CN111374980A - Application of pyrazinamide and flumazenil in preparation of anticonvulsant medicine - Google Patents
Application of pyrazinamide and flumazenil in preparation of anticonvulsant medicine Download PDFInfo
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- CN111374980A CN111374980A CN202010189204.XA CN202010189204A CN111374980A CN 111374980 A CN111374980 A CN 111374980A CN 202010189204 A CN202010189204 A CN 202010189204A CN 111374980 A CN111374980 A CN 111374980A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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Abstract
The invention provides an application of pyrazinamide and flumazenil in preparation of an anticonvulsant drug. The technical scheme is based on experimental means research and discovers that when pyrazinamide and flumazenil are combined according to a specific proportion, severe symptoms in the convulsion morbidity process can be effectively relieved. On the basis, the invention researches the pharmacological action principle, and experiments show that although the combination of pyrazinamide and flumazenil has no effect on neurotransmitters when a single medicine is used, under the combined condition of the invention, the AMPA receptor activity and the NMDA receptor activity are obviously inhibited, and the invention has exact curative effects of reducing excitatory postsynaptic current and relieving delayed damage of nerve cells. Based on the beneficial findings, the invention determines the new application of the combination of pyrazinamide and flumazenil in preparing the anticonvulsant drug, not only widens the optional range of the anticonvulsant drug, but also expands the medical application of the pyrazinamide and the flumazenil, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, and further relates to a novel medical application of a substance, in particular to an application of combination of pyrazinamide and flumazenil in preparation of an anticonvulsant medicine.
Background
Convulsions (convulsion) are commonly called cramps, convulsions, also called tetany. It is manifested as paroxysmal twitching of limbs and facial muscles, usually accompanied by up-turning of the eyes, staring or strabismus, and unclear consciousness. Sometimes accompanied by white foam in mouth or dragging of mouth corner, apnea, and bluish purple complexion, the attack time is more than 3-5 minutes, and the attack sometimes occurs repeatedly, even in a continuous state.
Convulsions are acute and serious diseases mainly characterized by rhythmic movement of limbs and coma, and can occur in any season. Transient tics in general have little if any significant effect on the brain, but long-term tics, especially persistent states, can lead to permanent nervous system damage. Convulsion can be accompanied by heat or not accompanied by heat, wherein the heat accompanied by heat is mostly caused by infectious diseases, and intracranial infectious diseases commonly include meningitis, brain abscess, encephalitis, cerebral parasitosis and the like; extracranial infectious diseases are often febrile convulsion and various serious infections (such as toxic bacillary dysentery, toxic pneumonia, septicemia, etc.). The non-heat accompanied diseases are mostly caused by non-infectious diseases, and besides common epilepsy, the diseases also include water and electrolyte disorder, hypoglycemia, drug poisoning, food poisoning, hereditary metabolic diseases, brain trauma, cerebroma, etc.
Anticonvulsants are a class of drugs that clinically combat or relieve pathological hyperexcitability states in the central nervous system, eliminating or relieving involuntary strong contractions of the skeletal muscles of the whole body. Commonly used are magnesium sulfate injection, barbiturates, chloral hydrate and the like. Magnesium sulfate solution is injected, absorbed magnesium ions can inhibit central nervous system, however, adverse reaction is serious, blood magnesium accumulation can occur, muscle excitability can be inhibited when the blood magnesium concentration reaches 5mmol/L, sensory reaction is slow, knee tendon reflex disappears, respiration starts to be inhibited, respiration can stop and arrhythmia can occur when the blood magnesium concentration reaches 6mmol/L, cardiac conduction block can occur, the concentration is further increased, and heartbeat can stop. Barbiturates mainly comprise sodium phenobarbital and sodium phenytoin, and have the effect of resisting epilepsy by stabilizing the function of brain cell membranes and increasing the effects of inhibitory neurotransmitters 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) in brain to prevent the propagation of abnormal discharge; these herbs have strong sedative effect, but they should be used with cautions clinically because they can cause mental problems such as behavioral changes, clumsiness, gait instability, confusion, slurred pronunciation, trembling hands, and nervousness. Chloral hydrate can be used as hypnotic and anticonvulsant for treating insomnia, dysphoria and convulsion; however, it may inhibit myocardial contractility, shorten the refractory period of the myocardium, and inhibit the respiratory and vasomotor centers of medulla oblongata; moreover, the health organization in 2017 has listed the cancer causing substance as class 2A, so that the cancer causing substance should be avoided as much as possible in clinic.
