CN108888636A - A method for the treatment of diabetes and atherosclerosis - Google Patents
A method for the treatment of diabetes and atherosclerosis Download PDFInfo
- Publication number
- CN108888636A CN108888636A CN201810921795.8A CN201810921795A CN108888636A CN 108888636 A CN108888636 A CN 108888636A CN 201810921795 A CN201810921795 A CN 201810921795A CN 108888636 A CN108888636 A CN 108888636A
- Authority
- CN
- China
- Prior art keywords
- blood
- stem cell
- navel
- blood stem
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 58
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 36
- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 26
- 210000000130 stem cell Anatomy 0.000 claims abstract description 81
- 210000004369 blood Anatomy 0.000 claims abstract description 79
- 239000008280 blood Substances 0.000 claims abstract description 79
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 17
- 239000008103 glucose Substances 0.000 claims abstract description 17
- 210000005259 peripheral blood Anatomy 0.000 claims abstract description 17
- 239000011886 peripheral blood Substances 0.000 claims abstract description 17
- 210000004027 cell Anatomy 0.000 claims abstract description 15
- 210000004700 fetal blood Anatomy 0.000 claims abstract description 8
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 6
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 6
- 150000003626 triacylglycerols Chemical class 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 9
- 230000036760 body temperature Effects 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000002158 endotoxin Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000001990 intravenous administration Methods 0.000 claims description 6
- 238000011084 recovery Methods 0.000 claims description 6
- 230000000740 bleeding effect Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000002504 physiological saline solution Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 210000001113 umbilicus Anatomy 0.000 claims description 4
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 238000009534 blood test Methods 0.000 claims description 2
- 230000005284 excitation Effects 0.000 claims description 2
- 230000003054 hormonal effect Effects 0.000 claims description 2
- 210000005087 mononuclear cell Anatomy 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000010241 blood sampling Methods 0.000 claims 1
- 210000000224 granular leucocyte Anatomy 0.000 claims 1
- 210000001988 somatic stem cell Anatomy 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 150000002632 lipids Chemical class 0.000 abstract description 7
- 208000037260 Atherosclerotic Plaque Diseases 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 230000003516 hyperlipidaemic effect Effects 0.000 abstract description 2
- 230000008859 change Effects 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 210000001367 artery Anatomy 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000006170 carotid stenosis Diseases 0.000 description 8
- 208000026106 cerebrovascular disease Diseases 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 230000032683 aging Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002203 pretreatment Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000009168 stem cell therapy Methods 0.000 description 3
- 238000002660 stem cell treatment Methods 0.000 description 3
- 238000009580 stem-cell therapy Methods 0.000 description 3
- 208000004434 Calcinosis Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- 208000000501 Lipidoses Diseases 0.000 description 1
- 206010024585 Lipidosis Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- -1 compound carbohydrate Chemical class 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229940107333 phenergan Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000009146 rhinoscleroma Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000004231 tunica media Anatomy 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Developmental Biology & Embryology (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Zoology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
A method of diabetes and atherosclerosis are treated, include following steps:The first step prepares navel blood stem cell;Second step excites autologous peripheral blood stem cells;Cord blood cells factor infused blood is made navel blood stem cell be combined with autologous peripheral blood stem cells and is treated by third step;4th step, the arteriosclerosis plaque area of regular follow-up curer, blood glucose, the variation of triglycerides index.Navel blood stem cell is combined autologous peripheral blood stem cells treatment atherosclerotic plaque and is reduced, and shows that treatment is effective;It is obvious to treat diabetic's short-term effect, but the duration is shorter, therapeutic effect needs to be consolidated raising;Hyperlipemic patients blood lipid level can be quickly substantially reduced, and the duration is longer, obvious to the therapeutic effect of this kind of patient.Navel blood stem cell combines autologous peripheral blood stem cells treatment diabetes and atherosclerosis, and it is more significant, more without side-effects than other domestic and international product effects to treat diabetes and atherosclerosis.
Description
Technical field
The present invention relates to field of biotechnology, more specifically, in particular to a kind of to treat diabetes and Atherosclerosis
The method of change.
