CN115554390A - Application of vancomycin hydrochloride in preparation of agent for reducing neurotoxin beta-methylamino-L-alanine level - Google Patents
Application of vancomycin hydrochloride in preparation of agent for reducing neurotoxin beta-methylamino-L-alanine level Download PDFInfo
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- UJVHVMNGOZXSOZ-UHFFFAOYSA-N 2-amino-3-(methylamino)propanoic acid Chemical compound CNCC(N)C(O)=O UJVHVMNGOZXSOZ-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 108010059993 Vancomycin Proteins 0.000 title claims abstract description 65
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 title claims abstract description 57
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61P25/00—Drugs for disorders of the nervous system
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Abstract
The invention provides an application of vancomycin hydrochloride in preparing a reagent for reducing the level of neurotoxin beta-methylamino-L-alanine, belongs to the technical field of biological pharmacy, and also provides an application of vancomycin hydrochloride in preparing a medicine for treating autism; the medicine is an oral preparation, and the potency of each 1mg of the medicine is more than or equal to 1000 vancomycin hydrochloride units calculated according to anhydrous substances. The vancomycin hydrochloride can realize the treatment of autism by reducing the concentration of neurotoxin BMAA; solves the technical problem that the existing medicine for treating the core symptom of the autism is lack of specific medicines.
Description
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to application of vancomycin hydrochloride in preparation of a reagent for reducing the level of neurotoxin beta-methylamino-L-alanine.
Background
Currently, treatment of autism is based on educational intervention, with supplements/medications as adjunctive. Because patients with autism have multiple developmental disorders and emotional behavior abnormalities, doctors can adopt comprehensive intervention measures combining means such as educational intervention, behavior correction, supplement/drug treatment and the like according to the specific conditions of the patients, but the prognosis of patients with autism is generally poorer.
The purpose of education intervention is to cultivate the self-care and independent living ability of children patients, reduce the disability degree of children, improve the quality of life and strive to enable part of children patients to have the ability of independent study, work and life after the children grow up. The method for intervention training mainly takes behavioral intervention based on Application Behavior Analysis (ABA) as a basis. Other intervention approaches also include augmented and alternative communication, structured education (TEACCH), and interpersonal development intervention (RDI), among others.
The drug therapy is only an auxiliary symptomatic treatment measure, and can improve emotional behavior abnormalities of autistic patients, such as emotional instability, irritability, self-laughing, hyperactivity, self-injury and aggressive behaviors. Alternative drugs include antipsychotics (such as risperidone and aripiprazole), antidepressants, drugs to treat attention deficit hyperactivity disorder, and the like. In the face of the current situation that a specific medicine aiming at the core symptom of the autism is not available, finding a specific medicine becomes a problem to be solved urgently at present.
Disclosure of Invention
In order to change the current situation that no specific medicine exists in autism, the invention provides the application of vancomycin hydrochloride in preparing a reagent for reducing the level of neurotoxin beta-methylamino-L-alanine, wherein the treatment of autism is realized by reducing the concentration of neurotoxin BMAA.
The invention provides an application of vancomycin hydrochloride in preparing a reagent for reducing the level of neurotoxin beta-methylamino-L-alanine.
The invention provides an application of vancomycin hydrochloride in preparing an improver for treating diseases caused by neurotoxin beta-methylamino-L-alanine.
Preferably, the disease is a neurological disorder disease.
Preferably, the neurological disorder disease includes, but is not limited to, parkinson's disease, alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and the like.
The invention provides an application of vancomycin hydrochloride in preparing a medicine for treating autism.
Preferably, the vancomycin hydrochloride can be replaced by a vancomycin hydrochloride structural analogue, such as vancomycin, norvancomycin hydrochloride and the like.
Preferably, the medicament comprises an excipient, and the medicament is a freeze-dried product.
Preferably, the potency of the drug is more than or equal to 1000 vancomycin hydrochloride units per 1mg calculated as anhydride.