Pyrazinamide is also called as carbamoylpyrazine or isonicotinamide, is a derivative of nicotinamide, has a specific killing effect on mycobacterium tuberculosis, particularly under a lower pH environment, permeates into phagocytes and enters into mycobacterium tuberculosis, and amidase in the mycobacterium tuberculosis removes acylamino of the pyrazinamide, converts the pyrazinic acid into pyrazinoic acid and plays an antibacterial role; moreover, pyrazinamide is similar to nicotinamide in chemical structure, and can interfere dehydrogenase by substituting nicotinamide, prevent dehydrogenation, prevent oxygen utilization of mycobacterium tuberculosis, influence normal metabolism of bacteria, and cause death. In the prior art, pyrazinamide is only used for treating tuberculosis, and no report related to the fact that pyrazinamide has a nerve regulation function is found.
Flumazenil is a selective benzodiazepine antagonist and is mainly used for rescuing benzodiazepine drug poisoning and ethanol poisoning. The research of using the compound as an anticonvulsant medicine is not seen in the prior art; furthermore, prior art studies suggest that flumazenil, due to its chemical structure close to that of benzodiazepines, partially antagonizes the anticonvulsant effect of sodium valproate.
Disclosure of Invention
The invention aims to provide the application of the combination of pyrazinamide and flumazenil in preparing an anticonvulsant drug aiming at the technical defects of the prior art so as to solve the technical problem of serious adverse reaction of the anticonvulsant drug in the prior art.
Another technical problem to be solved by the present invention is how to further improve the anticonvulsant effect of the drug.
The invention also aims to solve the technical problem of how to expand the medical application of pyrazinamide and flumazenil.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the application of the combination of pyrazinamide and flumazenil in preparing anticonvulsant medicaments.
Preferably, the mass ratio of pyrazinamide to flumazenil is 1: 7.
Preferably, the medicament also comprises midazolam, fentanyl citrate and propofol.
Preferably, the medicine comprises the following components in parts by weight: 10 parts of pyrazinamide, 70 parts of flumazenil, 3 parts of midazolam, 1 part of fentanyl citrate and 2 parts of propofol.
Preferably, the effective dose of pyrazinamide in the medicament is 2mg/kg d.
Preferably, the effective dose of flumazenil in the medicament is 14mg/kg d.
Preferably, the drug inhibits aberrant discharge of cortical neurons.
Preferably, the agent inhibits AMPAR activity and inhibits rapid excitatory synaptic transmission in the central nervous system.
Preferably, the agent inhibits NMDA receptor activity.
Preferably, the medicament is in the form of injection.
In the above technical scheme, AMPA receptors (α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, AMPARs) mediate central nervous system rapid excitatory synaptic transmission, whose dynamic expression in the postsynaptic membrane is associated with the induction and maintenance of long-term potentiation, long-term inhibition, and participation in regulating learning and memory activities.
The NMDA receptor (N-methyl-D-aspartic acid receptor), which is a subtype of the ionotropic glutamate receptor, plays important physiological roles in the development of the nervous system, such as the regulation of the survival of neurons, the regulation of the development of dendrites and axon structures of neurons, the participation in the formation of synaptic plasticity, and the like. NMDA receptors and cation channels are predominantly Mg2+The channels are coupled to form NMDA receptor-ion channel complexes. Extracellular Mg at normal resting membrane potential2+Blocking the NMDA response. Activation of NMDA receptors requires excitatory neurotransmitters and depolarization of the postsynaptic membrane, in a depolarized state, Mg2+The blocking effect of (3) is released. When GABA inhibition function is disordered, the sensitivity of neurons to GABA transmitters is reduced, excitatory amino acid synthesis and release are increased, the activity of NMDA receptors is increased, and under the environment, one neuron discharges to cause the imbalance of the whole neural network pad, so that synchronous discharge is generated quickly. The research of the invention finds that when pyrazinamide and flumazenil are connected in a specific ratio, the activity of an NMDA receptor can be effectively inhibited, and then the convulsion symptom can be quickly relieved.
