CN106420790A - Application of hypoxanthine nucleotide in preparation of heart muscle force enhancing preparation - Google Patents
Application of hypoxanthine nucleotide in preparation of heart muscle force enhancing preparation Download PDFInfo
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- CN106420790A CN106420790A CN201610819770.8A CN201610819770A CN106420790A CN 106420790 A CN106420790 A CN 106420790A CN 201610819770 A CN201610819770 A CN 201610819770A CN 106420790 A CN106420790 A CN 106420790A
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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Abstract
The invention discloses an application of hypoxanthine nucleotide in preparation of a heart muscle force enhancing preparation. Experiments show that hypoxanthine nucleotide as a flavor enhancer in food can effectively enhance contractility of cardiac muscle cells or the whole heart, so that hypoxanthine nucleotide can be taken as the heart muscle force enhancing preparation and becomes an ingredient for treating heart muscle force weakening diseases such as cardiac failure, myocarditis, myocardial infarction and the like.
Description
Technical field
The invention belongs to field of medicaments, it is related to the medicinal usage of nucleotide, particularly to inosine monophosphate, IMP in preparation
Strengthen the application in the pharmaceutical preparation of myocardium power.
Background technology
At present with regard to the purposes of inosine monophosphate, IMP (IMP), it is concentrated mainly on animal and Food Science.Hypoxanthine core
Thuja acid also known as inosinic acid, usually as a kind of tasty agentss, for increasing or evaluating the delicate flavour degree of meat food.
In the middle of the 19th century, doctor Liebig of Germany isolates inosinic acid from steamed beef soup；1913, the little jade of Japan was new
Taro confirms that inosinic acid and its esters have delicate flavour；Nineteen sixty utilizes microbial fermentation processes to produce the core such as inosinic acid and guanyl
Thuja acid based food flavour enhancer is successful, and the production development making food flavor enhancer is to a new level.
, since being found, foreign scholar is from Food Science, biochemistry, physiology and threpsology angularly to it for inosinic acid
Conduct extensive research, result of study mainly has following several respects：Oneself determines that in meat, inosinic acid is mainly derived from A T P's
Degraded；The factor of impact inosine absolute acid stability is mainly the effect of temperature, pH and enzyme；The content of different types of animal inosinic acid
There is larger difference；Determine the chemical property of inosinic acid and the safety in food；Determine inosinic acid fresh with glutamic acid type
The synergism of taste agent and the impact to flavour of food products；Physiologic Studies finds, the sensitive position in oral cavity for the inosinic acid is mainly
Back of tongue, nervus glossopharyngeus play a major role, but Transduction Mechanism in vivo requires study to its nerve stimulation；In food industry
In, inosinic acid is used as flavour enhancer.
Content of the invention
It is an object of the invention to exploring the new application in field of medicaments for the inosine monophosphate, IMP, specifically study it for the heart
The effect of myocyte, and the application as myocardium power reinforcing agent.
Present invention research finds, inosine monophosphate, IMP (IMP) has enhancing heart positive inotropic and do not cause the rhythm of the heart to lose
Normal effect, and experiments prove that the mechanism of this effect.
The present invention passes through to detect the shadow to rat myocardial cell function for the IMP using the unicellular dynamic edge detecting system of IonOptix
Ring, result display IMP can strengthen the contraction of myocardial cell and myocardial cell calcium transient is had no significant effect.
The present invention is tested by Perfused isolated heart it was demonstrated that the impact to cardiac function for the IMP, illustrates that IMP directly makees
Use heart and can strengthen ventricular systole pressure, improve cardiac function.
Above-mentioned description of test, inosine monophosphate, IMP has the effect of the contractility strengthening myocardial cell or overall heart,
May be used in the preparation of myocardium power reinforcing agent.
Thus, the present invention provides a kind of pharmaceutical preparation for strengthening myocardium power, comprises inosine monophosphate, IMP as work
Property composition.Inosine monophosphate, IMP and pharmaceutically acceptable adjuvant can be made various forms of pharmaceutical preparatioies.