Preferably, the medicament is an oral preparation
Compared with the prior art, the invention has the following beneficial effects: the vancomycin hydrochloride provided by the invention can obviously reduce the concentration of neurotoxin beta-methylamino-L-alanine, the neurotoxin beta-methylamino-L-alanine is taken as a target point, the vancomycin hydrochloride can interfere the combination of BMAA and an antibody thereof, the vancomycin hydrochloride realizes the treatment of autism by reducing the concentration of the neurotoxin BMAA in the blood of an autism patient, and can also realize the treatment of other neurological disorder diseases including but not limited to Parkinson disease, alzheimer disease, progressive supranuclear palsy, amyotrophic lateral sclerosis and the like.
Drawings
FIG. 1 shows the binding of vancomycin to BMAA using Pymol software;
FIG. 2 is a standard curve plotting the absorbance at 450nm versus the concentration of the standard in test 1 of example 2, the absorbance being plotted on the abscissa and the concentration being plotted on the ordinate in ppb;
FIG. 3 is a standard curve plotting the absorbance at 450nm versus the concentration of standard in test 2 of example 2, with absorbance on the abscissa and concentration on the ordinate in ppb.
Detailed Description
The invention provides an application of vancomycin hydrochloride in preparing an agent for reducing neurotoxin beta-methylamino-L-alanine (BMAA) level. In the invention, the application of the vancomycin hydrochloride is not limited to preparing medicines for treating diseases, and the application also comprises reducing the concentration of neurotoxin beta-methylamino-L-alanine in experimental research.
According to the invention, the software is used for carrying out molecular docking analysis on vancomycin hydrochloride and BMAA to determine the docking area of the vancomycin hydrochloride and the BMAA, the concentration of the BMAA in a solution system after the vancomycin hydrochloride and the BMAA are combined is detected by using an ELISA test, the vancomycin hydrochloride can be combined with the BMAA, and the concentration of the BMAA in the solution system is obviously reduced.
The invention also provides the application of vancomycin hydrochloride in preparing an improver for treating diseases caused by neurotoxin beta-methylamino-L-alanine.
In the present invention, the disease is preferably a neurological disorder disease, and further preferably includes parkinson's disease, alzheimer's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis.
The invention provides an application of vancomycin hydrochloride in preparing a medicine for treating autism. In the invention, the vancomycin hydrochloride can be replaced by norvancomycin hydrochloride.
In the present invention, the medicament preferably comprises an excipient, which is preferably mannitol; the mass ratio of the vancomycin hydrochloride to the excipient is mannitol; in the present invention, the medicament is preferably a lyophilized product; the potency of the drug is preferably more than or equal to 1000 vancomycin hydrochloride units per 1mg calculated by anhydrous substance.
In the present invention, the medicament is preferably an oral preparation. The dosage form of the oral preparation is not particularly limited, and the oral preparation can be prepared by adopting the conventional oral preparation dosage form in the field; in the present invention, the dosage form of the oral preparation includes, but is not limited to, oral liquid dosage form, tablet, capsule. In the invention, the medicine reacts with BMAA in intestinal tract to reduce the concentration of the BMAA in human body until the existence of the BMAA in human body is eliminated; finally achieving the purpose of improving and treating the autism.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
ELISA method for detecting concentration of neurotoxin in blood of autism patient
1. Sample source
Sample sources and inclusion criteria were as follows:
patients diagnosed with autism. Exclusion criteria: (1) (ii) suffering from other psychiatric disorders (such as schizophrenia) and other neurodevelopmental disorders; (2) suffering from a genetic metabolic disease; (3) history of major physical diseases such as severe neurological diseases and craniocerebral injury history;
16 autistic children, 15 men and 1 woman were combined; the age is 3-7 years old;
2. blood collection and supernatant acquisition:
venous blood was collected at 3ml using a disposable blood collection tube, and then centrifuged at 3000rpm for 5 minutes using a centrifuge, and the supernatant was collected as a serum sample.
3, ELISA detection:
coating a reaction plate: adding PBS containing goat anti-rabbit antibody of 1 mug/ml into an ELISA reaction plate, and carrying out sealed incubation for 16 hours at 4 ℃; patting dry the reaction plate, washing the plate hole with PBS containing 0.2% Tween-20, patting dry the reaction plate, and obtaining the coated ELISA plate;
add reference/standard solution: 100 μ l of diluted BMAA calibrator/standard was sequentially added to the well-coated wells at concentrations of 0ppb, 5ppb, 25ppb, 100ppb, 250ppb, and 500ppb, respectively. At least two parallel wells were made for each concentration.
