CN106035316B - A kind of Celsior of improvement preserves liquid and preparation method thereof for the heart - Google Patents
A kind of Celsior of improvement preserves liquid and preparation method thereof for the heart Download PDFInfo
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- CN106035316B CN106035316B CN201610256995.7A CN201610256995A CN106035316B CN 106035316 B CN106035316 B CN 106035316B CN 201610256995 A CN201610256995 A CN 201610256995A CN 106035316 B CN106035316 B CN 106035316B
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- heart
- celsior
- liquid
- improvement
- preserves
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
Abstract
The invention discloses a kind of Celsior of improvement to preserve liquid, preparation method and application for the heart, and the group of the organ preservative fluid is divided into potassium chloride；Magnesium chloride；Calcium chloride；Mannitol；Histidine；Reduced glutathione；Sodium glutamate；Sodium lactonic；BI 1356；Surplus distilled water.Preparation method is to be added to the container distilled water, sequentially adds potassium chloride, magnesium chloride, calcium chloride, and stirring to color becomes clear；Mannitol, histidine, reduced glutathione, sodium glutamate are added, stirring to color becomes clear；Then sodium lactonic is added, stirring to color becomes clear；The pH value and osmotic pressure value of solution are adjusted, distilled water constant volume places 4 DEG C of Cord bloods.Advantages of the present invention：With good long period organ preservation effect；Promote the recovery of heart function after being filled again for the heart.
Description
【Technical field】
The present invention relates to organ preservative fluid fields, are that a kind of Celsior of improvement preserves liquid and its system for the heart specifically
Preparation Method.
【Background technology】
Heart transplant has been widely accepted as effective therapy of whole latter stage heart disease.Currently, Cord blood is
Clinic transport is for most important measure during the heart, but the effectively holding time is less more than 6 hours, this makes remotely to be obtained for the heart
At difficulty, and for the heart after Cord blood the recovery of heart function also inefficiency when Reperfu- sion.Therefore effective preservation liquid is explored,
It is for the recovery for heart heart function after heart reperfusion injury, promotion long-time ischemic to extend the simple Cord blood time limit, mitigate
Heart transplant is successfully crucial.
Celsior liquid be a kind of high sodium, low potassium, low viscosity extracellular fluid type preserve liquid, be easy to uniformly diffuse to group
Gap is knitted, perfusion effect is improved, conducive to making to cool down for the heart in the short time.Mannitol and Lactobionate in component are macromolecular complex
Matter prevents edema and interstitial edema, the inside and outside water with extra vascular of statocyte as impermeable dose.Reduced form paddy Guang
Sweet peptide, histidine and mannitol, can scavenging hydroxyl, prevent the endothelial cell damage of Mediated by Free Radicals.Histidine/lactose
Acid buffering system can prevent to be poisoned into the cell and promote energy regeneration.Sodium and magnesium ion can limit Ca2+ influx, prevent cardiac muscle cell
Interior " calcium overload ".Calcium overload can activated membrane phospholipase A2, cause cell damage.But micro calcium ion also can avoid " calcium is unusual "
Phenomenon.So-called " calcium is unusual " refers to after no calcium perfusion liquid stops jumping heart, occurring Calcium accumulation inside cells after Reperfu- sion instead, excessively
Calcium make cardiac muscle in tetanic contraction state the phenomenon that.Low potassium can make quickly to stop to fight for the heart, and can limit voltage and rely on
Property calcium channel opening, mitigate ischemic caused by endothelium and cellular damage.But simple Celsior liquid fails to make
6 hours.