According to the pharmaceutical scheme provided by the invention, the effective dose of pyrazinamide is 2 mg/kg.d, and the effective dose of flumazenil is 14 mg/kg.d, which are both lower than the effective doses of the pyrazinamide and the flumazenil which are used for treating respective indications at present, and the safety is good under the dosage condition, and the safety can be verified based on the existing pharmacokinetic research.
The invention provides an application of pyrazinamide and flumazenil in preparation of an anticonvulsant drug. According to the technical scheme, the influence of various compounds on convulsion symptoms and pathological processes of the convulsion symptoms is researched based on experimental means, and the result shows that the convulsion symptoms can be effectively relieved when the pyrazinamide and the flumazenil are combined according to a specific proportion, and the exact therapeutic effect is achieved on severe symptoms such as paroxysmal limb and facial muscle twitching, involuntary limb rhythmic movement, coma and the like. On the basis, the invention researches the pharmacological action principle, and experiments show that although the combination of pyrazinamide and flumazenil has no effect on neurotransmitters when a single medicine is used, under the combined condition of the invention, the AMPA receptor activity and the NMDA receptor activity are obviously inhibited, and the invention has exact curative effects of reducing excitatory postsynaptic current and relieving delayed damage of nerve cells. Based on the beneficial findings, the invention determines the new application of the combination of pyrazinamide and flumazenil in preparing the anticonvulsant drug, not only widens the optional range of the anticonvulsant drug on the premise of ensuring the safety, but also expands the medical application of the pyrazinamide and the flumazenil, and has wide application prospect.
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FIG. 1 shows the results of an AMPA receptor activity inhibition assay in accordance with an embodiment of the present invention.
FIG. 2 is a graph of the results of an NMDA receptor activity inhibition assay in accordance with an embodiment of the present invention.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be described in detail in the following embodiments in order to avoid unnecessarily obscuring the details. Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in 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.
1. Experiment grouping
Experimental group 1: an anticonvulsant drug comprises pyrazinamide and flumazenil, wherein the mass ratio of the pyrazinamide to the flumazenil is 1: 7; in the medicine, the effective dose of the pyrazinamide is 2mg/kg d; in the medicament, the effective dose of flumazenil is 14mg/kg d.
Experimental group 2: an anticonvulsant drug comprises pyrazinamide, flumazenil, midazolam, fentanyl citrate and propofol, and the mass ratio of the pyrazinamide, the flumazenil, the midazolam, the fentanyl citrate and the propofol is 10: 70: 3: 1: 2; in the medicine, the effective dose of the pyrazinamide is 2mg/kg d; in the medicament, the effective dose of flumazenil is 14mg/kg d.
Experimental group 3: pyrazinamide in a dose of 2mg/kg d.
Experimental group 4: flumazenil in a dose of 14mg/kg d.
Experimental group 5: phenytoin sodium in a dosage of 500 mg/d.
Experimental group 6: chloral hydrate in an amount of 0.8 g/time, 3 times a day.
2. AMPA receptor Activity inhibition assay
Cerebellum was removed from 8 day old CD mice, minced into 1mm thick pieces, and incubated in a calcium-magnesium free Tyrode solution containing 0.1% trypsin at 37 ℃ for 15 minutes. The tissue was then developed using a fine pore size Pasteur pipette. Cell suspension at 10 per well5Cells were plated into poly-D-lysine coated 96-well tissue culture plates. The culture consisted of minimal basal medium (MEM) containing Earle's balanced salt solution, 10% heat-inactivated fetal bovine serum, 2mM L-glutamate, 21mM glucose, penicillin-streptomycin (100 units/ml) and 25mM KCl. After 24 hours, the culture broth was replaced with a fresh culture broth containing 10. mu.M cytarabine to inhibit cell division. The cultures should be used at 6-8 DIV.
