CN106265674A - Tetramethyluric acid prevention and the application for the treatment of diabetes - Google Patents

Tetramethyluric acid prevention and the application for the treatment of diabetes Download PDF

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Publication number
CN106265674A
CN106265674A CN201610585500.5A CN201610585500A CN106265674A CN 106265674 A CN106265674 A CN 106265674A CN 201610585500 A CN201610585500 A CN 201610585500A CN 106265674 A CN106265674 A CN 106265674A
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China
Prior art keywords
diabetes
tetramethyluric acid
type
medicine
tetramethyluric
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CN201610585500.5A
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龚频
常相娜
杨文娟
王兰
陈福欣
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Shaanxi University of Science and Technology
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Shaanxi University of Science and Technology
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Priority to CN201610585500.5A priority Critical patent/CN106265674A/en
Publication of CN106265674A publication Critical patent/CN106265674A/en
Priority to CN201710250574.8A priority patent/CN106943408B/en
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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
    • A61K31/33—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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The invention discloses tetramethyluric acid prevention and the application for the treatment of diabetes, in the type i diabetes model of alloxan induction and the type ii diabetes model of STZ induction, tetramethyluric acid all demonstrates preferable hypoglycemic activity；Modeling the last fortnight is administered result and shows also there is preferable preventive effect.Tetramethyluric acid oral administration effect is preferable, in the range of dosage is 0.5～100mg/kg, having good safety and effectiveness, the dosage of 1～20mg/kg can play good preventive effect, is expected to very much the new oral hypoglycemic medicine being developed into preventing, control diabetes.