BI 1356 (linagliptin) is a kind of dipeptidyl peptidase IV (ipeptidyl-peptidase
4inhibitor, DPP-4) inhibitor, because can by inhibit DPP-4 to internal incretin glucagon-like peptide
(glucagon-likepeptide-1, GLP-1) and glucose-dependent insulinotropic peptide (gastric inhibitory
Polypeptide, GIP) etc. a variety of hormones degradation, promote insulin secretion to reduce blood glucose, clinically mainly used for treating 2
Patients with type Ⅰ DM.Recent studies have found that it can also play the cardiovascular protective effect in addition to blood sugar reducing function.BI 1356 can pass through
The approach such as activated protein kinase A activate cardioprotective kinases, to reducing myocardial infarction area；By inducing myocardial infarction
Electro physiology state when Cardioprotective gene and correlative protein expression increase, stablize heart ischemia afterwards, the rhythm of the heart loses when weakening ischemic
Normal neurological susceptibility, cardiac muscle cell's mitochondria obstacle mediates myocardium protecting action when improving ischemia-reperfusion.It can increase simultaneously
GLP-1 is horizontal, and GLP-1 and its receptor combination active cell survival-signal access improve the left ventricular remodeling after myocardial infarction.Cardiac muscle
Recombined human Stromal cell-derived factor-1α (CXCL12/SDF-1a) horizontal expression increases after infarct, it is to attract stem cell to the heart
The important chemotactic factor (CF) of dirty injury region mediates a series of Myocardial Regenerations and repair process by being combined with CXCR4.BI 1356 can
By inhibiting DPP-4, increases the degradation to SDF-1a, promote Myocardial Regeneration；Also cardiac activities peptide is can be done directly on, by non-
GLP-1 Dependents adjust the activity of brain natriuretic peptide, neuropeptide tyrosine, SDF-1a.Various research prompts, BI 1356 can pass through GLP-1
Or non-GLP-1 approach plays the protective effect to heart.But in the prior art, BI 1356 is only capable of as clinical treatment purposes,
Its protective effect and mechanism in the research or experiment for being detached from human body is still not clear.
【Invention content】
Present invention technical problems to be solved first are to provide a kind of Celsior of improvement and preserve liquid for the heart, to obtain
Extend the effect of the recovery of heart function after being filled again for the heart for heart holding time, promotion.
The present invention solves above-mentioned technical problem and is achieved through the following technical solutions：
A kind of Celsior of improvement preserves liquid for the heart, which is characterized in that in 1000ml preserves liquid, component is respectively：
Potassium chloride 1.12g；Magnesium chloride 2.64g；Calcium chloride 0.01g；
Mannitol 10.93g；Histidine 4.66g；Sodium glutamate 3.74g；Sodium lactonic 6.90ml；
Reduced glutathione 0.92g；BI 1356 1.18 × 10-7~3.54 × 10-7g；
Surplus is distilled water.
The present invention also provides a kind of Celsior of above-mentioned improvement for the preparation method of heart preservation liquid, including specific steps are such as
Under：
According to 1000ml configuration amounts the specific steps are,
(1) 800ml distilled waters are added and are more than in 1000ml containers, sequentially add potassium chloride 1.12g, magnesium chloride
2.64g, calcium chloride 0.01g, stirring to color become clear；Add mannitol 10.93g, histidine 4.66g, sodium glutamate
3.74g, sodium lactonic 6.90ml, stirring to color become clear；Then reduced glutathione 0.92g, BI 1356 is added
1.18×10-7~3.54 × 10-7G, stirring to color become clear；
(2) PH of solution is adjusted to 7.30, osmotic pressure is adjusted to 320mOsm/L, and distilled water is settled to 1000ml, places 4 DEG C
Cord blood.
The present invention also provides BI 1356 in the Celsior for preparing a kind of above-mentioned improvement for the application of heart preservation liquid.
BI 1356 the improvement Celsior for the heart preserve liquid in for prevent for core ischemia Reperfusion injury.
BI 1356 the improvement Celsior for the heart preserve liquid in by activate PI3K/Akt accesses reach prevention supply
The purpose of core ischemia Reperfusion injury.
The beneficial effects of the invention are as follows：
1. perfusion effect can be improved in high sodium (100mmol/L) and low potassium (15mmol/L), shorten for heart temperature fall time.
2. low potassium (15mmol/L) can make quickly to stop to fight for the heart, and can mitigate endothelium caused by ischemic and cellular damage.