Background technique
Diabetes are common diseases, and frequently-occurring disease, illness rate is just with the raising of living standards of the people, aging of population, life
The change of mode living and increase sharply.The whole world has more than 1.5 hundred million diabetics at present, and China has about 3,000 ten thousand, occupies the second in the world
Position, diabetes have become the third-largest killer after developed country's relaying cardiovascular and cerebrovascular diseases and tumour, come to society and economy-zone
Heavy burden is the worldwide public health problem for seriously threatening human health.Current medical level can not cure completely
Diabetes.Nowadays the principle for the treatment of diabetes is that strict glycemic control level is up to standard, protects pancreas B cell function, prevents and prolong
The occurrence and development of slow complication.
The main reason for atherosclerosis is coronary heart disease, cerebral infarction, peripheral vascular disease.Lipidosis is artery congee
The lesion basis of sample hardening, its main feature is that involvement arterial disease since inner membrance, generally first has lipid and the accumulation of compound carbohydrate, goes out
Blood and thrombosis, and then proliferation of fibrous tissue and calcinosis, and have the gradually transformation and calcification of arterial media, lead to artery
Wall thickening is hardened, lumen of vessels is narrow.Lesion often involves big-and-middle muscular artery, is enough to block lumen of artery once developing to, then this is dynamic
The tissue or organ that arteries and veins is supplied are by ischemic or necrosis.Since the lipid appearance gathered in endarterium is athero- in yellow,
Referred to as atherosclerosis.There are the modes such as drug therapy, operative treatment, complex treatment to the treatment of atherosclerosis.But
Drug therapy and operative treatment may bring a degree of side effect to patient, and complex treatment needs reasonable diet,
Adhere to appropriate physical exertion, reasonable arrangement work and life, controls susceptible factor, be long-term therapeutic modality, taboo is more, no
Easily adhere to.
Stem cell is the core link for exploring growth in humans, development and aging, and from the point of view of clinical medicine, stem cell is treated
Method may thoroughly change the treatment method of many diseases, many intractable especially by tissue and organ substitution and repairing and treating
Disease.It recent studies have shown that, stem cell can effectively treat blood disease, autoimmune disease, diabetes, treatment multiple sclerosis
Disease, myocardial infarction, Chronic Obstructive Pulmonary Disease etc., and it is likely to become the new strategy of senile disease treatment.Stem-cell therapy
Carry out in world wide.Currently, more and more scientists study the related disease as caused by aging with stem-cell therapy,
It even inquires into and extends the service life with stem cell.A large amount of experiment has shown that stem cell has anti-aging effects, some clinical tests
As a result it is effective to treatment aging degenerative disease to also show stem cell.
New material is looked into according to third party to show:It is not found both at home and abroad with this using navel blood stem cell treatment diabetes and artery congee
The pertinent literature of sample hardening.Domestic such research is mostly to use a kind of stem-cell therapy ischemic disease (such as cerebral thrombosis, diabetes
Foot etc.), cirrhosis, diabetic heart illness, neuropathy etc., treatment and hyperlipidemia to animation atherosclerotic plaque are controlled
Treatment then has not been reported;Treat a kind of report of the diabetes then using single stem cell without joint allosome treatment diabetes self
Road.Foreign literature treats the report of diabetes, but is limited to the treatment of type-1 diabetes mellitus:To the treatment of animation atherosclerotic plaque and
The treatment of hyperlipidemia is also rarely reported.Therefore, it develops and a kind of utilizes navel blood stem cell treatment diabetes and atherosclerosis
Method have important social benefit.
Summary of the invention
(1) technical problem
Therefore, a kind of method using navel blood stem cell treatment diabetes and atherosclerosis, Cheng Liaoben how to be developed
Field technical staff's urgent problem to be solved.
(2) technical solution
In view of the above-mentioned problems, the contents of the present invention are to provide a kind of method for treating diabetes and atherosclerosis, no
Side effect with Drug can enhance human body constitution and improve function of human body.
A method of diabetes and atherosclerosis are treated, include following steps:
The first step prepares navel blood stem cell;
Second step excites autologous peripheral blood stem cells;
Third step, by cord blood cells factor infused blood, make navel blood stem cell and autologous peripheral blood stem cells be combined into
Row treatment;
4th step, the arteriosclerosis plaque area of regular follow-up curer, blood glucose, the variation of triglycerides index.
In the first step, the navel blood stem cell is that bleeding of the umbilicus is aseptically acquired mononuclearcell, and is matched
Set FBS protective agent 1:1 mixes at 4 DEG C, makes DMSO final concentration of 10%, using near -40 DEG C of 1 DEG C/min program cooling, then with 5
DEG C/quickly near -100 DEG C of the cooling of the rate program of min, it then puts into ultra-low temperature liquid nitrogen and saves backup.
