CN112675221A - Application of long pepper total alkaloids and piperine in preparation of adjuvant therapy medicines for Parkinson's disease - Google Patents
Application of long pepper total alkaloids and piperine in preparation of adjuvant therapy medicines for Parkinson's disease Download PDFInfo
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Abstract
The invention discloses long pepper total alkaloid and application of piperine in preparation of a Parkinson disease adjuvant therapy medicament. The invention provides a long pepper total alkaloid and a new application of a piperine medicament in a product with at least one function of the following a-e: a. prevention and/or adjuvant treatment of parkinson's disease; b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa; c. inhibiting the growth of enterococcus faecalis; d; reducing the metabolism of enterococcus faecalis to levodopa; e. reducing peripheral conversion of levodopa. Experiments prove that the long pepper total alkaloids and the piperine have the effects of inhibiting the activity of tyrosine decarboxylase, inhibiting the growth of enterococcus faecalis and reducing the metabolism of the enterococcus faecalis on levodopa, and can be used for preparing the Parkinson disease adjuvant therapy medicine.
Description
Technical Field
The invention belongs to the field of traditional Chinese medicine chemistry and molecular biology, and relates to application of long pepper total alkaloids and piperine in preparation of an adjuvant therapy medicament for Parkinson's disease.
Background
Parkinson's Disease (PD) is a common age-related neurodegenerative disease with loss of dopaminergic neurons in the dense substantia nigra of the brain and exhaustion of dopamine at the basal ganglia as the main pathological manifestations. The clinical manifestations mainly include resting tremor, muscular rigidity, unstable posture, bradykinesia and other obvious motor symptoms, and also can be accompanied by non-motor symptoms such as anxiety, depression, sleep disorder, cognitive dysfunction and the like, and the life quality of patients is seriously influenced. As society gradually ages, PD patients are showing a global and sharp increase. According to statistics, by 2015, the population of PD patients is over 620 ten thousand worldwide, the prevalence rate is increased by nearly 22% compared with 1990, and by 2040, the population of PD patients is expected to break 1700 ten thousand. PD not only seriously affects the physiological and psychological health of patients, but also brings great economic burden to families and society.
The current drug treatment for parkinson's disease is still dominated by levodopa replacement therapy. Levodopa (Levodopa, L-DOPA) is a precursor substance of dopamine, can penetrate blood brain barrier, and can directly supplement dopamine deficiency in brain of a patient after being converted into dopamine by catalysis of DOPA decarboxylase. L-DOPA has a rapid and effective improvement of motor symptoms in PD patients at the initial stage of treatment, and is called the "gold standard" for PD-treating drugs. However, oral administration of L-DOPA has extremely high peripheral conversion rates, and studies have shown that only 1-3% of the drug is able to "escape" the catalytic action of enzymes in the peripheral system and ultimately enter the brain for therapeutic effect. Dopamine produced by a large amount of conversion in the peripheral system can activate dopamine receptors located in the cardiac muscle, vascular smooth muscle, and the like, and thus side effects such as orthostatic hypotension and arrhythmia are produced. In addition, most patients suffer from a decrease in the efficacy of the drug or a delay in the "on" period as soon as several years or even months after receiving L-DOPA treatment, so that the patients have to increase the dosage of L-DOPA to stabilize the condition, which may further aggravate the side effects. Repeating the steps seriously affects the life quality of the patients. At present, aiming at the problems existing in the levodopa treatment in clinic, the improvement is attempted by a combined medication mode. However, research results show that the improvement effect is not ideal, the inhibition effect on the peripheral metabolism of L-DOPA is insufficient, the incidence rate of adverse reactions in treatment is high, and the intervention effect on the dyskinesia and non-motor symptoms of patients is weak. Recent research shows that enterococcus faecalis is probably the main metabolic bacterium of L-DOPA in human intestinal tract, and the process of catalyzing L-DOPA decarboxylation by Tyrosine Decarboxylase (TDC) expressed by the bacterium is a key link of intestinal flora influencing the treatment effect of L-DOPA. Therefore, finding effective components with the functions of regulating intestinal flora, reducing the abundance of enterococcus faecalis in the intestinal tract and intervening the catalysis and expression of metabolic enzymes becomes a new direction for developing the adjuvant therapy medicaments for the Parkinson's disease.
