative conditions, hypernatremia can occur quickly. If emesis complicates the disease, the situation becomes even more acute because both fluid intake and desmopressin administration are affected.
In addition to organic diabetes insipidus caused by hypothalamic dysfunction, a considerable proportion of drugs for treating psychiatric disorders, such as depressive drugs, psychiatric drugs or antiepileptic drugs, also induce central diabetes insipidus with secondary hyponatremia. This is one of the side effects of many psychotropic drugs.
In general, few studies on central diabetes insipidus treatment drugs are currently available, and few treatment drugs are available for clinical selection, especially few studies on drugs for relieving polydipsia symptoms are available; furthermore, diabetes insipidus induced by psychotropic drugs has not received attention.
Disclosure of Invention
The research finds that the M-type cholinergic receptor agonist can relieve the symptoms of polydipsia, such as polydipsia caused by diabetes insipidus and polydipsia caused by psychotropic drugs. After standard, scientific and rigorous tests and pharmacological experiments are carried out, the application of the M-type cholinergic receptor stimulant in preparing the medicine for relieving the polydipsia symptoms is provided. In addition, a medicament for relieving the symptoms of polydipsia is also provided.
Tests prove that the phenomenon of animal diabetes insipidus and drinking water increase disappears when the experimental animals are jointly taken with the anti-mental disease medicament lithium chloride and the M-type cholinergic receptor agonist pilocarpine, which indicates that the M-type cholinergic receptor agonist can relieve polydipsia symptoms, diabetes insipidus and polydipsia polyuria, especially the polydipsia symptoms, the diabetes insipidus and the polydipsia polyuria caused by the anti-mental disorder medicament.
In one embodiment, the polydipsia symptoms are polydipsia symptoms caused by diabetes insipidus. Specifically, the polydipsia symptoms are polydipsia symptoms caused by central diabetes insipidus.
In one embodiment, the drug for relieving polydipsia symptoms is a drug for relieving polydipsia caused by diabetes insipidus.
In one embodiment, the diabetes insipidus is diabetes insipidus induced by a psychiatric drug.
In one embodiment, the polydipsia symptoms are polydipsia symptoms induced by a psychiatric medication.
In one embodiment, the psychiatric medication comprises at least one of an anti-schizophrenia medication, an anti-mania medication and an antidepressant medication.
In one embodiment, the antimanic drug comprises an antimanic drug comprising a lithium salt.
In one embodiment, the anti-schizophrenia drug comprises at least one of chlorpromazine, olanzapine, quetiapine, haloperidol, clozapine.
In one embodiment, the antidepressant drug comprises at least one of amitriptyline, sertraline, and fluoxetine.
In one embodiment, the M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine.
A medicament for relieving polydipsia symptoms comprises an M-type cholinergic receptor agonist.
In one embodiment, the pharmaceutical composition further comprises a psychotropic medication, and the dosage ratio of the psychotropic medication to the M-type cholinergic receptor agonist is 300:1-3: 1.
In one embodiment, the psychiatric medication comprises at least one of an anti-schizophrenia medication, an anti-mania medication and an antidepressant medication.
In one embodiment, the antimanic drug comprises an antimanic drug comprising a lithium salt.
In one embodiment, the antimanic drug comprises at least one of lithium carbonate and a lithium salt-containing drug.
In one embodiment, the anti-schizophrenia drug comprises at least one of chlorpromazine, olanzapine, quetiapine, haloperidol, clozapine.
In one embodiment, the antidepressant drug comprises at least one of amitriptyline, sertraline, and fluoxetine.
In one embodiment, the M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine.
In one embodiment, the medicament for relieving polydipsia symptoms comprises pilocarpine and lithium chloride in a dosage ratio of 1:300 to 1: 3.
In one embodiment, the concentration of the M-type cholinergic receptor agonist is 1mg/kg to 100 mg/kg.
In one embodiment, the psychiatric disorder treatment agent is a lithium ion-containing antimanic agent at a concentration of 0.3mM to 0.8 mM.
Drawings
FIG. 1a is a graph comparing the water intake of the groups of mice of example 1;
FIG. 1b is a graph showing a comparison of food consumption of the groups of mice of example 1;
FIG. 1c is a graph comparing the caloric production of groups of mice from example 1;
FIG. 1d is a graph comparing the activity levels of the groups of mice of example 1.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
One embodiment of the present study provides the use of an M-type cholinergic receptor agonist in the preparation of a medicament for alleviating symptoms of polydipsia.