In the second step, before exciting autologous peripheral blood stem cells, treat preceding physical examination to curer, survey T,
P, R, BP, carry out ultrasonic image inspection, and Blood routine examination checks blood routine, blood biochemistry, tumor markers, hormonal readiness etc.
Index collects each achievement data before treating.
Excitation autologous stem cells process be:A. 37 DEG C of water bath with thermostatic control recoveries are carried out to navel blood stem cell, washs DMSO, makes
DMSO concentration is obtained below 1%.B. to one unit of curer's intravenous drip navel blood stem cell, after observation 2-3 days, subcutaneous injection
Granulocyte colony stimulating factor, hereinafter referred to as G-CSF, dosage are 7 μ g/kg, and 2 times/day, administration time need to be spaced ten hours twice
More than, 5-7 days as a treatment course.C. body temperature and constitutional symptom are observed daily after curer's medication.Beginning every morning medication in 3rd day
2h afterwards, routine of having a blood test of taking a blood sample, observation indices variation.Whether there is or not stem cells for 4th day beginning blood smear microscopically observation, such as
There is stem cell to observe its quantity and form.General 5-7 days or so stem cell populations reach peak value.D. promote stem cell homing:When
After stem cell reaches peak value in blood, second of navel blood stem cell intravenous drip is carried out, extra stem cell homing is promoted.
In the third step, 37 DEG C of water bath with thermostatic control recoveries are carried out to navel blood stem cell, is infused into and controls after endotoxin detection
Treatment person's blood.
The navel stem cell frozen is thawed according to cell recovery process.Appropriate physiological saline centrifuge washing is added 3 times, then
Stem cell is added in physiological saline of the 100mg containing 1% albumin, reagents carries out endotoxin detection, is bleeding of the umbilicus after qualified
Stem cell medicine.
Further, the cord blood cells therefore endotoxin detection, testing result are feminine gender, can just be carried out in next step, such as
As a result it is the positive, discards.Endotoxin is detected as negative product sampling and is detected with infusion person blood, and no haemolysis etc. is bad anti-
Ying Caike is fed back.
Further, the cord blood cells factor is stored refrigerated after taking out in ultra-low temperature liquid nitrogen, should return in time in 6h
It is defeated.
In 4th step, in entire treatment course, respectively after curer treats one month, three months, five months, seven months
It is checked, checks the arteriosclerosis plaque area, blood glucose target, triglycerides index of curer.
(3) beneficial effect
Navel blood stem cell auxiliary autologous peripheral blood stem cells are treated in the present invention, the not immune row of autologous stem cells
Reprimand, can be with long-term surviving, but the activity of cell is insufficient;Improve the existence ring of autologous stem cells with the method for input cell factor
Border, the two, which is used in combination, embodies mutual supplement with each other's advantages, and without side-effects during treating diabetes and atherosclerosis, does
After cell is gone back to the nest, high activity, young navel blood stem cell facilitate autologous stem cells and preferably play a role, using input bleeding of the umbilicus
To restore, organ function reaches treatment diabetes to the tissue that stem cell and autologous peripheral blood stem cells reparation are damaged and artery is athero-
The purpose of hardening.
In addition, present invention application high-speed centrifugation technology, guarantees the purity of stem cell in cord blood stem cell;Using ultralow temperature
The cell activity of Techniques of preserving guarantee cord blood stem cell;Endotoxin detection is carried out using reagents, guarantees navel blood stem cell system
Safety in standby returning step.
Detailed description of the invention
Fig. 1 is simple process figure of the present invention.Fig. 2 is pretherapy and post-treatment right carotid artery plaque area in specific embodiment
Variation diagram, Fig. 3 are pretherapy and post-treatment left carotid artery plaque area change figures in specific embodiment, and Fig. 4 is specific embodiment
Middle blood glucose level variation diagram, Fig. 5 are triglyceride levels figures in specific embodiment.
Specific embodiment
Present invention will be further explained below with reference to the attached drawings and examples.
A method of diabetes and atherosclerosis are treated, include following steps:As shown in Figure 1,1. preparing navel
Hemocytoblast;2. exciting autologous peripheral blood stem cells;3. navel blood stem cell infused blood is made navel blood stem cell and autologous peripheral
Hemocytoblast, which is combined, to be treated;4. the arteriosclerosis plaque area of regular follow-up curer, blood glucose, triglycerides index become
Change.