The fructus Piperis Longi is dry, nearly mature or mature fruit cluster of Piper longum L. of Piper of Piperaceae (Piperaceae), and is a common medicine for Chinese traditional medicine, Mongolian medicine, Tibetan medicine and Uighur medicine. Long Pepper is pungent and warm in flavor, can warm the middle-jiao to dispel cold, and descend qi to relieve pain, and is commonly used for regulating stomach fire and treating gastrointestinal diseases such as stomach cold, abdominal pain, hiccup, diarrhea and the like. Modern pharmacological research shows that amide alkaloid components rich in the long pepper have wide pharmacological activities of antibiosis, anti-inflammation, antioxidation, neuroprotection and the like. At present, the researches on the intervention of the piper longum total alkaloids and the piperine on the Parkinson disease are mostly based on approaches such as anti-inflammation, antioxidation and the like, and no researches and reports on the tyrosine decarboxylase inhibitor and the intervention on the growth and metabolic functions of enterococcus faecalis exist.
Disclosure of Invention
The invention aims to provide application of long pepper total alkaloids and piperine in preparation of an adjuvant therapy medicament for Parkinson's disease.
The invention claims the application of Piper longum total alkaloids Piper Longum Alkaloid (PLA) in the preparation of a product with at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
The invention also claims the application of piperine in preparing products with at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
The product is in particular a medicament or a pharmaceutical preparation.
The peripheral transformation of the levodopa refers to the peripheral transformation of the levodopa into Dopamine (DA) outside the brain after the levodopa is orally taken.
The pharmaceutical preparation is any pharmaceutically acceptable dosage form, and comprises at least one of tablets, capsules, injections, granules, suspensions and solutions.
The invention also claims a medicine or a medicine composition or a medicine preparation, the active component of which is the Piper longum alkaloid total alkaloid,
the drug or the drug composition or the drug preparation has at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
The invention also claims a medicament or a pharmaceutical composition or a pharmaceutical preparation, the active ingredient of which is piperine,
the drug or the drug composition or the drug preparation has at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
Specifically, the medicine or the pharmaceutical composition or the pharmaceutical preparation is any pharmaceutically acceptable dosage form, including at least one of tablets, capsules, injections, granules, suspensions and solutions.
The Piper longum total alkaloids Piper Longum Alkaloid (PLA) is the total alkaloid component in the Piper longum medicinal material; comprises at least one of Piperone Piperine, Dipperlonguminine Dihydropiperlonguminine, Piperlonguminine Piperlonguminine, Piperanine Piperlonguminine, Methyl-piperate piperonate, Pelletorine, Guineensine Guinei-Nekaline, Pipercallosine, Dehydropiperonaline, Pipernatine, Retrofiramide and Brachyamide B.
The invention utilizes molecular docking technology and enzymatic reaction experiments to screen and verify the tyrosine decarboxylase inhibition activity of 12 amide components contained in the long pepper.
Experiments prove that: the piper longum total alkaloids, the piperine, the dihydropiperlonguminine, the piperlonguminine and the Pipernonanine show obvious inhibition effect (I% > 10%) on tyrosine decarboxylase, wherein the piper longum total alkaloids and the piperine have good inhibition effect and can inhibit the catalysis effect of the tyrosine decarboxylase on the levodopa to a certain degree.
In order to further explore the intervention effect of the piperine and the long pepper total alkaloid on the growth of enterococcus faecalis and the metabolism of levodopa, the invention adopts a trace broth dilution method and an enterococcus faecalis in-vitro metabolism experiment for testing.
Experiments prove that: diluting the compound by 2 times by trace broth dilution method, adding bacterial liquid, mixing, and culturing at 35 deg.C for 18-24 h. OD of each bacterial liquid was measured by a microplate reader600The results of the light absorption values (bacterial liquid concentrations) show that the piperine and the long pepper total alkaloid both have the inhibition effect on the growth of the enterococcus faecalis and show dose dependence. Inoculating enterococcus faecalis into TSB liquid culture medium containing levodopa, adding high, medium and low dose piperine or fructus Piperis Longi total alkaloid, and incubating at 35 deg.C for 72h in anaerobic jar. The production amount of dopamine in each culture system is detected by an HPLC-ECD method. The results show that, compared with the normal group, piperine andthe long pepper total alkaloids can reduce the metabolism of enterococcus faecalis on levodopa and show dose dependence.