Adding a serum sample: 100 μ l of each serum sample was added sequentially to the other coated wells.
Adding a binding solution: add 50. Mu.l of BMAA-HRP conjugate to each well.
Adding an antibody solution: add 50. Mu.l of BMAA antibody solution to each well.
And (3) incubation: after mixing for 30 seconds, incubation was carried out for 90 minutes at room temperature in the dark.
Washing the plate: the contents of the wells were decanted and each well was washed with at least 250 μ l of 0.2% tween-20 in PBS, patted dry and repeated four times.
Color development and reaction termination: after washing the plate, adding 150 mu l of TMB color development liquid into each reaction plate hole for color development, uniformly mixing for 30 seconds, placing at room temperature in a dark place, keeping the temperature for 30 minutes, and then adding 100 mu l of stop solution into each hole to terminate the reaction;
and (3) detection: within 15 minutes after the termination of the reaction, the reaction plate was placed in a microplate reader, and the OD450 value was read.
Calculating BMAA concentration of the sample: and drawing a standard curve of the absorbance of the standard substance at 450nm and the concentration of the BMAA, and calculating the concentration of the BMAA of the sample according to the standard curve.
The results of the measurement of the BMAA concentration in 16 patients with autism are shown in Table 1.
TABLE 1 BMAA concentration measurements in 16 autistic patients
4. Analysis of correlation between BMAA concentration in blood of autistic patient and autism severity
The correlation analysis of the concentration of the neurotoxin BMAA in the blood of the autism patient and the severity of the autism patient is carried out, the concentration of the neurotoxin BMAA in the blood of the autism patient is found to have significant correlation with the severity of autism symptoms, and the P value is 0.011. The results are shown in Table 2. The results of this example show that the neurotoxin BMAA plays a very important role in the etiology of autism. Eliminating or reducing BMAA toxicity may improve the condition of autism.
TABLE 2 correlation of toxin concentration and autism rating scale evaluation results
Example 2
Molecular docking analysis of vancomycin hydrochloride with BMAA using software
Software installation
The common software AutoDock Vina, MGLtools, pyMOL and ChemDraw software were installed.
Downloading structure files of protein receptors
Obtaining a protein receptor file of vancomycin hydrochloride: the PDB file for vancomycin is downloaded from the RCSBPDB website (https:// www. Rcsb. Org /).
Preparation of Small molecule ligands
Small molecule BMAA ligand file acquisition: and obtaining an SDF file of the BMAA through ChemDraw software, and obtaining a mol2 file of the BMAA through optimizing a mechanical structure.
And then operating in AutoDockTools to obtain a pdbqt file of BMAA.
Preparation of protein receptors
First, the PDB file of vancomycin hydrochloride was opened by operating in PyMOL, and the water molecules were deleted, the small molecule ligands in the protein structure were removed, and the other molecules bound were removed.
And then operating in AutoDockTools software, and storing as a pdbqt file of vancomycin after hydrogenation, charge calculation and atom type addition.
Determining a docking area
Opening a pdbqt file of protein vancomycin in AutoDock, displaying the protein by using a secondary structure in AutoDockTools, adjusting the coordinates, length, width and height of the GridBox according to an action site, and storing a box parameter file.
Creating a configuration file
Txt is a configuration file.
Entering a command mode: and selecting the current working directory, inputting 'cmd', and entering a command working window.
Inputting in a command window: tnt, vina-config.
The picture obtained by using Pymol software for vancomycin and BMAA binding is shown in fig. 1, wherein blue is vancomycin molecules and red is BMAA molecules.
Experiment for interfering combination of BMAA and antibody thereof by vancomycin hydrochloride
In the experiment, vancomycin hydrochloride and BMAA are premixed, the concentration of the BMAA is detected by an ELISA method, and the capacity of the vancomycin hydrochloride for reducing the concentration of the BMAA can be calculated by comparing the detection results of the BMAA with the same concentration without being treated by the vancomycin hydrochloride.