Description

Tetramethyluric acid prevention and the application for the treatment of diabetes
Technical field
The invention belongs to pharmaceutical field, relate to tetramethyluric acid answering in the medicine of preparation prevention and treatment diabetes With, and in preparation application of the medicine of Collaborative Control blood glucose in diabetic complication.
Background technology
Diabetes (Diabetes Mellitus, DM) are a kind of metabolic diseases, and its feature is that the blood glucose of patient is long-term Higher than standard value.Hyperglycemia can cause the symptom being commonly called as " three-many-one-little ", i.e. polydipsia, polyphagia, polyuria and weight loss.If no Treating, may cause many complication, wherein, acute complications includes diabetes DKA and hyperosmosis height blood Sugar non-keto acid stupor；Long-term complications includes cardiovascular disease, apoplexy, chronic kidney disease, diabetic foot and retinopathy Become etc..
Diabetes have two origin causes of formation: pancreas cannot produce enough insulins, or cell is to insulin insensitivity.? Clinicing aspect diabetes are then divided into three classes:
Type i diabetes is owing to health cannot produce enough insulins, is also designated as insulin-dependent glycosuria in the past Sick (insulin-dependent diabetes mellitus, IDDM) or juvenile diabetes, the cause of disease is failed to understand at present.II It is abnormal that patients with type Ⅰ DM starts from Insulin Resistance, along with the secretion of disease progression insulin also may become not enough gradually.This Individual type be referred to as in the past non-insulin-dependent diabetes mellitus (non insulin-dependent diabetes mellitus, NIDDM) or adult diabetes mellitus, the cause of disease is overweight or lacks motion, shows that it is sent out for a long time with health according to another current research Scorching reaction is relevant.Type III gestational diabetes is also common diabetes kind, and it refers to that the past does not has diabetes medical history, but in bosom Between the pregnancy period, blood glucose is higher than normal value.
Effectively controlled by oral drugs blood glucose (particularly post-prandial glycemia) be current treating diabetes important means it One, and for the therapeutic scheme of insulin injection, convenient and be prone to accept, the therefore research and development of orally-taken blood sugar reducing medicine Remain highly important in present stage.
Tetramethyluric acid (theacrine), chemical entitled 1,3,7,9-tetramethyluric acid or Tetramethyluric Acid or 1,3,7,9-Tetramethyl-7,9-dihydro-1H-purine-2,6,8 (3H)-trione, No. CAS is 2309- 49-1, is at first from Chinese southern Folium Ligustri pubescentis, asAnd Camellia kucha (Theobromagrandiflorum) A kind of xanthine alkaloid extracted in (Camellia assamica var.kucha) etc..Modern pharmacology research shows, Tetramethyluric acid has the multiple pharmacological effect such as antiinflammatory, analgesia and dopamine neuron protection.
Although tetramethyluric acid has physiologically active, relatively low toxicity and the attribute of natural origin widely, but existing Technology not finding, tetramethyluric acid has and can reduce I type and the report of type ii diabetes blood glucose.
Summary of the invention
It is an object of the invention to provide tetramethyluric acid prevention and the application for the treatment of diabetes.
Tetramethyluric acid application in the medicine of preparation prevention and treatment diabetes.
Described treatment diabetes refer to reduce the blood glucose of diabetics, improve polydipsia polyphagia, the symptom of body weight reduction.
Described diabetes are I type and type ii diabetes.Preferably, for treatment, described diabetes refer to I type and II type sugar Urine disease, for prevention, described diabetes refer to type ii diabetes.
The route of administration of described medicine is oral administration.
The preparation of described medicine is tablet, pill, capsule or powder.
The dose therapeutically effective of described tetramethyluric acid is 0.5～100mg/kg.
The dosage of described tetramethyluric acid prevention diabetes is 1～20mg/kg.
Tetramethyluric acid can be also used for preparation and controls the medicine of blood glucose.Especially for preparation in diabetic complication The medicine of Collaborative Control blood glucose.
The present invention on the basis of existing technology, the more in-depth study internal blood sugar lowering character of tetramethyluric acid, In the type i diabetes model of alloxan induction and the type ii diabetes model of STZ induction, tetramethyluric acid all demonstrates preferably Hypoglycemic activity；Modeling the last fortnight is administered result and shows, tetramethyluric acid also has the effect preferably preventing diabetes.Tetramethyl Uric acid oral administration effect is preferable, in the range of dosage is 0.5～100mg/kg, has good safety and an effectiveness, 1～ The dosage of 20mg/kg can play good preventive effect, and result shows, tetramethyluric acid can be as novel anti-glycosuria Medicine or candidate compound.
Accompanying drawing explanation
Fig. 1 is the tetramethyluric acid impact on normal mouse sugar dosis tolerata.
Fig. 2 is the impact of the type i diabetes mouse blood sugar that alloxan is induced by tetramethyluric acid.
Fig. 3 is the impact of the type ii diabetes mouse blood sugar that STZ is induced by tetramethyluric acid.
Fig. 4 is the impact of the type ii diabetes Mouse Weight that STZ is induced by tetramethyluric acid.
Fig. 5 is the tetramethyluric acid preventive effect to mice type ii diabetes.
Detailed description of the invention
With embodiment, the present invention is elaborated below in conjunction with the accompanying drawings.
The present invention more deeply and widely have studied its pharmacology on the basis of the existing physiologically active of tetramethyluric acid Activity.Present invention finds the new application of tetramethyluric acid: i.e. can use dose-dependent reduction I type and type ii diabetes model to move The blood glucose of thing, and effectively control body weight, and have prevention diabetes effect；Meanwhile, it is a discovery of the invention that tetramethyluric acid has preferably Physicochemical property, it is possible to making various dosage form, its preparation is in extensive range, and the various dosage forms such as tablet, pill, powder, capsule are equal Can be realized by conventional formulation technologies.
(1) tetramethyluric acid impact on normal mouse sugar dosis tolerata
The standard method of assay method list of references report, sketches and is: the C57BL/6 mice fasting of male and female half and half before experiment 12h, with the glucose dose gavage of 4g/kg (concentration is as 0.35g/mL) body weight；Gastric infusion simultaneously.Exist respectively by blood glucose meter After administration 0,0.5,1,1.5,2,2.5h measure blood glucose (BG, Blood Glucose).
Administering mode
(1) blank group (being called for short K group): with other groups equal-volume normal saline (20mL/kg)；
(2) tetramethyluric acid group (being called for short T group): dosage is T1:5mg/kg, T2:10mg/kg, T3:20mg/kg, and solvent is Normal saline, a small amount of DMSO hydrotropy, gastric infusion；
(3) positive control medicine group (being called for short P group): metformin is dissolved in ultra-pure water, and final concentration is 10g/L, according to 10mg/kg gastric infusion；