Curer's blood is inputted in navel blood stem cell, should be noted following points for attention:
I. such as curer's body temperature is more than 38.5 DEG C, and same day pause feeds back cord blood stem cell.
II. navel blood stem cell preparation from laboratory take out after, need it is stored refrigerated, for ensure cell activity should within 6h and
When feed back.
III. curer's name, admission number, cell quantity, series of cell preparation examining report should be recorded and checked in detail.
Whether close inspection cell suspension has floccule and muddiness before navel blood stem cell is fed back, and gently reverses infusion bag 3 times up and down,
To mix well, by blood transfusion routine operation intravenous drip, blood transfusion apparatus pipeline should be flicked in infusion process or is gently reversed above and below defeated
Liquid bag prevents the adherent holding of cell from feeding back unobstructed.
IV. during venous re-transfusion, whether there is or not shiver, generate heat, nervous, uncomfortable in chest, fash, pruitus by close observation curer
Equal adverse reactions.As shivered during venous re-transfusion, should stop inputting navel blood stem cell, replacement blood transfusion apparatus intravenous drip is raw
Reason salt water, keeps vein unobstructed, while phenergan 12.5-25mg is penetrated in intramuscular injection, can take the circumstances into consideration to fill in rice with using when still having uncomfortable react
Loose 2.5-5mg observes curer's vital sign, and sample is sent to laboratory detection.
If there is heating paresthesia, Physical temperature-lowering can be given or drug cooling of following the doctor's advice.Curer's body temperature increases usually defeated
Occur in 4-8h after note, continues 2-8h.Body temperature can drink more water simultaneously close observation Temperature changing at 38.5 DEG C or less;If body temperature
When more than 38.5 DEG C, the modes such as warm sponge bath should be given and be cooled to that body temperature is normal, when necessary can antipyretic-antalgic drug.
If the point of puncture fed back is increased if any redness, pain, Pi Wen, scleroma, 50% magnesium sulfate applying hot soaks is given.
Specific embodiment:By to 102 curers using navel blood stem cell be transfused joint autologous peripheral blood stem cells into
Row treatment carries out observation, blood glucose measurement, the blood lipid measurement of atherosclerotic plaque variation before and after treatment to it respectively.
There are the iconography data of specific atherosclerotic plaque before there are 5 treatments in 102 curers, through 1~2
A course of therapy, after 3 months, the area change of carotid artery atherosclerosis plaques is as shown in Fig. 2, Fig. 3 and table 1, table 2.Fig. 2 is to control
Front and back right carotid artery plaque area change figure is treated, table 1 is pretherapy and post-treatment right carotid artery plaque area change table.
Fig. 3 is pretherapy and post-treatment left carotid artery plaque area change figure, and table 2 is pretherapy and post-treatment left carotid artery plaque area
Change table.Blank rectangle frame represents the data before treatment in Fig. 2, Fig. 3, and slanted bar frame represents the data after treatment.
The pretherapy and post-treatment data shown by Fig. 2, Fig. 3 and table 1, table 2 can be seen that the arteriosclerosis plaque after treatment
It is obviously reduced.In order to exclude measurement error, we set area change within 20% person be variation unobvious, reduction face
Product be greater than 20% be it is effective, as standard, 4 effective, 1 stabilizations in 5 volunteers that we observe, efficient 80%.
The pretherapy and post-treatment right carotid artery plaque area change table of table 1
The pretherapy and post-treatment left carotid artery plaque area change table of table 2
The hyperglycemia person 37 in 102 curers, hyperlipidemia person 65, after 1~2 course of therapy respectively 1,
3, blood glucose and blood lipid are checked after 5,7 months, 10% or more person of decline is effective before relatively treating with blood lipid after treatment and blood glucose level.
3 blood glucose level of table changes table
Fig. 4 is blood glucose level variation diagram, wherein " * * " indicates that otherness is extremely significant, P<0.01.Table 3 is blood glucose level variation
Table, the alphabetical difference in parameter top represent the significant (P of otherness<0.05), letter is identical represents the not significant (P of otherness>0.05).