45Ca induced by drug activation of AMPA receptor2+The effect of uptake can be measured in rat cerebellar granule cell cultures. Cultures in 96-well plates were preincubated for 3 hours in serum-free medium and then incubated in serum-free medium containing 0.5mM DTT, 10. mu.M glycine and twice as muchMg-free of drug at final concentration2+Balanced salt solution (in mM: 120NaCl, 5KCl, 0.33 NaH)2PO4，1.8CaCl2220 glucose and 10.0HEPES, pH 7.4) for 10 minutes. An equal volume of kainic acid and 45Ca containing 100. mu.M of the AMPA receptor agonist was added rapidly2+(Final specific activity: 250Ci/mmol) in balanced salt solution to start the reaction. After 10 minutes of reaction at 25 ℃, 45Ca was aspirated2+And the cells were washed 5 times in ice-cold balanced salt solution containing 0.5mM EDTA but no added calcium to stop the reaction. The cells were then lysed by incubation in 0.1% Triton-X100 overnight and the lysates were then assayed for radioactivity. The results of the experiment are shown in FIG. 1.
As shown in fig. 1, no inhibition of AMPA receptor activity was shown when pyrazinamide alone (experimental group 3) or flumazenil alone (experimental group 4); the drug combination scheme of the invention can obviously reduce the activity of AMPA receptor, and the effect is better than that of phenytoin sodium and chloral hydrate. In the case where the drug of the present invention sufficiently antagonizes AMPA receptors, it is reasonable to believe that excitatory postsynaptic currents mediated by AMPA receptors are inhibited, thereby inhibiting the abnormal firing of cerebral cortical neurons.
3. NMDA receptor Activity inhibition assay
The inhibitory effect of drugs on NMDA receptors was evaluated by changes in the concentration of calcium in primary cultured rat cortical cells. Intracellular calcium was measured on primary neurocortical cell cultures from 17-day-old rat embryos. After isolation, cells were plated into standard 96-well microplates in 95% air, 5% CO2Cultures were maintained at 37 ℃ in ambient until assayed.
Cultures were used for intracellular calcium measurements after 4-7 days in vitro culture. Ca before measurement2+Sensitive fluorescent dye, Fluo-4/AM (2-2.5. mu.M) loaded cells. By mixing with a solution (140mM NaCl, 5mM KCl, 2mM CaCl) also used in the measurement25mM HEPES [4- (2-hydroxyethyl) -1-piperazineethane-sulfonic acid]5mM HEPES-Na, 20mM glucose, 10. mu.M glycine, pH 7.4) was washed twice to stop the reaction. Then adding the above-mentioned solution and dissolving them in the above-mentioned solventTest compounds in liquid (90. mu.L/well). Intracellular calcium measurements were performed using a fluorescence plate reader. Intracellular calcium concentration was reflected by NMDA-induced elevation in Fluo-4-fluorescence using 40. mu.M. The inhibitory potency of the test compounds was assessed by calcium content in the presence of different experimental groups of drugs. The results of the experiment are shown in FIG. 2.
As shown in fig. 2, the drug of the present invention significantly reduced NMDA receptor activity, which is also better than phenytoin sodium and chloral hydrate. The combination condition of the invention can be proved to play a synergistic effect because the NMDA receptor activity is not inhibited when the pyrazinamide or the flumazenil is singly administered. Based on the antagonistic action of the NMDA receptor, the medicine can treat the discharge phenomenon caused by the increase of the activity of the NMDA receptor and the delayed damage of nerve cells.
4. Experiment of therapeutic Effect
240 convulsive patients were randomly collected, including 138 males and 102 females at age 6-65 years, with the average age of 37 years. Randomly dividing the medicine into 6 groups, and respectively adopting the experimental groups 1-6 to carry out medicine administration for 6 months; treatment efficacy was assessed during the period starting at month 2 and ending at month 6.
