CN111803473A - Application of nortriptyline in treating Parkinson's disease - Google Patents
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- CN111803473A CN111803473A CN201910283470.6A CN201910283470A CN111803473A CN 111803473 A CN111803473 A CN 111803473A CN 201910283470 A CN201910283470 A CN 201910283470A CN 111803473 A CN111803473 A CN 111803473A
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- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960001158 nortriptyline Drugs 0.000 title claims abstract description 24
- 208000018737 Parkinson disease Diseases 0.000 title abstract description 82
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims abstract description 212
- 229960003638 dopamine Drugs 0.000 claims abstract description 106
- 230000000903 blocking effect Effects 0.000 claims abstract description 6
- 102000009123 Fibrin Human genes 0.000 claims abstract description 5
- 108010073385 Fibrin Proteins 0.000 claims abstract description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229950003499 fibrin Drugs 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- -1 alias Chemical compound 0.000 claims 1
- 230000007170 pathology Effects 0.000 abstract description 19
- 238000002474 experimental method Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 230000001681 protective effect Effects 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
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- 210000002569 neuron Anatomy 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
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- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010006100 Bradykinesia Diseases 0.000 description 2
- 208000006083 Hypokinesia Diseases 0.000 description 2
- 208000002740 Muscle Rigidity Diseases 0.000 description 2
- 206010071390 Resting tremor Diseases 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 210000001723 extracellular space Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
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- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 102000019355 Synuclein Human genes 0.000 description 1
- 108050006783 Synuclein Proteins 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical group CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 description 1
- 229950002652 safinamide Drugs 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The theory of dopamine channels states that dopamine molecules pass through dopamine functional channels to reach dopamine active cavities to play a dopamine functional role. The science and pathology of Parkinson's disease states that Parkinson's disease occurs when dopamine functional pathways are blocked by fibrin. This is because occlusion of dopamine functional channels results in a decrease in dopamine-functional factors and a decrease in functional dopamine content. The invention discloses a method for controlling Parkinson's disease by applying nortriptyline to treat, wherein nortriptyline is adopted and is a substance capable of blocking dopamine protective channels. Mouse and animal experiments prove that the nortriptyline can block dopamine protection channels, dredge blocked dopamine functional channels and has the effect of treating and controlling the Parkinson's disease.
Description
1. Field of the invention
Parkinson's disease, ancient times. This Disease is known as Parkinson's Disease because the United kingdom physician JamesParkinson studied the Disease carefully in 1817 and published a paper after which the physician's name Parkinson named the Disease (Parkinson's Disease). At present, about 1000 million Parkinson patients worldwide exist, wherein Chinese Pa patients exceed 200 ten thousand, and the number of the Parkinson patients in three and forty years old in the young is rapidly increased. Parkinson's disease includes four major conditions: (1) resting tremor, (2) muscle rigidity, (3) bradykinesia, (4) abnormal gait and unstable posture, and many possible complications make the life of a patient abnormally hard, often have a feeling of death, but are not easy to die, and are serious, distressing and disabling diseases.
Parkinson's disease is currently considered an incurable, uncontrollable, disabling disease and is also wanting to afflict humans. Obviously, the method is closely related to the fact that the nature of the Parkinson disease is not comprehensively and deeply known, and is obviously related to the fact that the disease causes are not correctly aimed at, proper medicines are not available, and reasonable medicines are not available.
The most essential reason is the production and release of dopamine molecules into the intercellular spaces by the substantia nigra dopamine cells, which has not been the cause for a long timePeople ignore. None have studied the sites where dopamine molecules actually act in their receptors, nor have they studied whether dopamine molecule channels are a problem in dopamine receptors. In the intercellular space, there are other various particles including Na+,K+,Ca2+,H2And O. Each of these particles has a channel, why are the dopamine molecules without channels? How can there be no channel? Clearly, the dopamine molecule should have its channels.