Can be obtained from the data of Fig. 4 and table 3, In Treatment of Hyperglycemia person treatment after, the 1st month and 3rd month blood glucose level it is equal
Decline, blood glucose level increases within the 6th month.1 month after treatment, blood glucose level is remarkably decreased, and has conspicuousness compared with pre-treatment
Difference (P<0.01).3 months after treatment, blood glucose level was increased compared with 1st month, but was still had compared with pre-treatment significant
Sex differernce (P<0.01).6 months blood glucose levels resume treatment preceding level substantially after treatment, and there was no significant difference compared with pre-treatment
(P>0.05)。
The variation of 4 triglyceride levels of table
Fig. 5 is triglyceride levels figure, wherein " * * " indicates that otherness is extremely significant, P<0.01.Table 4 is triglycerides water
Flat variation table, the alphabetical difference in parameter top represent the significant (P of otherness<0.05), letter is identical represents the not significant (P of otherness>
0.05).B ultrasound color Doppler of the measurement using domestic mindray, model DC-8.
Can be obtained by the data of Fig. 5 and table 4, after treatment, the 1st month, 3 months and 6th month triglyceride levels under
Drop is in compared with pre-treatment significant difference (P<0.01).But 6th month and 3rd month triglyceride levels are without significant
Sex differernce (P>0.05).
It is through above-described embodiment research shows that:It is controlled by 1~2 course for the treatment of navel blood stem cell joint autologous peripheral blood stem cells
It treats atherosclerotic plaque to reduce, shows that treatment is effective;Treat diabetic's short-term effect it is obvious, but the duration compared with
Short, therapeutic effect needs to be consolidated raising;Hyperlipemic patients blood lipid level can be quickly substantially reduced, and the duration is longer, to this
The therapeutic effect of class patient is obvious.
In addition all volunteer's symptoms and Index for examination at least one improvement by treatment.Therefore according to the above research
Results presumption stem cell is helpful for treatment diabetes and atherosclerosis.
Navel blood stem cell combines autologous peripheral blood stem cells treatment diabetes and atherosclerosis, treats diabetes and moves
Pulse atherosclerosis is more significant, more without side-effects than other domestic and international product effects, therefore promotion prospect is quite wide, band after popularization
The market economy come is also considerable.Especially then there is breakthrough medical value to the therapeutic effect of artery sclerosis, because
It is for atherosclerosis the main reason for leading to cardiovascular and cerebrovascular disease, and cardiovascular and cerebrovascular disease is in China's various diseases respectively
The second of the lethal cause of disease and third position, cerebrovascular disease are then first of the disability rate in various diseases.Artery sclerosis has
Effect treatment declines to a great extent the death rate and disability rate that make China resident.Navel blood stem cell combines autologous peripheral blood stem cells treatment
Diabetes and atherosclerosis have remarkable result and without side-effects, have compared with various treatment methods in the world excellent
Gesture has very important social benefit, and economic benefit is also that other treatment methods are incomparable.
The present invention is not limited to the above-described embodiments, anyone can obtain other various shapes under the inspiration of the present invention
The product of formula.It is all according to equivalent changes and modifications within the scope of the patent application of the present invention, all should belong to covering scope of the invention.
Claims (6)
1. a kind of method for treating diabetes and atherosclerosis, it is characterised in that:It include following steps:
The first step prepares navel blood stem cell;
Second step excites autologous peripheral blood stem cells;
Cord blood cells factor infused blood is made navel blood stem cell be combined with autologous peripheral blood stem cells and is controlled by third step
It treats;
4th step, the arteriosclerosis plaque area of regular follow-up curer, blood glucose, the variation of triglycerides index.
2. a kind of method for treating diabetes and atherosclerosis according to claim 1, it is characterised in that:Described
In the first step, the navel blood stem cell is that bleeding of the umbilicus is aseptically acquired mononuclearcell, with configuration FBS protective agent 1:1
It is mixed at 4 DEG C, makes DMSO final concentration of 10%, using near -40 DEG C of 1 DEG C/min program cooling, then with the rate journey of 5 DEG C/min
It quickly near -100 DEG C of sequence cooling, then puts into ultra-low temperature liquid nitrogen and saves backup.
3. a kind of method for treating diabetes and atherosclerosis according to claim 1, it is characterised in that:Described
In second step, before exciting autologous peripheral blood stem cells, curer is carried out to treat preceding physical examination, T, P, R, BP is surveyed, is surpassed
Sound image check, Blood routine examination check the indexs such as blood routine, blood biochemistry, tumor markers, hormonal readiness, collect treatment
Preceding each achievement data.