A cholinergic receptor agonist is a drug that binds to a cholinergic receptor and produces a similar effect to the transmitter acetylcholine. The M-type cholinergic receptor agonist mainly comprises choline esters and alkaloids. Choline esters, such as acetylcholine, have a major role in vasodilation, slowing heart rate, slowing atrioventricular node and purkinje fiber conductance, and weakening myocardial contractility. Alkaloids such as pilocarpine have effects of miosis, lowering intraocular pressure, and regulating spasm.
The present study found that the M-type cholinergic receptor agonist is capable of alleviating symptoms of polydipsia, such as polydipsia caused by diabetes insipidus, and found that it is useful in combination with a therapeutic agent for mental disease for alleviating symptoms of polydipsia caused by the use of a therapeutic agent for mental disease. After standard, scientific and rigorous tests and pharmacological experiments are carried out, the application of the M-type cholinergic receptor stimulant in preparing the medicine for relieving the polydipsia symptoms is provided. Experiments prove that the phenomenon of diabetes insipidus and drinking water increase of animals disappears when the experimental animals are jointly administered with the anti-mental disease medicament lithium chloride and the M-type cholinergic receptor agonist pilocarpine, which indicates that the M-type cholinergic receptor agonist can relieve the diabetes insipidus and polydipsia, and particularly relieve the polydipsia symptoms, diabetes insipidus and polydipsia polyuria caused by the anti-mental disorder medicament.
The symptom of polydipsia is the symptom of dysphoria and thirst. The predominant manifestation of polydipsia is increased drinking. It should be noted that the M-type cholinergic receptor agonist is not limited to relieve the polydipsia symptoms caused by diabetes insipidus and those caused by psychotropic drugs, but can also be used for relieving polydipsia symptoms caused by other reasons.
Wherein the polydipsia symptoms are polydipsia symptoms caused by diabetes insipidus. Specifically, diabetes insipidus is central diabetes insipidus.
Wherein, the medicament for relieving the polydipsia symptoms is also used for relieving polydipsia caused by diabetes insipidus. The medicine for relieving the polydipsia symptoms can also relieve the symptoms of polydipsia and diuresis of patients and reduce the risk of kidney injury of the patients.
Wherein the diabetes insipidus is diabetes insipidus caused by psychotropic drugs. Specifically, diabetes insipidus is central diabetes insipidus.
Wherein the polydipsia symptoms are polydipsia symptoms caused by psychotropic drugs.
In one embodiment, the psychiatric medication comprises at least one of an anti-schizophrenia medication, an anti-mania medication and an antidepressant medication.
Wherein the antimanic drug comprises an antimanic drug comprising a lithium salt. Specifically, the antimanic drug comprises at least one of lithium carbonate and lithium chloride. The lithium carbonate mainly plays a pharmacological role of lithium ions, the treatment dosage has no obvious influence on the mental behaviors of normal people, and the lithium salt has obvious effect on treating the symptoms of the mental disorders such as mania and the like. Here, the antimanic drug is exemplified as a clinically common antimanic drug, and the antimanic drug is not limited to lithium carbonate and lithium chloride, and may be other antimanic drugs.
The anti-schizophrenia drug comprises at least one of chlorpromazine, olanzapine, quetiapine, haloperidol and clozapine. Here, the anti-schizophrenia drug is not limited to chlorpromazine, olanzapine, quetiapine, haloperidol, clozapine, but may be other anti-schizophrenia drugs.
The antidepressant drug comprises at least one of amitriptyline, sertraline and fluoxetine. It should be noted that, the antidepressant drugs commonly used in clinic are listed here, and the antidepressant drugs are not limited to amitriptyline, sertraline and fluoxetine, but may be other antidepressant drugs.
In one embodiment, the M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine. Wherein pilocarpine is a clinically common M-type cholinergic receptor agonist.
Based on the above applications, one embodiment of the present study further provides a drug for alleviating the symptoms of polydipsia, including an M-type cholinergic receptor agonist.