The specific experimental operation is as follows:
test 1: adding 200 mu l of BMAA with the concentration of 500bbp into two 1.5ml centrifuge tubes respectively, adding vancomycin hydrochloride with the equal molar concentration in one centrifuge tube, and starting an ELISA experiment within 5 minutes after uniformly mixing; diluting the rest of the centrifuge tubes with an equal volume of buffer solution (deionized water); the concentration of BMAA was determined by ELISA as described in example 1 for up to 5 minutes after treatment with vancomycin hydrochloride and without treatment with vancomycin hydrochloride. The result shows that the concentration of the sample which begins to be detected within 5 minutes after the sample is mixed with vancomycin is consistent with that of the untreated sample, and the concentration is unchanged. The results are shown in Table 3:
TABLE 3 results of ELISA test (450 nm absorbance) within 5 minutes of vancomycin hydrochloride treatment
| OD 450 | Kind of sample | OD 450 | Sample (I) | |
| A | 1.240 | Std0 | 0.340 | Std4 |
| B | 1.277 | Std0 | 0.326 | Std4 |
| C | 1.149 | Std1 | 0.220 | Std5 |
| D | 1.163 | Std1 | 0.204 | Std5 |
| E | 0.915 | Std2 | 0.325 | Sample No. 1 |
| F | 0.939 | Std2 | 0.334 | Sample 1 |
| G | 0.571 | Std3 | ||
| H | 0.576 | Std3 |
Description of the samples:
Std0-Std5 as standard (concentrations: 0, 5, 25, 100, 250, 500ppb, respectively)
2. Sample 1 is a vancomycin hydrochloride treated sample, and the treatment time is less than or equal to 5 minutes.
Data processing:
drawing a standard curve: a standard curve of the 450nm absorbance versus the concentration of the standard is shown in FIG. 2.
The average absorption value of sample 1 was 0.3295, and the concentration of sample 1 was calculated to be 231ppb by a standard curve; the corresponding sample not treated with vancomycin hydrochloride (i.e., std 4) had an average absorption value of 0.333, and the concentration of the control sample was calculated by the standard curve to be 231ppb; the concentrations were the same and there was no difference.
Test 2: adding 200 mu l of BMAA with the concentration of 500bbp into two 1.5ml centrifuge tubes respectively, adding vancomycin hydrochloride with the equal molar concentration in one centrifuge tube, and treating for 30 minutes; adding an equal volume of buffer solution (deionized water) into the remaining centrifugal tube for dilution; the concentration of BMAA was measured after 30 minutes of treatment with vancomycin hydrochloride and without treatment with vancomycin hydrochloride by ELISA as described in example 1. As a result, after the treatment of vancomycin hydrochloride for 30 minutes, the concentration value detected was 21% lower than that of untreated BMAA. The results are shown in Table 4.
TABLE 4 results of ELISA test (450 nm absorbance) within 5 minutes of vancomycin hydrochloride treatment
| OD 450 | Kind of sample | OD 450 | Kind of sample | |
| A | 1.192 | Std0 | 0.319 | Std4 |
| B | 1.099 | Std0 | 0.290 | Std4 |
| C | 1.143 | Std1 | 0.212 | Std5 |
| D | 1.001 | Std1 | 0.202 | Std5 |
| E | 0.836 | Std2 | 0.329 | Sample 2 |
| F | 0.844 | Std2 | 0.354 | Sample 2 |
| G | 0.546 | Std3 | ||
| H | 0.551 | Std3 |
Description of the samples:
Std0-Std5 as standard (concentrations: 0, 5, 25, 100, 250, 500ppb, respectively)
2. Sample 2 was a vancomycin hydrochloride treated sample for 30 minutes.
Data processing:
drawing a standard curve: a standard curve of the 450nm absorbance versus the concentration of the standard is shown in FIG. 3.
