CN101766811B

CN101766811B - Application of exenatide acetate or analogue thereof in preparing drug for treating or preventing diabetes complicated with cerebral infarction

Info

Publication number: CN101766811B
Application number: CN2008102080895A
Authority: CN
Inventors: 徐娟; 乔德水; 高雪芹
Original assignee: Jiangsu Wanbang Biological Pharmaceutical Co Ltd; Shanghai Fosun Pharmaceutical Group Co Ltd
Current assignee: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd.; Jiangsu Wanbang Biopharmaceutical Group Co ltd; Shanghai Fosun Pharmaceutical Group Co Ltd
Priority date: 2008-12-29
Filing date: 2008-12-29
Publication date: 2012-07-04
Anticipated expiration: 2028-12-29
Also published as: CN101766811A

Abstract

The invention discloses an application of exenatide acetate or an analogue thereof in preparing a drug for treating or preventing diabetes complicated with cerebral infarction, belonging to the field of pharmacy. The exenatide acetate or the analogue thereof can obviously improve the hemarheology index of a patient, not only effectively mitigate the diabetes manifestation of the patient, but also improve a nerve function, thereby being beneficial to recovering the whole state of illness.

Description

Exenatide or its analog merge the purposes in the cerebral infarction medicine in preparation treatment or prevent diabetes

Technical field

The present invention relates to pharmaceutical field, particularly, the present invention relates to Exenatide and merge the application in the cerebral infarction medicine in preparation treatment or prevent diabetes.

Background technology

Exenatide (is claimed Yi Xina peptide or Yi Kena peptide again; Exenatide) be the exendin-4 of synthetic; Be the analog of a kind of human glucagon-like-peptide-1 (GLP-1), the aminoacid sequence of its aminoacid sequence and GLP-1 partially overlaps, so it has identical physiological function with GLP-1.After Exenatide and pancreas GLP-1 receptors bind, the beta Cell of islet excreting insulin be can stimulate, thereby type ii diabetes patient's empty stomach and post-prandial glycemia reduced, slow down the carrying out property decline of beta Cell of islet function.Because so the glucose regulating action of Exenatide simulation GLP-1 is the incretin agonist that is otherwise known as.Exenatide is used to treat diabetes; It has been Anmilin Mediciens Co.,Ltd's list marketing; Trade name

Chinese patent CN00804847.9 discloses Exendin agonist peptide formulations and medication thereof, wherein discloses the compound structure and its preparation method of Exenatide.

Diabetes are common chronic diseases of a kind of serious harm human health.At present, there are nearly 200,000,000 diabeticss in the whole world, and closely half lives in the Asian-Pacific area.Wherein, China has 5,000 ten thousand diabeticss approximately.The complication that is caused by diabetes like inpairment of vision, low level amputation, heart disease etc., brings huge misery for patient and family members thereof, but most of patient fails effective blood sugar control because of reasons such as treatment means fall behind.

There are some researches show that about 10-30% cerebrovascular patient suffers from diabetes; And the atherosclerotic incidence rate of diabetic is wanted many 5 times than the normal person, and the time ratio normal person of taking place is early also more serious.This be since diabetics owing to hypoinsulinism causes sugar, fat and protein metabolism disorder; Be main with carbohydrate metabolism disturbance wherein, the amount that insufficient insulin makes conversion of glucose store for fat reduces, and fat is decomposed into triglyceride and free fatty in a large number; Cholesterol is synthetic vigorous; Make particularly cholesterol increase of blood fat, cause the infringement of blood vessel, be prone to form arteriosclerosis; In addition, the blood of diabetic often is hypercoagulability, and platelet function also often changes, and these can be as the factor that forms cerebral thrombosis.The concurrent cerebral infarction of diabetics is more than cerebral hemorrhage, and middle Microinfarct is more than the sheet infraction again, and with multiple in the majority.

Summary of the invention

The inventor is through broad research test discovery, and Exenatide or its analog have obvious treatment and/or preventive effect to diabetes complicated with cerebral infarction.

One of technical problem to be solved by this invention provides Exenatide or the purposes of its analog in the medicine of preparation treatment or prevent diabetes merging cerebral infarction.

Two of technical problem to be solved by this invention provides and a kind ofly is used for treating or prevent diabetes merges the pharmaceutical composition that contains Exenatide or its analog of the medicine of cerebral infarction.

The invention discloses Exenatide or its analog purposes in the medicine of preparation treatment or prevent diabetes merging cerebral infarction.