3. high sodium (100mmol/L) and high magnesium (13mmol/L) can limit Ca2+ influx, prevent in cardiac muscle cell " calcium overload ".
4. micro-calcium (0.25mmol/L) can avoid " calcium is unusual " phenomenon.
5. mannitol and Lactobionate can prevent edema and interstitial edema.
6. histidine/lactobionic acid buffer system can prevent to be poisoned into the cell and promote energy regeneration.
7. glutamic acid can promote the synthesis of energy of the cardiac muscle cell during ischemia-reperfusion.
8. the BI 1356 added, as DPP-4 inhibitor, research finds that it can prolong by activating PI3K/Akt accesses
The recovery of heart function after length is filled for heart Cord blood time, promotion for the heart again.
【Specific implementation mode】
Embodiment 1, improvement Celsior preserve the formula of liquid for the heart (by taking 1000ml as an example)：
The preparation of raw material：Potassium chloride 1.12g；Magnesium chloride 2.64g；Calcium chloride 0.01g；Mannitol 10.93g；Histidine
4.66g；Sodium glutamate 3.74g；Sodium lactonic 6.90ml；Reduced glutathione 0.92g；BI 1356 1.18 × 10-7~
3.54×10-7g；Enough distilled waters.
Embodiment 2, improvement Celsior preserve the preparation method of liquid for the heart (for configuring 1000ml)：
By 800ml distilled waters be added be more than 1000ml containers in, sequentially add potassium chloride 1.12g, magnesium chloride 2.64g,
Calcium chloride 0.01g, stirring to color become clear；Add mannitol 10.93g, histidine 4.66g, sodium glutamate 3.74g, breast
Sodium saccharate 6.90ml, stirring to color become clear；Then reduced glutathione 0.92g, BI 1356 1.18 × 10 is added-7~
3.54×10-7G, stirring to color become clear；The PH of solution is adjusted to 7.30, osmotic pressure is adjusted to 320mOsm/L, distilled water constant volume
To 1000ml, 4 DEG C of Cord bloods are placed.
Embodiment 3, improvement Celsior preserve the experiment of liquid effect for the heart.
Using In vitrofertilization non-circulating type Langendorff perfusion functional test models, by with simple Celsior for the heart
It preserves liquid phase to compare, a kind of improvement Celsior for studying designed, designed preserves 4 DEG C of low temperature guarantors of liquid long period (9 hours) for the heart
Deposit the preservation effect of In vitrofertilization.
Study subject：Male SD rat, 250~300g of weight
According to so preservation liquid ingredient different grouping is：
Group 1：Simple Celsior liquid stops fighting and preserving 9 hours groups (Celsior)；
Group 2：DPP-4 inhibitor low concentration (BI 1356 containing 0.25nmol/L in Celsior liquid) simultaneously preserves 9 hours
Group (0.25nM)；
Group 3：In DPP-4 inhibitor concentration (BI 1356 containing 0.5nmol/L in Celsior liquid) and preserve 9 hours
Group (0.5nM)；
Group 4：DPP-4 inhibitor high concentration (BI 1356 containing 0.75nmol/L in Celsior liquid) simultaneously preserves 9 hours
Group (0.75nM)；
Implementation process：
Chest is opened after rat weight, cut at aortic bifurcation centrifugation it is dirty, be transferred in the KH liquid of precooling fast after removing residual blood
Speed, which shifts, to be simultaneously fixed on Langendorff perfusion devices, with being passed through 95%O in advance2And 5%CO2The KH liquid rows being fully saturated are normal
The constant pressure infusing (76mmHg) that drives in the wrong direction is advised, keeps temperature to be constant at 37 DEG C during entire perfusion.Left auricle of heart is cut, pressure biography will be connected with
The empty sacculus of sensor is sent into left ventricle, and pressure sensor connect with MedLab System of organism signal, noted into sacculus
Water makes In vitrofertilization left ventricular end-diastolic pressure maintain 6~8mmHg, and records sacculus water injection rate.Balance perfusion 30min
Afterwards, rat cardiac ventricular hemodynamic index heart rate (HR) is recorded by MedLab System of organism signal, left ventricle is sent out
Exhibition pressure (LVDP), left ventricular pressure change rate (± dP/dtmax) etc., and measure coronary artery discharge (CF).Then heart is removed,
Through aortic root retroperfusion heart cryopreservation solution (Celsior liquid), heart is made to stop to fight rapidly to be placed on containing various concentration
The Celsior of drug is preserved in liquid, (4 DEG C) preservation 9h of low temperature.Heart is taken out after Cord blood, and heart is replaced in
In Langendorff perfusion devices, adjusting water injection rate makes it and preserves preceding consistent after being inserted into empty sacculus.With constant temperature (37 DEG C),
95%O2And 5%CO260min is perfused in the KH liquid of saturation again, records hemodynamic index when perfusion 30,45,60min.