The average absorption value of sample 2 was 0.3415, and the concentration of sample 2 was 196ppb calculated by the standard curve; the corresponding vancomycin-untreated sample (i.e., std 4) had an average absorption of 0.3045, and the concentration of the control sample was calculated by the standard curve to be 248ppb; the difference between the concentrations was 51ppb, and the BMAA concentration decreased by 21% after 30 minutes of vancomycin treatment compared to the control sample.
And (4) conclusion: the concentration of the sample which begins to be detected within 5 minutes after the sample is mixed with vancomycin is consistent with that of the untreated sample, and the concentration is unchanged. However, after 30 minutes of treatment with vancomycin hydrochloride, the concentration values detected were 21% lower than the untreated BMAA concentration. Indicating that the reaction of vancomycin with BMAA takes some time and is not instantaneous. The longer the reaction time, the more pronounced the effect of vancomycin in reducing BMAA concentration will be. Since lowering the concentration of BMAA is advantageous for improving the condition of autism, vancomycin can be used for preparing an agent for improving autism.
Example 3
Preparation of autism improver from vancomycin hydrochloride
The titer of each 1mg of the drug is not less than 1000 vancomycin hydrochloride units calculated by anhydrous substance. The preparation is lyophilized powder, and is administered after dissolving in water.
The freeze-drying process conditions of the vancomycin hydrochloride are as follows: using 25% mannitol as excipient, wherein the primary drying vacuum degree is 0.25-0.65mbar, the primary drying temperature is 20 deg.C, and the maximum drying temperature is 25 deg.C. The obtained finished product can meet the requirements of CP, USP and EP pharmacopoeia.
After being taken orally, the medicine reacts with BMAA in intestinal tract to reduce the concentration of BMAA in human body until the BMAA is eliminated. Finally achieving the purpose of improving and treating the autism.
The embodiments show that vancomycin hydrochloride provided by the invention can significantly reduce the concentration of neurotoxin beta-methylamino-L-alanine, and treatment of autism is realized by taking neurotoxin beta-methylamino-L-alanine as a target point.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. Use of vancomycin hydrochloride in the manufacture of an agent that reduces the level of neurotoxin beta-methylamino-L-alanine.
2. Use of vancomycin hydrochloride in the preparation of an improver for the treatment of a disease caused by neurotoxin beta-methylamino-L-alanine.
3. Use according to claim 2, wherein the disease is a neurological dysfunction disease.
4. The use according to claim 3, wherein the neurological disorders comprise Parkinson's disease, alzheimer's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis.
5. Application of vancomycin hydrochloride in preparing medicine for treating autism.
6. Use according to claim 5, wherein the vancomycin hydrochloride is capable of being replaced by norvancomycin hydrochloride.
7. Use according to claim 5 or 6, wherein the medicament comprises an excipient and the medicament is a lyophilisate.
8. The use according to claim 7, wherein the medicament has a potency of not less than 1000 vancomycin hydrochloride units per 1mg anhydrous.
9. The use of claim 5, wherein the medicament is an oral formulation.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211378726.XA CN115554390A (en) | 2022-11-04 | 2022-11-04 | Application of vancomycin hydrochloride in preparation of agent for reducing neurotoxin beta-methylamino-L-alanine level |
| ZA2023/03628A ZA202303628B (en) | 2022-11-04 | 2023-03-16 | Application of vancomycin hydrochloride in preparation of reagent for reducing the level of neurotoxin beta-methylamino l-alanine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211378726.XA CN115554390A (en) | 2022-11-04 | 2022-11-04 | Application of vancomycin hydrochloride in preparation of agent for reducing neurotoxin beta-methylamino-L-alanine level |
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| Publication Number | Publication Date |
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| CN115554390A true CN115554390A (en) | 2023-01-03 |
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| CN202211378726.XA Withdrawn CN115554390A (en) | 2022-11-04 | 2022-11-04 | Application of vancomycin hydrochloride in preparation of agent for reducing neurotoxin beta-methylamino-L-alanine level |
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| Country | Link |
|---|---|
| CN (1) | CN115554390A (en) |
| ZA (1) | ZA202303628B (en) |
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- 2022-11-04 CN CN202211378726.XA patent/CN115554390A/en not_active Withdrawn
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