Exenatide of the present invention is meant the chemical compound that has with trade name

same structure.

Exenatide analog of the present invention includes but not limited to have high homology with Exenatide and has the peptide variant of GLP-1 receptor-binding activity.The peptide variant of preferred Exenatide be meant that certain amino acid residue is by conservative substituted variant in the Exenatide sequence.Described " conservative replace " is meant and utilizes another and be substituted the aminoacid that aminoacid has identical net charge and have about identical size and a shape and replace this aminoacid.When the carbon atom on their side chains and hetero atom sum differ when being no more than 4, the aminoacid with aliphatic or substituted aliphatic amino acid side chain is that size is identical haply; When the number of branches on their side chain differs when being no more than 1, they roughly are of similar shape; The aminoacid that has phenyl or substituted-phenyl on the side chain can think that size is identical with shape.As giving an example, below in 5 groups, utilize that another aminoacid causes guarding replacement in aminoacid replacement this group on the same group:

Group 1: glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, and alpha-non-natural amino acid with C1～C4 aliphatic lateral chain or C1～substituted aliphatic lateral chain of C4 hydroxyl (straight chain or single side chain).

Group 2: glutamic acid, aspartic acid and have the alpha-non-natural amino acid of the C1～C4 aliphatic lateral chain (no branch or a branch) of carboxylic acid-substituted.

Group 3: lysine, ornithine, arginine and have amide or the alpha-non-natural amino acid of the substituted C1 of guanidine radicals～C4 aromatic series side chain (no branch or a branch).

Group 4: glutamine, N and have the alpha-non-natural amino acid of the substituted C1 of amide～C4 aliphatic lateral chain (no branch or a branch).

Group 5: phenylalanine, phenylglycine, tyrosine and tryptophan.

Preferably, the guarantor collects for carrying out through natural amino acid.

Exenatide analog of the present invention comprises that also Exenatide or aforementioned and Exenatide have high homology and have the trim of the peptide variant of GLP-1 receptor-binding activity, includes but not limited to that polyethyleneglycol modified, polyamino acid is (like polylysine.Polyglutamic acid and poly-aspartate) modify.Chinese patent CN00809516.7 discloses the method for modifying Exenatide, introduces the present invention in full at this, as a reference.

Preferably, Exenatide analog of the present invention comprises that Exenatide or aforementioned and Exenatide have high homology and have the carbowax modifier of the peptide variant of GLP-1 receptor-binding activity.

Exenatide of the present invention can be bought through the commercial channel, also can prepare through the standard method of solid-phase peptide synthetic technology.For example, can use the peptide synthesizer of Appied Biosystems and the synthetic Exenatide of the present invention of solid phase synthesis reagent or its peptide variant of Midwest Biotech, operation is carried out according to the production description.Can be with reference to the synthetic Exenatide of the present invention of synthetic method or its peptide variant of plain peptide-1 analog of Chinese patent CNO1811213.7 pancreas hyperglycemia appearance.

Exenatide of the present invention or its analog generally use with the form of pharmaceutical composition, and this compositions contains Exenatide or its analog and the pharmaceutically acceptable auxiliaries as active component of treating effective dose.Usually with the subcutaneous injection administration, main dosage form is an injection.

Through the compositions of Exenatide or its analog of subcutaneous injection administration, generally be the aqueous solution form of sterilization, i.e. injection.These compositionss can contain pharmaceutic adjuvant, preferably, are selected from a kind of or its any mixture in glycine, mannitol, glucose, sucrose, lactose, polyvinylpyrrolidone, Polyethylene Glycol and the polyhydric alcohol etc.

When using Exenatide or its analogue treatment diabetes complicated with cerebral infarction; Give Exenatide or its analog with treatment or prevention effective dose with the patient of needs; Described " treatment effective dose " is meant and under the condition that does not cause patient's unacceptable side-effects, can produces the amount of required therapeutic effect." required therapeutic effect " comprising: the improvement of the symptom relevant with symptom with disease, delay the symptom relevant with disease or symptom appearance, compare the increase in life-span or have higher quality of life with the situation that not have to treat with respect to the situation of not treating.In the present invention; " effective dose " of treatment diabetes complicated with cerebral infarction be meant with give with patient's Exenatide or its analog before and after and with do not compared with the matched group of Exenatide or its type thing, hemorheology index such as whole blood height are cut viscosity, whole blood hangs down the amount that viscosity, blood plasma viscosity, erythrocyte aggregation index and fibrinogen content have obvious improvement or significant difference of cutting.Be used for effective dose that prevent diabetes merges cerebral infarction be meant with the situation of not treating mutually specific energy obviously reduce the amount of fasting glucose and GH.