Through long-term basic research, under the support of national science foundation projects, two dopamine molecular channels are discovered very fortunately, one is a 'dopamine functional channel', and the other is a 'dopamine protective channel' (actaphys. -chim.sin.2017,23,927; actaphys. -chim.sin.2011,17,2432). Based on a 'dopamine functional channel', the concepts of total dopamine, 'functional dopamine' and non-functional dopamine are defined, and a functional dopamine content formula G is researched and establishedD＝f×TDThus, a dopamine channel theory is established, and the essence of the Parkinson disease is found as follows: the functional dopamine is deficient, and the scientific pathology of Parkinson's disease and the new pathology of Parkinson's disease are proposed. We also scientifically defined parkinson's disease, named: "functional dopamine deficiency syndrome". Based on dopamine channel theory and Parkinson's disease science and pathology, the essential problem of the Parkinson's disease is basically solved on the academic theory. Based on the science and pathology of Parkinson's disease, through the technology for treating the dopamine function conversion factor through the series of treatments and the application of the medicine, the Parkinson's disease becomes a curable or controllable simple disease from difficult, complicated and uncontrollable disabling diseases, and the time for thoroughly controlling the magic of the Parkinson's disease comes early, so that the human is benefited. Since 1817, James Parkinson's doctors carefully observed the disease, at least 5000 million people all over the world suffered from the disease, and the disease is just about to victimize humans, which cannot be ignored, and is the time of stopping.
2. Background of the invention
At present, the research on Parkinson's disease generally adopts ' dopamine function science ' and old dopamine neuron apoptosis pathology. The science of dopamine function states that dopamine molecules in a living body have functions of regulating and controlling movement of the living body and the like by combining different types of dopamine receptors, and are related to the Parkinson disease. Alvurd Carlsson (Arvid Carlsson), Paul Greengard (Paul Greengard) and Eric Kandel (Eric Kandel) have achieved the 2000 nobel prize for signal transduction by dopamine molecules. In 1960, Hornykliewic detected the remains of patients who died in the late stage of Parkinson's disease, and found that the patients died have serious striatal dopamine deficiency. Combined with dopamine function, the parkinson's old pathology appears: the mesencephalic substantia nigra dopaminergic neuron irreversibly undergoes progressive apoptosis, and the Parkinson's disease appears when the dopaminergic cell undergoes apoptosis to a certain degree.
According to the old pathology of apoptosis, the measures currently taken clinically are: (1) exogenous supplement and increase of dopamine (common medicines comprise medobatin, kinine and the like), (2) reduction of dopamine reduction in vivo (common medicines comprise selegiline, rasagiline and safinamide), (3) provision of pseudo dopamine function through an agonist, enhancement of dopamine function (common medicines comprise seforomao, peptidesda and the like), (4) antagonism of acetylcholine receptor function, reduction of acetylcholine function, and achievement of dopamine balance (common medicines comprise amantadine, amban and the like). These drugs only solve the problem of total dopamine, enhance the function of total dopamine, and do not relate to the problem of dopamine-functionalized factor. The principles and concepts of these therapies, limited to the problem of total dopamine, and to the problem of enhancing total dopamine function, are based on the old pathology of parkinson's disease. The principle and thought of the therapies only consider the Parkinson's disease essential problem as the' total dopamine 'problem, but not consider the Parkinson's disease essential problem as the 'functional dopamine' problem. It is clear that these therapies, the anti-parkinson drugs used, although achieving partial relief for a limited period of time, are gradually declining in the presence of parkinson's disease. As the disease ages, the condition of the patient is always worsened and aggravated, causing the condition to become an uncontrollable disabling disease.
3. Summary of the invention
Based on our research to establish workFormula of dopamine content GD＝f×TDIt can be seen that the current therapy only solves the total dopamine problem in the functional dopamine problem, namely the total dopamine content and the total dopamine function enhancing problem, namely T in the formulaDThat term, which does not relate to dopamine functionalization factors, is the term fta in the formula. The patent technology and the medicine of the invention are the technology and the medicine for solving the problem of the item f in the formula, and the technology and the medicine for solving the problem of the dopamine functional factor. At present, the clinical measures only solve the problems of total dopamine content and total dopamine function enhancement, but do not relate to the solution of dopamine functional factors. That is, the technology for solving the problem of dopamine-functionalized factor is currently a technical gap in clinical practice. The reason is that the basic scientific research in the past has not reached the understanding that the essential problems of parkinson's disease are: the 'functional dopamine deficiency' problem can not be scientifically recognized and proposed yet. And we, based on the functional dopamine content formula, GD＝f×TDThe application of scientific principles such as dopamine channel theory, Parkinson disease science pathology and the like invents a series of technologies and medicines for treating the dopamine function conversion factor.
The patent technology of the invention is a technology for blocking a dopamine protection channel by nortriptyline, thereby dredging a dopamine functional channel blocked by +/-synuclein fibrin and inventing the application of nortriptyline in treating Parkinson's disease. The method treats the Parkinson disease by injection or oral nortriptyline, and realizes the dredging of a dopamine functional channel by blocking the dopamine protective channel. The blockage of the dopamine protective channel by the nortriptyline can improve the dopamine functional factor, improve the content of functional dopamine and achieve the effect of treating and curing the Parkinson disease. In the substantia nigra of the midbrain, the main substance that blocks dopamine-functioning channels is fibrin, the most predominant of which, including alpha (±) synuclein.