The present study found that the M-type cholinergic receptor agonist is capable of alleviating symptoms of polydipsia, such as polydipsia caused by diabetes insipidus, and found that it is useful in combination with a therapeutic agent for mental disease for alleviating symptoms of polydipsia caused by the use of a therapeutic agent for mental disease.
In one embodiment, the M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine. Further, the M-type cholinergic receptor agonist is pilocarpine. Pilocarpine is a clinically common M-type cholinergic receptor agonist.
Wherein, the concentration of the M-type cholinergic receptor stimulant is 1 mg/kg-100 mg/kg. At this concentration, the M-type cholinergic receptor agonist has better effect of relieving polydipsia and diabetes insipidus.
In one embodiment, the medicament for relieving symptoms of polydipsia further comprises a psychiatric treatment. The dosage ratio of the psychotropic therapeutic drug to the M-type cholinergic receptor agonist is 300:1-3: 1. the research combines a mental disease treatment drug and an M-type cholinergic receptor agonist into a new drug, can relieve polydipsia symptoms, diabetes insipidus and the like caused by using the mental disease treatment drug while treating the mental disease, relieves the symptoms of polydipsia and diuresis of a patient, and reduces the risk of kidney injury.
Wherein the mental disease treatment drug comprises at least one of an anti-schizophrenia drug, an anti-mania drug and an antidepressant drug.
Specifically, the antimanic drug includes an antimanic drug containing a lithium salt. Further, the antimanic drug includes at least one of lithium carbonate and lithium chloride. The lithium carbonate mainly plays a pharmacological role of lithium ions, the treatment dosage has no obvious influence on the mental behaviors of normal people, and the lithium salt has obvious effect on treating the symptoms of the mental disorders such as mania and the like. Here, the antimanic drug is exemplified as a clinically common antimanic drug, and the antimanic drug is not limited to lithium carbonate and lithium chloride, and may be other antimanic drugs.
The anti-schizophrenia drug comprises at least one of chlorpromazine, clozapine and sulpiride. It should be noted that the examples of the anti-schizophrenia drug are commonly used in clinical practice, and the anti-schizophrenia drug is not limited to chlorpromazine, clozapine or sulpiride, and may be other anti-schizophrenia drugs.
Antidepressants include imipramine. Here, antidepressant drugs that are commonly used in clinical practice are listed, and the antidepressant drugs are not limited to imipramine, and may be other antidepressant drugs.
In one embodiment, the medicament for relieving symptoms of polydipsia comprises an antimanic medicament comprising lithium ions and pilocarpine. The dose ratio of the antimanic drug containing lithium ions to the pilocarpine is 300: 1-3:1. According to the proportion, the effect of lithium salt medicines on treating mental diseases can be exerted to a large extent, and the effect of M-type cholinergic receptor agonist on relieving polydipsia and diabetes insipidus can be improved.
Further, the dose ratio of the antimanic drug containing lithium ions to the pilocarpine is 300: 1-3:1. According to the proportion, the effect of lithium salt medicines on treating mental diseases can be exerted to a large extent, and the effect of M-type cholinergic receptor agonist on relieving polydipsia and diabetes insipidus can be improved. In one particular example, the dose ratio of antimanic drug containing lithium ions to pilocarpine is 1: 1.
Further, the concentration of the antimanic drug containing lithium ions is 0.3mM to 0.8 mM. The concentration of pilocarpine is 1 mg/kg-100 mg/kg. The concentration of the drug for treating mental diseases is not limited to the above concentration, and may be adjusted according to the actual therapeutic effect.
In one particular example, the antimanic drug containing lithium ions is lithium chloride. The dosage ratio of lithium chloride to pilocarpine is 300: 1-3:1. Specifically, the dosage ratio of lithium chloride to pilocarpine is 1: 1.
in one embodiment, the medicament for relieving the symptoms of polydipsia is administered orally or intraperitoneally. Wherein pilocarpine and lithium carbonate can be absorbed rapidly by oral administration.
The present study was able to alleviate the symptoms of polydipsia, for example, polydipsia caused by diabetes insipidus, by preparing a drug for alleviating the symptoms of polydipsia from an M-type cholinergic receptor agonist, and found that it can be used to alleviate the symptoms of polydipsia caused by the use of a psychotropic treatment drug in combination with a psychotropic treatment drug.