Drawings
FIG. 1 is a graph of piperine inhibition of tyrosine decarboxylase. Shown is the relative enzyme activity curve of TDC in each system at different concentrations of piperine treatment.
FIG. 2 shows the growth inhibition of enterococcus faecalis by piperine and Piper longum total alkaloids. (A, piperine B, long pepper total alkaloid). The figure shows the bacterial liquid OD of enterococcus faecalis treated by piperine or piper longum total alkaloids with different concentrations determined by trace broth dilution method600And (4) light absorption value.
FIG. 3 shows the inhibitory effect of piperine and Piper longum total alkaloids on L-dopa metabolism by enterococcus faecalis.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified. The enzymes and strains used in the following examples are as follows:
tyrosine decarboxylase is derived from Streptococcus faecalis (TDC, alkadin, batch number: G1520070);
enterococcus faecalis ATCC29212(Enterococcus faecalis ATCC29212, ZOMANBIO, Lot: ZK 3763).
Example 1 screening of alkaloid to TDC inhibitory Activity in Piper longum based on molecular docking
A Surflex-Dock template of SYBYL X-1.2 software is adopted to carry out trial docking on compound molecules and the constructed enzyme protein structure. The strength of the interaction between the compound and the protein is judged according to a cut-off value (Total score), the higher the score is, the higher the strength of the interaction is, the score is greater than 4.0, the certain binding activity is shown between the compound and the protein, and the score is greater than 6.0, the better binding activity is shown. .
The TDC (PDB database No. 5HSJ) protein structure was downloaded from the PDB database. The structure of the target protein is optimized, including increasing hydrogen atoms and charges and repairing lost amino acid residues. Selection in SYBYL X-1.2 software packageAMBER FF99 force field energy-optimizes protein structure. The "Ligand" option under the Protomol Generations module was used to determine the surrounding of known inhibitor small molecules
The space of (a) is the active pocket and the proto-molecule (protomol) is used to create the binding pocket. Other parameters adopt Surflex-docking default parameters in a SYBYL X-1.2 software package. Adopting SYBYL X-1.2 software to optimize the structure of the piperine and the analogues thereof, and utilizing a Surflex-Dock template to carry out trial docking on the compound molecules and the constructed TDC protein structure.
The results show that 12 amide alkaloid components in the long pepper can be combined with the active site of the TDC protein to a certain extent.
Table 1 shows the molecular docking scores of 12 amide components contained in piper longum and tyrosine decarboxylase. Table 1 shows the results of a trial docking of the compound with the TDC protein active pocket using SYBYL X-1.2 software to predict the interaction force between the compound and TDC with the obtained cut-off (Total Score).
TABLE 1 molecular docking scores of 12 amide components contained in Piper longum and tyrosine decarboxylase
Note: the novel Piperine (Piperine) and the novel Dihydropiperlonguminine (Dihydropiperlonguminine) and the novel Piperine (Piperine) Methyl-piperate (Methyl piperate) are rich in pellierine (Piperine) and Guineenine (Guinea Piperine).
Example 2 demonstration of the inhibitory Effect of alkaloids in Piper longum on tyrosine decarboxylase by enzymatic reaction
Tyrosine decarboxylase can catalyze the decarboxylation of levodopa to dopamine.The dopamine content in the reaction system can be measured by an HPLC-ECD method. By the formula I ═ CDA positive-CDA measurement)/CDA positiveX 100% the inhibition I% of the TDC by the compound is calculated.