Often group laboratory animal 7, totally 35, Roche blood glucose meter (ease ejector half, correct) tail vein blood measures, and often organizes reality Test data to average.Result shows, tetramethyluric acid can dose-dependent to normal mouse sugared dosis tolerata be improved Effect, during high dose (20mg/kg), its blood sugar lowering ability is with positive control medicine quite (Fig. 1).
(2) therapeutical effect of the type i diabetes mice that alloxan is induced by tetramethyluric acid
Model construction and the standard method of drug screening method list of references report, sketch and be: take C57BL/6 mice 40 Only, lottery is divided into model group (n=35) and Normal group (n=5).After water 12h is can't help in model group fasting, tail vein injection Alloxan 80mg/kg, 1 time/4 days, continuous 4 times.Normal group fasting be can't help water 12h pneumoretroperitoneum and injected isopyknic citron Acid buffer, 1 time/4 days, continuous 4 times.After last injection in 1 week, docking takes blood and measures blood glucose.Blood glucose for three days on end > 16.7mmol/L person is type i diabetes mice, within the 4th day, carries out medicament screening experiment.
Medicament screening experiment: taking the successful mice of modeling, fasting 12h, with 4g/kg (concentration is as 0.4g/mL) body weight Glucose dose gavage, simultaneously gastric infusion.With blood glucose meter respectively every day be administered after 0,0.5,1,1.5,2,2.5h measure blood Sugar (BG).
Administering mode
(1) blank group (be called for short K group): with other groups equal-volume normal saline (20mL/kg), 1 times/day, continuous 8 Week；
(2) tetramethyluric acid group (being called for short T group): concentration is T1:5mg/kg, T2:10mg/kg, T3:20mg/kg, and gavage is given Medicine, 1 times/day, continuous 8 weeks；
(3) positive control medicine group (being called for short P group): metformin is dissolved in ultra-pure water, and final concentration is 10g/L, according to 10mg/kg gastric infusion, 1 times/day, continuous 8 weeks；
Result shows, tetramethyluric acid can have necessarily by the dose-dependent type i diabetes mice to alloxan induction Therapeutical effect；During high dose (20mg/kg), its blood sugar lowering ability is with positive control medicine quite (Fig. 2).
(3) therapeutical effect of the type ii diabetes mice that STZ is induced by tetramethyluric acid.
Model construction and the standard method of drug screening method list of references report, sketch and be: take C57BL/6 mice 40 Only, lottery is divided into model group (n=35) and Normal group (n=5).After water 12h is can't help in model group fasting, tail vein injection STZ40mg/kg (0.01mol/L, pH 4.2), 1 times/day, continuous 5 days.The injection of water 12h pneumoretroperitoneum is can't help in Normal group fasting Isopyknic citrate buffer, 1 times/day, continuous 5 days.After last injection in 1 week, docking every day takes blood and measures blood glucose. Blood glucose for three days on end > 16.7mmol/L person is type ii diabetes mice, within the 4th day, carries out medicament screening experiment.
Medicament screening experiment: taking the successful mice of modeling, fasting 12h, with 4g/kg (concentration is as 0.4g/mL) body weight Glucose dose gavage, simultaneously gastric infusion.With blood glucose meter respectively every day be administered after 0,0.5,1,1.5,2,2.5h measure blood Sugar (BG).
Administering mode
(1) blank group (be called for short K group): with other groups equal-volume normal saline (20mL/kg), 1 times/day, continuous 8 Week；
(2) tetramethyluric acid group (being called for short T group): concentration is T1:5mg/kg, T2:10mg/kg, T3:20mg/kg, and gavage is given Medicine, 1 times/day, continuous 8 weeks；
(3) positive control medicine group (being called for short P group): metformin is dissolved in ultra-pure water, and final concentration is 10g/L, according to 10mg/kg gastric infusion, 1 times/day, continuous 8 weeks；
Result shows, tetramethyluric acid can have certain controlling by the dose-dependent type ii diabetes mice to STZ induction Treatment effect；During high dose (20mg/kg), its blood sugar lowering ability is with positive control medicine quite (Fig. 3).
(4) impact of the type ii diabetes Mouse Weight that STZ is induced by tetramethyluric acid
Modeling experiment is identical with (three).In experimentation, timing weighing every day Mouse Weight, respectively organizes the body weight of mice.
Administering mode
(1) Normal group (being called for short N group): induce without STZ, every day, injection organized equal-volume normal saline (20mL/ with other Kg), 1 times/day, continuous 8 weeks；
(2) blank group (be called for short K group): with other groups equal-volume normal saline (20mL/kg), 1 times/day, continuous 8 Week；
(3) tetramethyluric acid group (being called for short T group): concentration is T1:1mg/kg, T2:10mg/kg, T3:40mg/kg, and gavage is given Medicine, 1 times/day, continuous 8 weeks；
(4) positive control medicine group (being called for short P group): metformin is dissolved in ultra-pure water, and final concentration is 10g/L, according to 10mg/kg gastric infusion, 1 times/day, continuous 8 weeks；
Result shows, tetramethyluric acid can the body weight of type ii diabetes mice of dose-dependent increase STZ induction, make The body weight (Body Weight) of diabetic mice tends to normalization (Fig. 4).
(5) preventive effect of the mice type ii diabetes that STZ is induced by tetramethyluric acid.
Modeling experiment, with (three), is set up first 14 days from model and is started to give tetramethyluric acid, and dosage was administered with (three), every day Once, successive administration, to giving for the last time after STZ 8 weeks, surveys blood glucose on an empty stomach.
Result shows, tetramethyluric acid can reduce the rising of the lower mouse blood sugar of STZ induction, has type ii diabetes necessarily Preventive effect (Fig. 5).
(6) tetramethyluric acid preparation
6.1) tetramethyluric acid tablet
Tetramethyluric acid 200g, lemon yellow 0.02g, microcrystalline Cellulose 800g, micropowder silica gel 5g, magnesium stearate 10g, poly-second Alkene pyrrolidone 20g.
By above-mentioned tetramethyluric acid, lemon yellow, microcrystalline Cellulose, polyvinylpyrrolidone mix homogeneously, cross 80 mesh sieves, so Rear addition micropowder silica gel and magnesium stearate, tabletting after mixing.This tablet is used for preventing and treating the dosage that takes day of diabetes 0.5-50mg/ days (tetramethyluric acid).
6.2) tetramethyluric acid capsule
Tetramethyluric acid 200g, microcrystalline Cellulose 700g, sodium carboxymethyl cellulose 5g, sodium lauryl sulphate 15g, dioxy SiClx 15g.
By above-mentioned raw materials mix homogeneously, cross 80 mesh sieves, use roll-in method to pelletize, be packed into capsule.This capsule is for pre- Anti-and treatment diabetes the dosage that take day are 1-100mg/ days (tetramethyluric acid).
In a word, tetramethyluric acid provided by the present invention has significant blood sugar reducing function compared to blank group, it is possible to Substantially reducing the I type of alloxan induction and the blood glucose of the type ii diabetes mice of STZ induction, (this is for seeing to improve polydipsia polyphagia The experimental phenomena observed) and the symptom of body weight reduction.It addition, modeling the last fortnight gives tetramethyluric acid, the Portugal of mice can be increased Grape sugar tolerates, and plays certain preventive effect.Present invention research is to prevent, control that the scientific research of diabetes and clinical practice provide Theoretical foundation and experiment are supported.