4. a kind of method for treating diabetes and atherosclerosis according to claim 1, it is characterised in that:Excitation is certainly
The process of somatic stem cell is:
A. 37 DEG C of water bath with thermostatic control recoveries are carried out to navel blood stem cell, DMSO is washed, so that DMSO concentration is below 1%;
B. to one unit of curer's intravenous drip navel blood stem cell, after observation 2-3 days, subcutaneous injection granular leukocyte colony stimulate because
Son, hereinafter referred to as G-CSF, dosage are 7 μ g/kg, and 2 times/day, administration time need to be spaced ten hours or more twice, be treated for one within 5-7 days
Journey;
C. body temperature and constitutional symptom, 2h after beginning every morning medication in the 3rd day are observed after curer's medication daily, blood sampling is had a blood test often
Rule, observation indices variation, whether there is or not stem cells for the 4th day beginning blood smear microscopically observation, observe it if any stem cell
Quantity and form;
D. promote stem cell homing:After stem cell reaches peak value in blood, second of navel blood stem cell intravenous drip is carried out, is promoted
Make extra stem cell homing.
5. a kind of method for treating diabetes and atherosclerosis according to claim 1, it is characterised in that:Described
In third step, 37 DEG C of water bath with thermostatic control recoveries are carried out to navel blood stem cell, are infused into curer's blood after endotoxin detection.
6. a kind of method for treating diabetes and atherosclerosis according to claim 1, it is characterised in that:Described
In third step, the navel stem cell frozen is thawed according to cell recovery process;Appropriate physiological saline centrifuge washing is added 3 times, so
Stem cell is added in physiological saline of the 100mg containing 1% albumin afterwards, reagents carries out endotoxin detection, is navel after qualified
Hemocytoblast preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810921795.8A CN108888636A (en) | 2018-08-14 | 2018-08-14 | A method for the treatment of diabetes and atherosclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810921795.8A CN108888636A (en) | 2018-08-14 | 2018-08-14 | A method for the treatment of diabetes and atherosclerosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108888636A true CN108888636A (en) | 2018-11-27 |
Family
ID=64353979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810921795.8A Pending CN108888636A (en) | 2018-08-14 | 2018-08-14 | A method for the treatment of diabetes and atherosclerosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108888636A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113730439A (en) * | 2021-09-09 | 2021-12-03 | 陕西中鸿瑞康健康管理有限公司 | Stem cell factor freeze-dried powder capable of reducing triglyceride and preparation method and application thereof |
Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1770976A (en) * | 2003-02-13 | 2006-05-10 | 人类起源公司 | Use of umbilical cord blood to treat individuals having a disease, disorder or condition |
| CN101089176A (en) * | 2006-06-12 | 2007-12-19 | 中国人民解放军第四五八医院全军肝病中心 | Stem cell separating liquid and its separating method |
| CN103040860A (en) * | 2012-11-29 | 2013-04-17 | 刘学武 | A method for initiating mammalian stem cells and application of chlorine dioxide in the preparation of drugs for initiating mammalian stem cells |
| CN103255106A (en) * | 2012-02-16 | 2013-08-21 | 孙勇 | Autologous hematopoietic stem cell technology used for sub-health treatment |
| CN103687940A (en) * | 2011-07-06 | 2014-03-26 | 希司托赛尔有限公司 | Method for processing mesenchymal stem cells and the use thereof in the treatment of diseases associated with oxidative stress |
| CN105154404A (en) * | 2015-10-27 | 2015-12-16 | 东营凤起生物科技发展有限公司 | Astragalus extract FQR-8 and application of astragalus extract FQR-8 in tumor cell immunotherapy |
| CN105238755A (en) * | 2015-10-27 | 2016-01-13 | 东营凤起生物科技发展有限公司 | Gingseng extract product FQR1 and application thereof in tumour immunotherapy |
| WO2017027402A1 (en) * | 2015-08-07 | 2017-02-16 | Patara Pharma, LLC | Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders |
| WO2017030814A1 (en) * | 2015-08-19 | 2017-02-23 | Arvinas, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
| CN107372461A (en) * | 2017-04-10 | 2017-11-24 | 东营凤起生物科技发展有限公司 | A kind of high-efficiency activated store method of the DC CIK cells induced through Astragalus Root P.E FQR 8 |
| US20180055891A1 (en) * | 2016-08-29 | 2018-03-01 | Yong Zhao | Compositions and methods for reprogramming adult cells through the stemness of a platelet rich fraction of blood containing platelet-like cells in humans |
| US20180057797A1 (en) * | 2016-08-29 | 2018-03-01 | Hackensack University Medical Center | Methods for treating an immune disorder-related disease by reducing autoreactivity in a t cell compartment |
| CN107913290A (en) * | 2017-12-22 | 2018-04-17 | 北京再生生物科技研究院有限公司 | A compound cell preparation, preparation method and use thereof |
| CN108186790A (en) * | 2018-03-26 | 2018-06-22 | 马海周 | A kind of glutinous rehmannia extract, preparation method and the application in terms of CIK cell in vitro proliferation is promoted |
| CN109045282A (en) * | 2018-08-14 | 2018-12-21 | 东营凤起生物科技发展有限公司 | A method of delaying premature ovarian failure and treatment osteoporosis using navel blood stem cell infusion joint autologous peripheral blood stem cells |
| CN109172566A (en) * | 2018-10-06 | 2019-01-11 | 淮安安莱生物科技有限公司 | A kind of application of roseolic acid A in terms of anti-hematopoietic stem cell aging |
| CN110099921A (en) * | 2016-12-23 | 2019-08-06 | 干细胞生物科技公司 | Somatic stem cell for reducing IL-6 level purposes |
| CN110193027A (en) * | 2019-05-08 | 2019-09-03 | 广州市番禺区中心医院(广州市番禺区人民医院、广州市番禺区心血管疾病研究所) | A kind of preparation method and new opplication of stem cell excretion body |
-
2018
- 2018-08-14 CN CN201810921795.8A patent/CN108888636A/en active Pending
Patent Citations (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1770976A (en) * | 2003-02-13 | 2006-05-10 | 人类起源公司 | Use of umbilical cord blood to treat individuals having a disease, disorder or condition |
| CN101089176A (en) * | 2006-06-12 | 2007-12-19 | 中国人民解放军第四五八医院全军肝病中心 | Stem cell separating liquid and its separating method |
| CN103687940A (en) * | 2011-07-06 | 2014-03-26 | 希司托赛尔有限公司 | Method for processing mesenchymal stem cells and the use thereof in the treatment of diseases associated with oxidative stress |
| CN103255106A (en) * | 2012-02-16 | 2013-08-21 | 孙勇 | Autologous hematopoietic stem cell technology used for sub-health treatment |
| CN103040860A (en) * | 2012-11-29 | 2013-04-17 | 刘学武 | A method for initiating mammalian stem cells and application of chlorine dioxide in the preparation of drugs for initiating mammalian stem cells |
| WO2017027402A1 (en) * | 2015-08-07 | 2017-02-16 | Patara Pharma, LLC | Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders |
| WO2017030814A1 (en) * | 2015-08-19 | 2017-02-23 | Arvinas, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
| CN105238755A (en) * | 2015-10-27 | 2016-01-13 | 东营凤起生物科技发展有限公司 | Gingseng extract product FQR1 and application thereof in tumour immunotherapy |
| CN105154404A (en) * | 2015-10-27 | 2015-12-16 | 东营凤起生物科技发展有限公司 | Astragalus extract FQR-8 and application of astragalus extract FQR-8 in tumor cell immunotherapy |
| US20180055891A1 (en) * | 2016-08-29 | 2018-03-01 | Yong Zhao | Compositions and methods for reprogramming adult cells through the stemness of a platelet rich fraction of blood containing platelet-like cells in humans |
| US20180057797A1 (en) * | 2016-08-29 | 2018-03-01 | Hackensack University Medical Center | Methods for treating an immune disorder-related disease by reducing autoreactivity in a t cell compartment |
| US10729730B2 (en) * | 2016-08-29 | 2020-08-04 | Hackensack University Medical Center | Compositions and methods for reprogramming adult cells through the stemness of a platelet rich fraction of blood containing platelet-like cells in humans |
| CN110099921A (en) * | 2016-12-23 | 2019-08-06 | 干细胞生物科技公司 | Somatic stem cell for reducing IL-6 level purposes |
| CN107372461A (en) * | 2017-04-10 | 2017-11-24 | 东营凤起生物科技发展有限公司 | A kind of high-efficiency activated store method of the DC CIK cells induced through Astragalus Root P.E FQR 8 |
| CN107913290A (en) * | 2017-12-22 | 2018-04-17 | 北京再生生物科技研究院有限公司 | A compound cell preparation, preparation method and use thereof |