Described " pharmaceutically acceptable adjuvant " includes pharmaceutically acceptable carrier, excipient, diluent etc., they with
Active component inosine monophosphate, IMP is compatible.With the preparation pharmaceutical preparation of pharmaceutically acceptable adjuvant to ordinary skill
It is known for personnel.The pharmaceutical preparation of the present invention comprises inosine monophosphate, IMP as active component, by hypoxanthine core
Thuja acid and pharmaceutically acceptable adjuvant are combined, and are configured to various preparations, preferably solid preparation and liquid preparation.This
The preparation of invention can be unit dosage form, such as tablet, capsule (include sustained release or releasing pattern is released in delay), suppository,
The various dosage form such as pill, powder, unguentum, suspensoid, granule, tincture, syrup, emulsion agent, suspension, injection and various
Slow release formulation, thus being suitable for various form of medication, for example oral, parenteral injection, mucosa, muscle, intravenouss, subcutaneous, ophthalmic,
Intradermal or the form of medication through skin etc..
To sum up, present invention discover that inosine monophosphate, IMP can be used as a kind of cardiac muscle power reinforcing agent, it can effectively strengthen the heart
Myocyte or the contractility of overall heart, consequently, it is possible to become the cardiac muscle power such as heart failure, myocarditiss, heart infarction to weaken controlling of disease
Treat composition.
Brief description
Fig. 1 shows that embodiment 1 adopts unicellular dynamic edge detection system synchronous detecting IMP of IonOptix thin to rat heart muscle
Born of the same parents' contraction and the result of calcium transient.
Fig. 2 shows left ventricle development pressure (LVDP) and dP/dt (left ventricular contraction that in embodiment 2, perfusion IMP leads to
Pressure every point of rate of climb) change, illustrate that perfusion IMP makes the contractile function of isolated heart strengthen.
Specific embodiment
Below by embodiment, the present invention will be further described, but limits the scope of the present invention never in any form.
Embodiment 1, IMP strengthen mycardial contractility experiment
Cell function is detected using the unicellular dynamic edge detecting system of IonOptix.
(1) separation of rat myocardial cell
Tyrode：130mM NaCl, 5.4mM KCl, 0.5mM MgCl2, 25mM Hepes, 0.33mM NaH2PO4, 22mM
Glucose, adjusts pH to 7.35 with NaOH.Tyrode fills oxygen in advance more than 30 minutes and continues oxygenation in perfusing course.
Enzyme liquid 1：Tyrode 35mL, 8.75 μ L CaCl2(0.2M), II Collagenase Type 25mg, XIV type protease 3 mg；
Enzyme liquid 2：10mL enzyme liquid 1,7.5 μ L CaCl2(0.2M)；
Enzyme liquid 3：15mL enzyme liquid 1,50 μ L CaCl2(0.2M), BSA 40mg；
Multiple calcium liquid：Tyrode 20mL, 100 μ L CaCl2(0.2M), BSA 40mg.
Rat anaesthetizes (1mL/100g) with 20% Ethylurethanm solution, after Animal Anesthesia, opens thoracic cavity, takes out heart.Treat
After heart exclusion remained blood in freezing tyrode, by aorta insertion langendoff perfusion tube front end syringe needle, and with carefully
Knot is pricked.Maintain 37 DEG C of perfusate constant temperature using circulator bath system, perfusion rate is 3mL/min.First filled with no calcium tyrode
Flow liquid by after the exclusion of endocardial blood, then with enzyme liquid 1 perfusion.Circulated about 15 minutes with enzyme liquid 2 perfusion, when heart deliquescing
Left ventricle is cut (must not atrium and right ventricle) and shred in 37 DEG C of enzyme liquids 3.After the cardiac muscular tissue shredding and enzyme liquid 3 suspension
With the centrifugation 1 minute of 500rpm on centrifuge, remove enzyme liquid, with multiple calcium liquid re-suspended cell precipitation.Tissue disintegrating slag continues
After being suspended with enzyme liquid 3,500rpm is centrifuged 1 minute, goes enzyme liquid, with multiple calcium liquid re-suspended cell precipitation, is repeated 3 times, thinless to disintegrating slag
Till born of the same parents.The collection liquid of re-suspended cell several times is merged, standing makes cell precipitation in 30 minutes, sop up supernatant, add and answer calcium in right amount
Liquid re-suspended cell can be used for subsequent experimental.