Claims (9)

1. tetramethyluric acid is used for the application preventing and treating in the medicine of diabetes in preparation.
Apply the most as claimed in claim 1, it is characterised in that: described treatment diabetes refer to reduce the blood of diabetics Sugar, improves polydipsia polyphagia, the symptom of body weight reduction.
Apply the most as claimed in claim 1, it is characterised in that: described diabetes are I type and type ii diabetes.
Apply the most as claimed in claim 1, it is characterised in that: the route of administration of described medicine is oral administration.
Apply the most as claimed in claim 1, it is characterised in that: the preparation of described medicine is tablet, pill, capsule or dissipates Agent.
Apply the most as claimed in claim 1, it is characterised in that: the dose therapeutically effective of described tetramethyluric acid be 0.5～ 100mg/kg。
Apply the most as claimed in claim 1, it is characterised in that: described tetramethyluric acid prevention diabetes dosage be 1～ 20mg/kg。
8. tetramethyluric acid is used for the application controlling in the medicine of blood glucose in preparation.
9. tetramethyluric acid is in preparation application in the medicine of Collaborative Control blood glucose in diabetic complication.
CN201610585500.5A 2016-07-22 2016-07-22 Tetramethyluric acid prevention and the application for the treatment of diabetes Pending CN106265674A (en)

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CN201710250574.8A CN106943408B (en) 2016-07-22 2017-04-17 Application of tetramethyluric acid in preventing and treating diabetes

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115868562A (en) * 2022-09-30 2023-03-31 杨军贤 Method for preparing bitter sweet tea by extracting bitter sweet theophylline from new wild tea

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115868562A (en) * 2022-09-30 2023-03-31 杨军贤 Method for preparing bitter sweet tea by extracting bitter sweet theophylline from new wild tea

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Application publication date: 20170104