The evaluation was carried out using the following criteria:
and (3) healing: no disease was reoccurred in 5 months.
Special effects are as follows: the incidence frequency is reduced by more than 80% in 5 months compared with that before the medicine is taken, and the symptoms are obviously relieved during the incidence.
The method has the following advantages: the incidence frequency is reduced by more than 40% in 5 months compared with that before the medicine is taken, and the symptoms are exactly relieved when the medicine is taken.
No obvious curative effect is found: the disease frequency is reduced in 5 months compared with the disease frequency before the medicine is taken, or the symptoms are relieved during the disease onset, but the standards of recovery, special effect or effectiveness and the like are not met.
And (4) invalidation: the frequency of the disease is not reduced in 5 months compared with that before the medicine is taken, and the symptoms are not reduced during the disease.
The results of the experiment are shown in table 1 below:
TABLE 1 Experimental results for the treatment of cases
The experimental results in table 1 show that the experimental group 1 and the experimental group 2 based on the medication of the present invention have good therapeutic effects on patients with convulsion; and neither pyrazinamide alone (experimental group 3) nor flumazenil alone (experimental group 4) exhibited convulsive therapeutic effects; in addition, compared with experimental groups 5 and 6, the medicine of the invention has improved curative effect compared with the conventional convulsion treatment medicines such as phenytoin sodium, chloral hydrate and the like.
In conclusion, the combined scheme of pyrazinamide and flumazenil realizes the exact treatment effect on convulsion, and the treatment effect is not achieved by singly administering pyrazinamide or flumazenil; in addition, the invention has good treatment effect on convulsion, and is superior to conventional anticonvulsant medicines such as phenytoin sodium, chloral hydrate and the like.
The embodiments of the present invention have been described in detail, but the description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention. Any modification, equivalent replacement, and improvement made within the scope of the application of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The application of the combination of pyrazinamide and flumazenil in preparing anticonvulsant medicaments.
2. Use according to claim 1, characterized in that the mass ratio of pyrazinamide to flumazenil is 1: 7.
3. The use of claim 2, wherein the medicament further comprises midazolam, fentanyl citrate, propofol.
4. The use according to claim 3, wherein the medicament comprises the following components in parts by weight: 10 parts of pyrazinamide, 70 parts of flumazenil, 3 parts of midazolam, 1 part of fentanyl citrate and 2 parts of propofol.
5. The use according to claim 4, wherein the effective amount of pyrazinamide in the medicament is 2 mg/kg-d.
6. The use according to claim 5, wherein the effective amount of flumazenil is 14 mg/kg-d.
7. The use of claim 2, wherein the medicament inhibits neurocortical neuronal discharges.
8. The use of claim 2, wherein the medicament inhibits AMPAR activity and inhibits rapid excitatory synaptic transmission in the CNS.
9. The use of claim 2, wherein the medicament inhibits NMDA receptor activity.
10. The use according to claim 2, wherein the medicament is in the form of an injection.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070043032A1 (en) * | 2005-08-22 | 2007-02-22 | Pierre Mainville | Composition comprising a benzodiazepine agonist and a benzodiazepine antagonist |
| RU2537170C1 (en) * | 2013-11-20 | 2014-12-27 | Войсковая Часть 41598 | Method of preventing cerebral form of radiation sickness |
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- 2020-03-17 CN CN202010189204.XA patent/CN111374980A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070043032A1 (en) * | 2005-08-22 | 2007-02-22 | Pierre Mainville | Composition comprising a benzodiazepine agonist and a benzodiazepine antagonist |
| RU2537170C1 (en) * | 2013-11-20 | 2014-12-27 | Войсковая Часть 41598 | Method of preventing cerebral form of radiation sickness |
Non-Patent Citations (1)
| Title |
|---|
| 熊方武等: "《中国临床药物大辞典 化学药卷》", 31 August 2018, 中国医药科技出版社 * |
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