(2) adopt unicellular dynamic edge detection system (IonOptix company, the U.S.) the synchronous detecting myocardial cell of IonOptix
Shrink and calcium transient (Ca2+transient).
Fura-2/AM (final concentration 2 μ g/mL) and myocardial cell room temperature lucifuge are incubated 30min, are fluoresced light using bidifly
Electric dynode system (IonOptix, U.S.) detects fluorescence signal.The light of 75W ultraviolet xenon lamp transmitting passes through 340nm's or 380nm
Optical filter reaches 0.5Hz stimulates the lower myocardial cell shrinking, intracellular and Free Ca2+In conjunction with fluorescent material be excited, its
Penetrate light to be detected at 510nm and pass through photomultiplier tube record.Cell is in succession rapidly by 340nm and 380nm excitation light irradiation
And alternate sweep, Cytoplasmic Ca2+The change of concentration is reflected by the ratio of above two wavelength fluorescent intensity.
Appropriate (the general 30 μ l) myocardial cell suspensions taking incubation Fura-2/AM are placed in inverted microscope (Olympus) load
The little interior of cell perfusion on thing platform, with oxygen-containing Zinciodati Comp solution perfusion (1mL/min), the wide electrical field stimulation of 0.5Hz, 5ms ripple, field is pierced
Swash and produced by the platinum electrode that perfusion cell two bottom sides are inlayed, cellular contraction image is transferred to IonOptix's by 40 × object lens
MyoCam photographic system simultaneously presents on a monitor.Myocardial cell sarcomere (sarcomere) shrinkage amplitude and contraction/relaxation speed
The indexs such as degree by the automatic Real-time Collection of computer and record.Cell enter perfusion cell after, immediately sink and with cell bottom very
Fast adhesion, perfusate can not be washed away in conventional speeds.Selection elongated rod shape, cell edges refractivity are good, and band is clear, cell
On film, the ventricular muscle cell of no cavity carries out laboratory observation.Cellular contraction constant amplitude at least more than 5min before administration.System is remembered
The result of record is as shown in figure 1, the concentration of IMP used in experiment is 10-4M.
It is worth based on cell sarcomere shrinkage amplitude value before non-administration during statistics, after dosing, system recorded cell and receives
The value that the range value of contracting compares gained with basic value to react the impact to myocardial cell after dosing, as shown in Figure 1.Can from Fig. 1
To find out, after IMP perfusion, the shrinkage amplitude of myocardial cell strengthens.
Embodiment 2, the Perfused isolated heart detection impact to cardiac function for the IMP
Krebs-Henseleit (K-H) perfusate：NaCl 118.0mmol/L、KCI 4.7mmol/L、KH2PO4
1.2mmol/L、MgSO4·7H2O 1.2mmol/L、CaCl22.5mmol/L、NaHCO32.5mmol/L、Glucose
11.1mmol/L.
Rat anaesthetizes (0.5mL/100g) with 20% Ethylurethanm solution, after Animal Anesthesia, my humble abode intravenous injection heparin, and beat
Open thoracic cavity, the rapid heart that takes out is placed in 4 DEG C of Krebs-Henseleit (K-H) perfusate, gently extrudes heart, empties the heart
Aorta is fixed in the intubation of langendorff perfusion device by the blood of dirty interior residual immediately, meets K- through tee T switch
H perfusate, perfusate is with 95%O2And 5%CO2Fully saturation, perfusion pressure about 70mmHg, perfusion temperature is 37 DEG C about.From
The most advanced and sophisticated conduit with water pocket of left auricle insertion, adjusts water pocket Water filling degree, the preload making heart, within 10mmHg, passes through
Pressure transducer connects MedLab bio signal collection processing system record left ventricular pressure force curve, gathers each parameters of left ventricular function.