4. Description of the drawings
FIG. 1 shows the molecular structure of nortriptyline. Nortriptyline (Nortriptyline, allopurine)Nominated amitriptyline, noramitriptyline) with molecular formula C19H21N, chemical name is N-methyl-3- [10, 11-dihydro-5H-dibenzo [ a, d ]]Cycloheptatrien-5-ylidene]-1-propylamine.
5. Detailed description of the preferred embodiments
1) Animal establishment for Parkinson's disease
The + -synuclein contains 140 residues, is a fibrin, and a dimeric structure has been reported so far, as well as a fibrous state [ J Chem Phys,2018,148(12),123322 ]. At present, a plurality of biotechnology companies can well express and purify the +/-synuclein, and the purity of the obtained sample is more than 95%. The use of + -synuclein to generate murine models of Parkinson's disease has been reported in the literature [ Nature 2015,522,340 ]. The literature reports that about 200 g of experimental mice were injected with 2 microgram of + -synuclein into the substantia nigra of the midbrain, and then the spatial distribution of + -synuclein over time was observed by protein fluorescence tracking, and that the experimental mice had very standard parkinson's disease conditions and that apoptosis of dopamine neurons of the experimental mice was observed. The Parkinson disease experimental mice reported in the literature are analyzed by the old pathology of the Parkinson disease based on the dopamine neuron apoptosis mechanism. The observed Parkinson disease experimental mice can not automatically heal and recover health. Results have well demonstrated that + -synuclein, in laboratory mice, cannot be eliminated by its own mechanism, and at the same time, it has also been well demonstrated that laboratory mice cannot cure apoptotic dopamine neuron cells by themselves, thereby restoring health.
We also used ± -synuclein to generate parkinson's disease mice, according to the methods described in the above documents. However, we administered about 200 g of mice, each of which was injected with 5. mu.g of + -synuclein into the substantia nigra of the midbrain, 2.5 times as much as reported in the literature. Injecting 5 microgrammes of +/-synuclein at the substantia nigra part of a mouse, wherein the Parkinson disease of the experimental mouse appears next day, and the Parkinson disease caused by injection reasons and solution reagents is eliminated through a blank test. The next day after injection, the experimental mice did not, and could not develop, a significant amount of dopamine neuron apoptosis, but suffered from severe, standard parkinson's disease conditions. These parkinsonian symptoms can last for more than 2 months. Therefore, our experiments prove that the +/-synuclein can block dopamine functional channels of experimental mice to generate the Parkinson's disease. After the dopamine functional channel is blocked, the +/-synuclein can also produce other effects to cause a great deal of apoptosis of dopamine neurons. The Parkinson disease of the experimental mouse can be analyzed through Parkinson disease scientific pathology and Parkinson disease new pathology. Thus, we refer to the literature methods to uniquely establish standard parkinson's disease condition laboratory mice.
In addition, it is noted that it cannot be assumed that the production of animal models of parkinson's disease necessarily requires massive apoptosis of dopamine neurons. This animal model is based on the old pathology of parkinson's disease. This situation is possible for the later stages of a long-term parkinson's disease patient. However, in the early stage, early stage and middle stage of Parkinson's disease, the patient does not have the condition that large area dopamine neuron really die. Therefore, considering this animal model as a standard animal model of Parkinson's disease for studying Parkinson's disease in different situations has greatly misled and seriously jeopardized the study and treatment of Parkinson's disease. The current definition of parkinson's disease is four major conditions: (1) resting tremor, (2) muscle rigidity, (3) bradykinesia, (4) gait abnormalities and postural instability, and other complications. Therefore, Parkinson's disease is determined by the condition rather than by a particular cause. Massive apoptosis of dopamine neurons is only one cause of parkinson's disease, a condition that is likely to occur later in the long-term in parkinson's patients. Massive apoptosis of dopamine neurons does lead to a decrease in total dopamine content, however, this cannot be regarded as essential for parkinson's disease. A reduction in total dopamine content as a cause of the disease results in: functional dopamine reduction, which is the nature of parkinson's disease. Therefore, the ' functional dopamine ' is used as a standard to judge whether the Parkinson's disease exists or not. The functional dopamine content also comprises dopamine functional factors which are closely related to the smoothness of dopamine functional channels, so that the blockage of the dopamine functional channels is another cause of the Parkinson's disease. The old pathology of the Parkinson disease does not appear, but the old pathology of the Parkinson disease is regarded as an absolute pathology, which obviously brings great pain and life cost to a plurality of patients. The old pathology of the Parkinson disease is regarded as absolute pathology, and obviously, the research and the treatment of the Parkinson disease are greatly misled and seriously damaged, and the invention and the development of the medicine for treating the Parkinson disease are seriously influenced.