Furthermore, the study combines a psychotropic drug and an M-type cholinergic receptor agonist into a new drug, can relieve polydipsia symptoms, diabetes insipidus and the like caused by the psychotropic drug while treating the psychotropic, relieves the symptoms of polydipsia and diuresis of patients, and reduces the risk of kidney injury.
The following are specific examples.
Reagents and instruments used in the examples are all conventional in the art and are not specifically described. The experimental procedures, in which specific conditions are not indicated in the examples, are usually carried out according to conventional conditions, such as those described in the literature, in books, or as recommended by the manufacturer of the kits. The reagents used in the examples are all commercially available.
Example 1:
animal behavioral experiments: the drinking water and activity of the metabolism cage are detected, and the intervention time window is found out by detecting the time of drinking water peak after single or multiple times of administration through animal behavior experiments. Animals are forbidden to water in a metabolism cage for 24 hours in advance according to experimental groups to establish a thirst model, different drugs to be detected are injected into the abdominal cavity of the mouse on time after the water-forbidden time is reached, and then the mouse is placed in the metabolism cage immediately to detect the water intake and food intake of the mouse in the 1 st hour, the activity of the mouse in the horizontal (x axis and y axis) and the longitudinal axis (z axis) and the like, so that the effects of the different drugs to be detected are comprehensively analyzed, and a corresponding mechanism is discussed.
The specific experimental process is as follows:
1. materials for experiments:
the experimental animals were mice of the C57 strain (hermaphrodite halves) aged about 8 weeks and weighing about 25 g.
The first drug consisted of pilocarpine and lithium chloride in a 1:1 dosage ratio, with a pilocarpine concentration of 1mg/kg and a LiCl (i.e., lithium chloride) concentration of 0.154 mol/L.
The second drug consisted of pilocarpine and lithium chloride in a 1:1 dosage ratio, with a pilocarpine concentration of 10mg/kg and a LiCl (i.e., lithium chloride) concentration of 0.154 mol/L.
The administration mode of the medicine is intraperitoneal injection, and 0.3mL of the medicine is administered to C57 mice with the weight of about 25 g.
2. Experimental grouping and experimental procedure:
(i) experimental procedure for group: the C57 mice are forbidden to take water for 24h and are injected with 0.3mL of normal saline intraperitoneally at a rhythm point after 24h, the mice are immediately placed back into a metabolism cage after injection, and the water intake, food intake, activity and average calorie of the mice within 1h after injection are monitored by the metabolism cage.
(ii) Experimental procedure for group: c57 mice were deprived of water for 24h and normally fed with food, and 24h later, 0.154mol/L LiCl 0.3 mL/mouse was intraperitoneally injected at the rhythm point, and immediately returned to the metabolism cage after injection, and the water intake, food intake, activity and average calorie of the mice were monitored by the metabolism cage within 1h after injection. (ii) The group was lithium chloride for single administration of the anti-psychotic drug.
(iii) Experimental procedure for group: c57 mice were deprived of water for 24h and normally fed with food, and after 24h, were injected intraperitoneally with 0.3 mL/mouse of an equivalent mixed solution of physiological saline and 0.4mol/L pilocarpine at a rhythm point, and immediately returned to the metabolism cage after injection, and the water intake, food intake, activity and average calorie of the mice within 1h after injection were monitored by the metabolism cage.
(iv) Experimental procedure for group: c57 mice were deprived of water for 24h and normally fed with food, and 24h later were intraperitoneally injected with 0.3mL of an equivalent mixed solution of 0.154mol/L LiCl and 0.4mol/L pilocarpine at a rhythm point, and immediately returned to the metabolism cage after injection, and the water intake, food intake, activity and average calorie of the mice within 1h after injection were monitored by the metabolism cage. (iv) The composition is a combined medicine: the anti-psychotic drug lithium chloride and the M choline receptor agonist pilocarpine.
The test results are shown in FIGS. 1 a-1 d. FIG. 1a is a comparison of the water intake of the groups of mice of example 1, with the horizontal axis representing the groups of mice and the vertical axis representing the water intake. FIG. 1b is a graph showing the comparison of the food intake of each group of mice in example 1, wherein the abscissa represents the group of mice and the ordinate represents the food intake. FIG. 1c is a comparison of the heat production of the groups of mice of example 1, with the mice grouped on the abscissa and the heat production on the ordinate. FIG. 1d is a graph showing a comparison of the activity levels of the groups of mice in example 1, wherein the abscissa represents the groups of mice and the ordinate represents the activity level.