| CN108186790A (en) * | 2018-03-26 | 2018-06-22 | 马海周 | A kind of glutinous rehmannia extract, preparation method and the application in terms of CIK cell in vitro proliferation is promoted |
| CN109045282A (en) * | 2018-08-14 | 2018-12-21 | 东营凤起生物科技发展有限公司 | A method of delaying premature ovarian failure and treatment osteoporosis using navel blood stem cell infusion joint autologous peripheral blood stem cells |
| CN109172566A (en) * | 2018-10-06 | 2019-01-11 | 淮安安莱生物科技有限公司 | A kind of application of roseolic acid A in terms of anti-hematopoietic stem cell aging |
| CN110193027A (en) * | 2019-05-08 | 2019-09-03 | 广州市番禺区中心医院(广州市番禺区人民医院、广州市番禺区心血管疾病研究所) | A kind of preparation method and new opplication of stem cell excretion body |
Non-Patent Citations (2)
| Title |
|---|
| 卢爱俊等: ""自体外周血干细胞移植治疗20例糖尿病缺血性下肢血管病变的临床观察"", 《内蒙古医学杂志》 * |
| 柴怡: ""脐带血造血干细胞治疗糖尿病的研究进展"", 《生物技术世界》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113730439A (en) * | 2021-09-09 | 2021-12-03 | 陕西中鸿瑞康健康管理有限公司 | Stem cell factor freeze-dried powder capable of reducing triglyceride and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Warren et al. | A method of obtaining renal venous blood in unanesthetized persons with observations on the extraction of oxygen and sodium para-amino hippurate | |
| CN109045282A (en) | A method of delaying premature ovarian failure and treatment osteoporosis using navel blood stem cell infusion joint autologous peripheral blood stem cells | |
| Veljković et al. | Leukapheresis in management hyperleucocytosis induced complications in two pediatric patients with chronic myelogenous leukemia | |
| CN108888636A (en) | A method for the treatment of diabetes and atherosclerosis | |
| Ohara et al. | Comprehensive technical and patient-care optimization in the management of pediatric apheresis for peripheral blood stem cell harvesting | |
| Chenaitia et al. | Takotsubo cardiomyopathy associated with diving | |
| CN107029215A (en) | A kind of stem cell medicine and its preparation method and application | |
| Rosselot et al. | Venoarterial pulsatile circulatory assist in the treatment of resistant ventricular fibrillation | |
| Fitzgerald et al. | A case of increased platelet anti-heparin factor in a patient with Raynaud's phenomena and gangrene, treated by aspirin | |
| Zhang et al. | Intraoperative tumor lysis-induced fatal hyperkalemia | |
| Rudenko et al. | Cardiometric criteria for diagnostics, therapy, and prediction of COVID-19 virus infection development under hospital conditions | |
| Lin et al. | Extracorporeal Cardiopulmonary Resuscitation Treatment of Cardiac Arrest during Pregnancy: Case Report and Mini-review | |
| RU2228197C1 (en) | Method for treatment of pulmonary tuberculosis | |
| RU2398525C1 (en) | Method of treating lung cancer | |
| CN102389408A (en) | Application of saturated amine compound in preparing medicament for treating ischemic diseases | |
| Dehghan et al. | Insulin Edema in Type 2 Diabetes Mellitus: A Case Report Study | |
| Szemis et al. | Assessment of donation potential after circulatory death as the first step in implementing and running a hospital program of organ procurement | |
| Antoniades | Hypoglycaemic effect of adipose-tissue extracts in adrenalectomised rats | |
| UA145507U (en) | METHOD OF COMBINED TREATMENT OF TYPE 2 DIABETES MELLITUS AND ITS COMPLICATIONS | |
| Mehdipour | Investigating Systemic Aging and its Effects on Aged Tissues by Utilizing a Small Animal Blood Exchange Model | |
| CN113116933A (en) | Stem cell composition for preventing and treating diabetic foot and application thereof | |
| Erkan et al. | Investigations of factors affecting mortality in our ECMO (Extracorporeal membrane oxygenation) applications | |
| RU130506U1 (en) | DEVICE FOR LOADING DOXORUBICIN IN ERYTHROCYTES FOR THERAPEUTIC PURPOSES | |
| CN111214486A (en) | Magnesium-rich artificial cerebrospinal fluid and preparation method and application thereof | |
| Swamidoss et al. | Appendix D: Case Study for Chapter 7 on Anesthetic Techniques and Their Clinical Application for Specific Orthopedic Procedures |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181127 |
|
| RJ01 | Rejection of invention patent application after publication |