It is as follows to 1 testing index result of example：
1 BI 1356 of table is to the influence (Mean ± SEM, n=8) for heart HR and LVDP recovery rate after cold preservation 9h
Compared with Celsior groups, * P<0.05, * * P<0.01.
2 BI 1356 of table is to the influence (Mean ± SEM, n=8) for heart HR × LVDP recovery rates after cold preservation 9h
Compared with Celsior groups, * * P<0.01.
3 BI 1356 of table to after cold preservation 9h for the heart+dP/dtmaxWith-dP/dtmaxInfluence (Mean ± SEM, the n of recovery rate
=8)
Compared with Celsior groups, * P<0.05, * * P<0.01.
4 BI 1356 of table is to the influence (Mean ± SEM, n=8) for heart coronary flow recovery rate after cold preservation 9h
Compared with Celsior groups, * P<0.05, * * P<0.01.
Interpretation of result is as follows：
1. the recovery of heart function：Before Cord blood, each group isolated rat heart LVDP, HR, HR × LVDP ,+dP/
Dtmax and-dP/dtmax there are no significant difference (P>0.05).Compared with before preservation, the simple Celsior liquid of isolated rat heart
After Cord blood 9h, with the extension (30~60min) of multiple filling, LVDP, HR × LVDP ,+dP/dtmax and-dP/dtmax are aobvious
It writes and declines (P<0.05).Compared with Celsior groups, be added in Celsior liquid 3 kinds of various concentrations (0.25,0.5,
BI 1356 0.75nmmol/L) is remarkably improved the recovery (P of above-mentioned indices when multiple filling<0.05), wherein
The recovery rate of 0.75nmol/L BI 1356 groups is significantly higher than 0.25nmol/L and 0.5nmol/L groups (P<0.01).
2. the recovery of coronary flow：Before Cord blood, each group isolated rat heart coronary flow there was no significant difference (P>
0.05).Compared with before preservation, after the simple Celsior liquid Cord blood 9h of isolated rat heart, with multiple filling extension (30~
60min), coronary flow is decreased obviously (P<0.05).Compared with Celsior groups, 0.25nmol/L~0.75nmol/L DPP-4
Inhibitor group coronary flow recovery rate is obviously improved (P<0.01) after, but filling 45min, 60min again, 0.25nmol/L DPP-4
Without significant difference (P between inhibitor group and Celsior groups>0.05)
It is demonstrated experimentally that preserving (9 hours) long period preservation In vitrofertilization at 4 DEG C of liquid, and energy with the Celsior of this improvement
The heart function recovery being effectively promoted after being filled again for the heart.
The above is the preferred embodiment of the present invention, it is noted that for those skilled in the art,
Without departing from the inventive concept of the premise, several improvements and modifications can also be made, these improvements and modifications also should be regarded as this
In the protection domain of invention.
Claims (5)
1. a kind of Celsior of improvement preserves liquid for the heart, which is characterized in that in 1000ml preserves liquid, component is respectively：
Potassium chloride 1.12g；Magnesium chloride 2.64g；Calcium chloride 0.01g；
Mannitol 10.93g；Histidine 4.66g；Sodium glutamate 3.74g；Sodium lactonic 6.90ml；
Reduced glutathione 0.92g；BI 1356 1.18 × 10-7~3.54 × 10-7g；
Surplus is distilled water.