As can be seen from FIGS. 1a to 1d, the combined administration of lithium chloride and pilocarpine can eliminate the symptoms of polydipsia, diabetes insipidus and increased drinking water in animals, which indicates that pilocarpine can relieve the symptoms of polydipsia, diabetes insipidus and polydipsia, especially those caused by anti-psychotic drugs.
In conclusion, the present study was able to alleviate the symptoms of polydipsia, such as polydipsia caused by diabetes insipidus, by preparing a drug for alleviating the symptoms of polydipsia from an M-type cholinergic receptor agonist, and found that it can be used to alleviate the symptoms of polydipsia caused by the use of a psychotropic treatment drug in combination with a psychotropic treatment drug. Moreover, the psychotropic medication and the M-type cholinergic receptor stimulant are combined into a new medicine, so that the psychotropic medication can relieve polydipsia symptoms, diabetes insipidus and the like caused by using the psychotropic medication, relieve the symptoms of polydipsia and diuresis of patients and reduce the risk of kidney injury while treating the psychotropic medication.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (15)
- Use of an M-type cholinergic receptor agonist in the preparation of a medicament for alleviating a symptom of polydipsia.
- 2. The use according to claim 1, wherein the polydipsia symptoms are polydipsia symptoms caused by central diabetes insipidus.
- 3. The use according to claim 2, wherein the medicament for relieving polydipsia symptoms is also used for relieving polydipsia caused by diabetes insipidus.
- 4. The use according to claim 2, wherein said diabetes insipidus is diabetes insipidus induced by a psychotropic agent.
- 5. The use according to claim 1, wherein the polydipsia symptoms are polydipsia symptoms induced by psychotropic drugs.
- 6. The use according to any one of claims 4 to 5, wherein the therapeutic agent for a psychotic disorder comprises at least one of an anti-schizophrenia drug, an anti-mania drug and an anti-depressant drug.
- 7. The use of claim 6, wherein the antimanic drug comprises an antimanic drug comprising a lithium salt;and/or the anti-schizophrenia drug comprises at least one of chlorpromazine, olanzapine, quetiapine, haloperidol and clozapine;and/or the antidepressant drug comprises at least one of amitriptyline, sertraline and fluoxetine.
- 8. The use according to any one of claims 1 to 5 or 7, wherein said M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine.
- 9. A medicament for the relief of polydipsia symptoms comprising an M-type cholinergic receptor agonist.
- 10. The agent for relieving polydipsia according to claim 9, further comprising a psychiatric treatment agent, wherein the dosage ratio of said psychiatric treatment agent to said M-type cholinergic receptor agonist is 300:1-3: 1.
- 11. The medicament for relieving polydipsia according to claim 10, wherein said psychotropic treatment drug comprises at least one of an anti-schizophrenia drug, an anti-mania drug and an antidepressant drug.
- 12. The medicament for relieving symptoms of polydipsia according to claim 11, wherein said antimanic medicament comprises an antimanic medicament comprising lithium ions;and/or the anti-schizophrenia drug comprises at least one of chlorpromazine, olanzapine, quetiapine, haloperidol and clozapine;and/or the antidepressant drug comprises at least one of amitriptyline, sertraline and fluoxetine.
- 13. The agent for relieving symptoms of polydipsia according to any one of claims 9-12, wherein said M-type cholinergic receptor agonist is selected from at least one of acetylcholine, methacholine, and pilocarpine.
- 14. The medicament for relieving the symptoms of polydipsia according to claim 13, wherein said medicament for relieving the symptoms of polydipsia comprises pilocarpine and lithium chloride in a dosage ratio of 1: 300-1:3.
- 15. The medicament for relieving polydipsia according to claim 13, wherein the concentration of said M-type cholinergic receptor agonist is 1mg/kg to 100 mg/kg;and/or, the therapeutic agent for a psychiatric disease is an antimanic agent containing lithium ions at a concentration of 0.3mM to 0.8 mM.
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