And (3) taking a sterilized 1.5ml brown centrifuge tube, sequentially adding the solutions according to the adding sequence of a potassium acetate buffer solution (pH is 5.0), a PLP solution (1mM), a nicotinic acid solution (positive control) or a compound solution and a TDC enzyme solution (0.2mg/ml), and blowing and uniformly mixing after adding the solution every time. The centrifuge tube (total volume of liquid 600. mu.L) was placed in a metal bath preheated to 38 ℃ and incubated at constant temperature for 15 min. After being taken out, the levodopa solution (0.75mM) is added, and the mixture is blown and uniformly mixed. Putting the centrifuge tube (the total volume of the liquid is 1mL) into a metal bath, and reacting for 15min at the constant temperature of 38 ℃. After the reaction mixture was taken out, 0.7% perchloric acid was added to terminate the reaction. The tube was placed in a low temperature high speed centrifuge at 15000g and centrifuged at 4 ℃ for 5 min. And (5) sucking the centrifuged supernatant, and filtering the supernatant by using a filter membrane to obtain a sample. The dopamine content in each system was determined by HPLC-ECD.
FIG. 1 is a graph of piperine inhibition of tyrosine decarboxylase. FIG. 1 is a graph showing the relative enzyme activity of TDC in each system under various concentrations of piperine.
Table 2 shows the effect of piperine and Piper longum total alkaloids on TDC using formula I%DA positive-CDA measurement)/CDA positiveX 100% calculated, and the inhibition is expressed as inhibition (i.e. I%).
TABLE 2 inhibitory Effect of Piperine and Piper longum Total alkaloid on TDC
The results show that: piper longum total alkaloids, piperine, dihydropiperlonguminine, piperic acid methyl ester, piperlonguminine and Pipernonanine have tyrosine decarboxylase inhibiting effect (I% > 10%).
Wherein, the inhibition ratio of the long pepper total alkaloid is calculated according to the following method: the piperine content is about 50 percent of the total alkaloids in the long pepper, so the total alkaloid concentration is calculated according to the piperine content to prepare the long pepper total alkaloid solution. And (3) measuring the generation amount of the reacted dopamine by using the enzymatic reaction method, and substituting the measured generation amount into a calculation formula to obtain the inhibition rate of the long pepper total alkaloid.
Example 3 measurement of the Effect of Piperine and Piper longum Total alkaloid on the growth of enterococcus faecalis by a diluted Broth method
OD600Called turbidity, at 600nm, regularly shaped microorganisms have a linear relationship between concentration and absorbance, such as bacteria, yeast, etc. If the OD value is in the range of 0.3 to 0.7, it is 1ODBacterial suspension concentration was calculated as 1.0 × 109 CFU/ml.
A sterile 96-well plate was used, and 200. mu.L of the compound solution was added to the first well of each row, and 100. mu.L of the LTSB liquid medium was added to the wells of columns 2 to 12. Transferring 100 mu L of liquid medicine from the 1 st row of holes to the 2 nd row of holes by using a liquid transfer gun, uniformly mixing, sucking 100 mu L of liquid medicine from the 2 nd row of holes, adding the liquid medicine into the 3 rd row of holes, uniformly mixing, repeating the steps until the step reaches the 10 th row, sucking 100 mu L of liquid medicine after uniform mixing, and discarding. The enterococcus faecalis liquid (1X 10) was added to each well of the 1 st to 11 th columns in sequence5CFU/mL)100 μ L, mixing by gentle shaking, culturing at 35 deg.C for 18-24h, taking out, and determining OD with enzyme-labeling instrument600Lower absorbance values.
The results shown in FIG. 2 show that: when the administration concentration is 25 mug/mL, the inhibition rate of the piperine on the enterococcus faecalis is 20.23%. The inhibition rate of the long pepper total alkaloid is 25.25 percent. Experiments prove that the long pepper total alkaloid and the piperine have certain inhibition effect on the growth of enterococcus faecalis and show dose dependence.
Example 4 study of the intervention of Piperine and Piper longum Total alkaloid on L-DOPA metabolism by enterococcus faecalis
Tyrosine decarboxylase was found to be ubiquitously expressed in enterococci in human enterobacteria by searching for a reference genome of a human microorganism. 98.4% of enterococcus faecalis is searched to have tyrDC gene, wherein the homology of amino acid at the position is 99.8%, which shows that the enterococcus faecalis has the capability of stably expressing tyrosine decarboxylase and is the main metabolic bacteria of levodopa in human intestinal tracts. The metabolic condition of enterococcus faecalis can be evaluated by inoculating the bacterial liquid into a liquid culture medium added with levodopa, incubating for 72h at 35 ℃, and detecting the generation amount of dopamine in a culture system by using HPLC-ECD.