Use Krebs-Henseleit (K-H) perfusate heart perfusion at least 10min first, treat that heart stabilizer shrinks diastole
Afterwards, by tee T switch-mode regulation perfusion IMP, detect changes of cardiac function, result is as shown in Figure 2 it can be seen that Krebs- simultaneously
After Henseleit (K-H) perfusate perfusion, the change of isolated heart ventricular systole diastolic pressures steadily, as shown in A section in Fig. 2, fills
After stream IMP, isolated heart ventricular systole maximum pressure strengthens, as shown in B section in Fig. 2；Heart systolic pressure per minute changes (dP/
Dt part) also strengthen, after cardiac perfusion IMP is described, contractile ability strengthens, and cardiac function improves.
Claims (4)
1. purposes in the myocardium power reinforcing agent of preparation for the inosine monophosphate, IMP.
2. purposes as claimed in claim 1 is it is characterised in that described cardiac muscle power reinforcing agent is to weaken disease for preventing and treating myocardium power
The medicine of disease.
3. purposes as claimed in claim 2 it is characterised in that described cardiac muscle power weaken disease be heart failure, myocarditiss and/
Or heart infarction.
4. a kind of pharmaceutical preparation for strengthening myocardium power, comprises inosine monophosphate, IMP as active component, and pharmaceutically
Acceptable adjuvant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610819770.8A CN106420790A (en) | 2016-09-13 | 2016-09-13 | Application of hypoxanthine nucleotide in preparation of heart muscle force enhancing preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610819770.8A CN106420790A (en) | 2016-09-13 | 2016-09-13 | Application of hypoxanthine nucleotide in preparation of heart muscle force enhancing preparation |
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| CN106420790A true CN106420790A (en) | 2017-02-22 |
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| CN201610819770.8A Pending CN106420790A (en) | 2016-09-13 | 2016-09-13 | Application of hypoxanthine nucleotide in preparation of heart muscle force enhancing preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327362A (en) * | 2019-08-26 | 2019-10-15 | 北京大学 | Application of the inosinic acid in preparation antidepressant |
| CN110478363A (en) * | 2019-08-22 | 2019-11-22 | 北京大学 | The new medicine use of cIMP |
| JPWO2019131308A1 (en) * | 2017-12-27 | 2020-12-10 | 公立大学法人横浜市立大学 | Arrhythmia treatment with 9-β-D-arabinofuranosyl hypoxanthine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101052390A (en) * | 2004-09-17 | 2007-10-10 | 味之素株式会社 | Medicine and food for preventing / improving functional digestive disorder |
-
2016
- 2016-09-13 CN CN201610819770.8A patent/CN106420790A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101052390A (en) * | 2004-09-17 | 2007-10-10 | 味之素株式会社 | Medicine and food for preventing / improving functional digestive disorder |
Non-Patent Citations (3)
| Title |
|---|
| 朱平军等: ""肌苷对缺氧心肌跨膜电位和收缩强度的影响"", 《生理学报》 * |
| 罗红鹤等: ""先天性心脏病合并心功能不全患者心肌AMP分解途径的探讨"", 《中国病理生理杂志》 * |
| 魏旭东: "《血液病药物手册》", 31 May 2001 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2019131308A1 (en) * | 2017-12-27 | 2020-12-10 | 公立大学法人横浜市立大学 | Arrhythmia treatment with 9-β-D-arabinofuranosyl hypoxanthine |
| JP7137852B2 (en) | 2017-12-27 | 2022-09-15 | 学校法人福岡大学 | Arrhythmia treatment with 9-β-D-arabinofuranosylhypoxanthine |
| CN110478363A (en) * | 2019-08-22 | 2019-11-22 | 北京大学 | The new medicine use of cIMP |
| CN110478363B (en) * | 2019-08-22 | 2022-09-06 | 北京大学 | New medicinal application of cIMP |
| CN110327362A (en) * | 2019-08-26 | 2019-10-15 | 北京大学 | Application of the inosinic acid in preparation antidepressant |
| CN110327362B (en) * | 2019-08-26 | 2022-09-27 | 北京大学 | Application of hypoxanthine nucleotide in preparation of antidepressant drug |
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| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Chen Zhengju Inventor after: Gao Yuansheng Inventor after: Wang Shiqiang Inventor before: Chen Zhengju Inventor before: Wang Shiqiang |
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| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170222 |