2) Effect of nortriptyline in treating Parkinson's disease animal disorders
Our experiments and literature reports that the use of + -synuclein can establish and generate standard Parkinson's disease test mice. Therefore, the Parkinson disease experimental mouse can not be cured by relying on or depending on a self mechanism (namely, no external help is adopted) to recover the health. Thus, the mouse quasi-disease state of the Parkinson's disease experiment can be maintained for a long time, and the disease mouse cannot eliminate the cause of the disease by the self mechanism. We analyzed the cause that the dopamine channel of the experimental rat is blocked by the + -synuclein, and the dopamine neuron cell of the experimental rat is apoptotic by the + -synuclein as reported in the literature. In fact, apoptotic dopamine neuron cells should be difficult to revive, and therefore it should be difficult to restore the health of experimental mice. In addition, in our experiment, about 200 g of experimental mice are injected with 5 micrograms of the sample per mouse in the substantia nigra part of the mice, and the Parkinson's disease appears in the experimental mice the next day. The next day after injection, it is unlikely that the experimental mice will have a significant amount of dopamine neurons that die, but the experimental mice will have severe standard parkinson's disease conditions. These experiments fully demonstrated that the cause was the blockage of functional dopamine channels by + -synuclein in laboratory rats.
Since the etiology of Parkinson's disease is that the functional dopamine channels of laboratory mice are blocked by + -synuclein, if exogenous drugs are used to help the laboratory mice dredge: the functional dopamine channel blocked by the +/-synuclein increases and recovers the content of functional dopamine, and the Parkinson disease of the experimental mouse is cured, so that the health of the experimental mouse can be recovered. In another patent technical project, a technology for dredging functional dopamine channels and a technology for directly removing the +/-synuclein are adopted to dredge the functional dopamine channels blocked by the +/-synuclein, so that the Parkinson's disease is curedThe effect of (1). The technology of the patent improves functional factors, improves the content of functional dopamine, dredges and blocks the dopamine protection channel and treats and cures the Parkinson disease by the technology of blocking the dopamine protection channel. Nortriptyline is a tricyclic molecule, lipophilic, and enriched at the membrane site of the cell bilayer. The dopamine protection channel outlet directly enters the space of a cell double-layer membrane, and the cell double-layer membrane is the space of a binding target site of nortriptyline and a dopamine receptor. Nortriptyline and the dopamine receptor protection channel outlet have two action targets. One target is located in the middle of the receptor, and the interaction energy is 65kJ-1Left and right. The other target is positioned close to the inner part of the receptor, and the interaction energy is 76kJ-1Left and right. The interaction can ensure that the nortriptyline molecules are stably combined at the outlet of the dopamine protective channel within a certain time, and the effect of blocking the dopamine protective channel is achieved.
Based on the standard Parkinson disease experimental mice generated by adopting the +/-synuclein, 0.3 mg of nortriptyline is injected into the abdominal cavity of the experimental mice once a day. After about 30 days, the standard Parkinson disease symptoms of the experimental mice can be eliminated, the administration is stopped, and the experimental mice completely recover to be healthy. And the laboratory mice continue to maintain normal health status without any help. Therefore, the standard Parkinson disease mouse experiment fully proves that the nortriptyline has the effect of curing the Parkinson disease.
Claims (2)
1. Nortriptyline (Nortriptyline, alias, noramitriptyline) with molecular formula C for treating and controlling Parkinson disease19H21N, chemical name is N-methyl-3- [10, 11-dihydro-5H-dibenzo [ a, d ]]Cycloheptatrien-5-ylidene]-1-propylamine.
2. The nortriptyline is applied to blocking a dopamine protection channel and dredging a dopamine functional channel blocked by fibrin.
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|---|---|---|---|---|
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-
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- 2019-04-10 CN CN201910283470.6A patent/CN111803473A/en active Pending
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|---|---|---|---|---|
| CN101146535A (en) * | 2005-03-25 | 2008-03-19 | 默克公司 | Method of treating male patients with testosterone supplements and 5α-reductase inhibitors |
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| Title |
|---|
| ALBERT F.G. LEENTJENS: "The Role of Dopamine Agonists in the Treatment of Depression in Patients with Parkinson’s Disease", 《DRUGS》 * |
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