Taking a sterile 6-hole plate;
a blank control group (containing L-DOPA, sterile) was set up: TSB liquid medium containing L-DOPA;
the TSB liquid culture medium containing L-DOPA is obtained by dissolving appropriate amount of L-DOPA in TSB liquid culture medium and mixing, and the concentration of L-DOPA is 0.6 mM;
normal control group (containing L-DOPA, having bacteria): diluting enterococcus faecalis liquid (1 × 10)5CFU/mL)1mL was mixed with 1mL of TSB broth containing L-DOPA;
piperine (PIP) group (L-DOPA free, PIP containing, mycosis): diluting enterococcus faecalis liquid (1 × 10)5CFU/mL)1mL was mixed with 1mL of TSB broth containing PIP;
the TSB liquid culture medium containing PIP is a culture medium obtained by dissolving a proper amount of PIP in the TSB liquid culture medium and mixing, and the concentration of PIP is 50 ug/mL;
long pepper total alkaloid (PLA) group (containing no L-DOPA and PLA and having bacteria): diluting enterococcus faecalis liquid (1 × 10)5CFU/mL)1mL and 1mL of TSB liquid culture medium containing PLA are mixed evenly;
the PLA-containing TSB liquid culture medium is obtained by mixing a proper amount of PLA dissolved in the TSB liquid culture medium, and the concentration of the PLA is 50ug/mL (measured by the concentration of piperine contained);
PIP combined administration group (containing L-DOPA and PIP, having bacteria): diluting enterococcus faecalis liquid (1 × 10)5CFU/mL)1mL was mixed with 1mL of TSB broth containing L-DOPA and PIP;
the TSB liquid culture medium containing L-DOPA and PIP is a culture medium obtained by mixing proper amounts of L-DOPA and PIP dissolved in the TSB liquid culture medium, wherein the concentration of L-DOPA is 0.6mM, and the concentration of PIP is 50 ug/mL;
PLA combined administration group (containing L-DOPA and PLA and having bacteria): diluting the fecal pelletsBacterial liquid (1X 10)5CFU/mL)1mL was mixed with 1mL of TSB broth containing L-DOPA and PLA;
the TSB liquid culture medium containing L-DOPA and PLA is a culture medium obtained by mixing a proper amount of L-DOPA and PLA dissolved in the TSB liquid culture medium, wherein the concentration of the L-DOPA is 0.6mM, and the concentration of the PLA is 50 ug/mL;
the above groups of substances were added to sterile 6-well plates, each group having three multiple wells. Slightly shaking and mixing, placing into constant temperature shaker at 35 deg.C for culturing for 72h, taking out, adding 10 times of methanol, centrifuging at 4 deg.C and 3500rmp in low temperature high speed centrifuge for 20min, collecting supernatant, and performing electrochemical detection.
The results shown in FIG. 3 show that: when the administration concentration of the piperine/long pepper total alkaloid is 25 mug/mL (high dose), compared with the normal group, the dopamine production amount of the piperine combined administration group is reduced by 14.69%, and the dopamine production amount of the long pepper total alkaloid combined administration group is reduced by 25.65%. Experiments prove that the long pepper total alkaloids and the piperine can reduce the metabolism of enterococcus faecalis to levodopa, and the effect of inhibiting the metabolism is dose-dependent.
Claims (10)
1. The application of long pepper total alkaloid Piper longum alkaloid in preparing a product with at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
2. Use according to claim 1, characterized in that: the Piper longum total alkaloids Piperlongum alkaloid comprises at least one of piperine, dihydropiperlonguminine, piperlonguminine, piperitonin, methyl piperinate, pellitorine, guaifenesin, Piercalosine, Dehydropiperonaline, Pipernonanate, Retrofactamide and Brachyamide B.
3. Use according to claim 1 or 2, characterized in that: the product is a medicament or pharmaceutical formulation.
4. The application of piperine in preparing products with at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
5. Use according to claim 4, characterized in that: the product is a medicament or pharmaceutical formulation.
6. Use according to any one of claims 3 or 5, characterized in that: the pharmaceutical preparation is any pharmaceutically acceptable dosage form, and comprises at least one of tablets, capsules, injections, granules, suspensions and solutions.