Treat or prevent diabetes merges the Exenatide of cerebral infarction or the dosage of its analog decide according to the order of severity, the treatment time of the state of an illness, general subcutaneous injection dosage is administration every day 2 times, at every turn 5-10 μ g.

Among the preferred embodiment of the present invention; Subcutaneous injection Exenatide 5 μ g; One day twice, successive administration 28 days, the treatment group is compared with matched group; Hemorheology index such as whole blood height cut that viscosity, whole blood are low to be cut viscosity, blood plasma viscosity, erythrocyte aggregation index and fibrinogen content and obviously improve, and blood viscosity significantly reduces.

Clinical experimental study to the present invention carried out shows; Exenatide is better than non-diabetic merging Cerebral Infarction Patients to diabetes complicated with cerebral infarction patient's curative effect; Exenatide is the diabetes performance of reduction of patient effectively; Can also improve function of nervous system, thereby help the recovery of the whole state of an illness of patient.

The specific embodiment

With specific embodiment the present invention is described further below.

Embodiment 1 Exenatide is to diabetes complicated with cerebral infarction patient's therapeutical effect

Experimental subject and grouping: wherein 246 examples were organized in treatment, matched group 102 examples with interior Cerebral Infarction Patients 348 examples in 48 hours in clinical picked at random morbidity.All cases are selected OHA for use according to the state of an illness, make fasting glucose be controlled at 6-8mmol/L, take stabilizing blood pressure, use low dose of dehydrant, calcium antagonist (nimodipine), and platelet suppressant drug (low-dosage aspirin), symptomatic treatments such as infection.The treatment group: subcutaneous injection Exenatide injection 5 μ g, be a course of treatment at twice, 28 day every day; Matched group: subcutaneous injection equivalent normal saline, be a course of treatment at twice, 28 day every day.2 courses of treatment of the heavier person's row of the state of an illness.

Analysis project and index: hemorheology index (the whole blood height is cut viscosity, low viscosity, blood plasma viscosity, erythrocyte aggregation index and the fibrinogen content cut of whole blood).

The result: two groups of patient treatment front and back hemorheology are learned relatively please see the following form (table 1) of index

Table 1 a liang group patient hemorheology is learned the index testing result

Annotate: relatively preceding with treatment, * P＜0.01; Compare with matched group ^#P＜0.05

Through χ ²The inspection statistics component analysis shows: the treatment group patient of diabetes complicated with cerebral infarction compares with the matched group patient, and Exenatide more can improve hemorheology index well, reduces blood viscosity, helps conditions of patients and recovers.

Embodiment 2 Exenatides are to the preventive effect of diabetes complicated with cerebral infarction

80 routine patients are divided into two groups according to the random table that computer SPSS software generates with person patient at random.40 examples are organized in treatment, male 21 examples, women 19 examples; Age 57.5-86.5 year; Neurological deficits score 15-39 branch, average (23.1 ± 7.8) are divided.Matched group 40 examples, male 23 examples, women 17 examples; Age 54.5-85.5 year; Neurological deficits score 14-38 branch, average (22.7 ± 6.6) are divided.Two groups of sexes, age, neurological deficits score are through statistical analysis, and difference does not have significance meaning (P＞0.05), has comparability.Two groups of patients all give conventional therapy (OADs, dehydrant and supporting treatment etc.).Subcutaneous injection Exenatide 5 μ g on this basis, one day twice, successive administration 28 days are organized in treatment; Matched group gives the normal saline of equivalent, and one day twice, also be 28 days the course of treatment.

The main detection and analysis indexes: fasting glucose (BS) and GH (HbA _1C)

Result: BS and HbA before and after two groups of patient treatments _1CRelatively please see the following form (table 2).

Table 2 a liang group patient hemorheology is learned the index testing result

Annotate: relatively preceding with treatment, * P＜0.05; Compare with matched group ^#P＜0.05

This result of study shows that Exenatide can obviously reduce fasting glucose and saccharification hemoglobin content, thereby to regulating sugar and lipid metabolism, delays the conditions of patients progress and have important function.

Claims

1. Exenatide merges the purposes in the cerebral infarction medicine in preparation treatment or prevent diabetes.