2. a kind of Celsior of improvement according to claim 1 preserves the preparation method of liquid for the heart, which is characterized in that press
According to 1000ml configuration amounts the specific steps are,
(1) 800ml distilled waters are added and are more than in 1000ml containers, sequentially add potassium chloride 1.12g, magnesium chloride 2.64g, chlorine
Change calcium 0.01g, stirring to color becomes clear；Add mannitol 10.93g, histidine 4.66g, sodium glutamate 3.74g, lactose
Sour sodium 6.90ml, stirring to color become clear；Then reduced glutathione 0.92g, BI 1356 1.18 × 10 is added-7~
3.54×10-7G, stirring to color become clear；
(2) PH of solution is adjusted to 7.30, osmotic pressure is adjusted to 320mOsm/L, and distilled water is settled to 1000ml, places 4 DEG C of low temperature
It preserves.
3. BI 1356 preserves the application of liquid in the Celsior for preparing a kind of improvement described in claim 1 for the heart.
4. application as claimed in claim 3, which is characterized in that BI 1356 is for preventing for core ischemia Reperfusion injury.
5. application as claimed in claim 3, which is characterized in that BI 1356 preserves liquid in the Celsior of the improvement for the heart
In by activate PI3K/Akt accesses achieve the purpose that prevent for core ischemia Reperfusion injury.
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| IT201900007446A1 (en) | 2019-05-29 | 2020-11-29 | Giuseppe Castellano | COMPOSITION INCLUDING CITRATE AND CARNITINE ABLE TO ACTIVATE THE PRODUCTION OF KLOTHO PROTEIN |
| CN113826614B (en) * | 2021-09-30 | 2023-03-14 | 佛山市第一人民医院（中山大学附属佛山医院） | Organ preservation solution |
| CN115720893B (en) * | 2022-08-08 | 2024-02-23 | 四川大学华西医院 | Parathyroid gland external preservation solution and preservation method |
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| WO2006060309A2 (en) * | 2004-11-24 | 2006-06-08 | The Trustees Of Columbia University In The City Of New York | Compositions and methods for ex vivo preservations of organs |
| CN101167450A (en) * | 2007-11-13 | 2008-04-30 | 浙江大学 | Organic preserving solution and its preparation method |
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| CN103338760A (en) * | 2010-11-15 | 2013-10-02 | 贝林格尔.英格海姆国际有限公司 | Vasoprotective and cardioprotective antidiabetic therapy |
| CN104202972A (en) * | 2012-03-16 | 2014-12-10 | 比托普股份公司 | Organ storage solution containing (hydroxy)ectoine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6242001B2 (en) * | 2014-03-13 | 2017-12-06 | 住友精化株式会社 | Biomaterial storage method, biomaterial production method, biomaterial, transplant material, transplant method, and biomaterial storage apparatus |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006060309A2 (en) * | 2004-11-24 | 2006-06-08 | The Trustees Of Columbia University In The City Of New York | Compositions and methods for ex vivo preservations of organs |
| US20100167260A1 (en) * | 2006-01-19 | 2010-07-01 | Medestea Research & Production Spa | Use of N-Piperidine Derivative Compositions for Protecting Biological Systems |
| CN101167450A (en) * | 2007-11-13 | 2008-04-30 | 浙江大学 | Organic preserving solution and its preparation method |
| CN101569302A (en) * | 2008-04-30 | 2009-11-04 | 上海交通大学医学院附属瑞金医院 | Preservative fluid for perfusing extracorporeal liver |
| CN103338760A (en) * | 2010-11-15 | 2013-10-02 | 贝林格尔.英格海姆国际有限公司 | Vasoprotective and cardioprotective antidiabetic therapy |
| CN104202972A (en) * | 2012-03-16 | 2014-12-10 | 比托普股份公司 | Organ storage solution containing (hydroxy)ectoine |
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