7. A medicine or pharmaceutical composition or pharmaceutical preparation contains Piper longum L.Alkaloid as active ingredient,
the drug or the drug composition or the drug preparation has at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
8. The drug or pharmaceutical composition or pharmaceutical preparation according to claim 7, characterized in that: the Piper longum total alkaloids Piperlongum alkaloid comprises at least one of piperine, dihydropiperlonguminine, piperlonguminine, piperitonin, methyl piperinate, pellitorine, guaifenesin, Piercalosine, Dehydropiperonaline, Pipernonanate, Retrofactamide and Brachyamide B.
9. A medicine or pharmaceutical composition or pharmaceutical preparation contains piperine as active ingredient,
the drug or the drug composition or the drug preparation has at least one function of the following a-e:
a. prevention and/or adjuvant treatment of parkinson's disease;
b. inhibiting the catalytic action of tyrosine decarboxylase on levodopa;
c. inhibiting the growth of enterococcus faecalis;
d; reducing the metabolism of enterococcus faecalis to levodopa;
e. reducing peripheral conversion of levodopa.
10. A medicament or pharmaceutical composition or pharmaceutical preparation according to any one of claims 7 to 9, characterized in that: the medicine or the medicine composition or the medicine preparation is any pharmaceutically acceptable dosage form, and comprises at least one of tablets, capsules, injections, granules, suspensions and solutions.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114015761A (en) * | 2021-09-24 | 2022-02-08 | 上海交通大学医学院附属瑞金医院 | Application of excrement tyrDC gene abundance as biomarker for predicting levodopa curative effect |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791336A (en) * | 2010-04-08 | 2010-08-04 | 首都医科大学 | Extract from long pepper and preparation method and application thereof |
| US8021701B1 (en) * | 2005-04-13 | 2011-09-20 | Perry Stephen C | Composition to retard the onset of symptoms of alzheimer's disease |
| CN106389410A (en) * | 2016-12-01 | 2017-02-15 | 首都医科大学 | Application of piperlonguminine in preparation of drugs for treating Parkinson's disease |
| CN110013504A (en) * | 2019-05-13 | 2019-07-16 | 首都医科大学 | Fructus piperis longi total alkaloid is adjusting intestinal flora and is improving the application in Parkinson's disease and Patients with Depression |
| CN111494379A (en) * | 2020-06-13 | 2020-08-07 | 首都医科大学 | Application of piperine in improving early olfactory disorder of Parkinson's disease |
-
2021
- 2021-01-05 CN CN202110006373.XA patent/CN112675221A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8021701B1 (en) * | 2005-04-13 | 2011-09-20 | Perry Stephen C | Composition to retard the onset of symptoms of alzheimer's disease |
| CN101791336A (en) * | 2010-04-08 | 2010-08-04 | 首都医科大学 | Extract from long pepper and preparation method and application thereof |
| CN106389410A (en) * | 2016-12-01 | 2017-02-15 | 首都医科大学 | Application of piperlonguminine in preparation of drugs for treating Parkinson's disease |
| CN110013504A (en) * | 2019-05-13 | 2019-07-16 | 首都医科大学 | Fructus piperis longi total alkaloid is adjusting intestinal flora and is improving the application in Parkinson's disease and Patients with Depression |
| CN111494379A (en) * | 2020-06-13 | 2020-08-07 | 首都医科大学 | Application of piperine in improving early olfactory disorder of Parkinson's disease |
Non-Patent Citations (3)
| Title |
|---|
| RONGRONGXU: "A selective and sensitive UFLC-MS/MS method for the simultaneous determination of five alkaloids from Piper longum L. and its application in the pharmacokinetic study of 6-OHDA-induced Parkinson"s disease rats", 《RSC ADVANCES》 * |
| YINGBI: "Neuroprotective effects of alkaloids from Piper longum in a MPTP-induced mouse model of Parkinson’s disease", 《PARMACEUTICAL BIOLOGY》 * |
| 毕赢: "荜茇化学成分及药理活性研究进展", 《中国药学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114015761A (en) * | 2021-09-24 | 2022-02-08 | 上海交通大学医学院附属瑞金医院 | Application of excrement tyrDC gene abundance as biomarker for predicting levodopa curative effect |
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