CN1277554A - Use of glycosaminoglycans for producing pharmaceutical preparations for treating diabetes-associated diseases of the eye - Google Patents

Abstract

The invention relates to the use of glycosaminoglycans for producing pharmaceutical preparations for preventing or treating diseases of the eye which are associated with diabetes.

Description

Glucosaminoglycan is used for the treatment of purposes in the pharmaceutical preparation of the ophthalmic relevant with diabetes in production

The present invention relates to glucosaminoglycan is used for preventing or the purposes of the pharmaceutical preparation of the ophthalmic that treatment is relevant with diabetes in production.The invention still further relates to the pharmaceutical preparation of the ophthalmic that is applicable to that treatment is relevant with diabetes.

The purposes that glucosaminoglycan, particularly heparin and Hirudoid Cream/gel (Heparinoide) are used for the pharmaceutical preparation of production for treating circulatory disorders is known.

The purposes that glucosaminoglycan is used for multiple other disease has been described recently.US 5,236, and 910 disclose glucosaminoglycan is used for the treatment of diabetic nephropathy and neuropathic purposes.(J.Americ.Soc.Nephrol.8 (1997) 456-462) such as van derPij1 described the purposes that low molecular weight heparin is used for the treatment of disease of the same race.

US 5,032, and 679 disclose the purposes that glucosaminoglycan is used to suppress smooth muscle cell proliferation and the disease with it relevant.

US 4,966, and 894 disclose the poly-sulfated heparin that is used for the treatment of the caused disease of retrovirus.

Retinopathy be the most common also be the most serious diabetic eye complication.In industrialized country, this is the main cause of losing one's sight.The blind danger of diabetics is difficult to prediction.This depends on multiple factor, for example the type of age, diabetes and persistent period.Assessment for danger also plays an important role to amphiblestroid survey result at present.

1980, about 2500 patients that select have been carried out epidemiological study from 10000 diabeticss at Wisconsin.The patient is divided into 3 groups to be studied: A: the age is below 30 years old and insulinize during onset diabetes, B: the age is more than 30 years old and insulinize during onset diabetes, C: " old age " patient of insulinize is not (referring to Klein etc., diabetes/metabolism summary, 5 (1989) 559-570).

Observe and write down the development of retinopathy by photography.Between follow-up period, the patient in the research is regularly checked, and treat by the method for laser photocoagulation when needed.

In the patient who is studied, the sickness rate of retinopathy is 50.1%, but only has 2.2% to exist and blind dangerous relevant condition.In " youth " group, the sickness rate of vision moderate lesion is 1.4%, 3.2% blind.

At present, laser photocoagulation is the unique effective Therapeutic Method of retinopathy.Also be not used at present the treatment active drug of definite retinopathy.

US 3,869, and 548 have put down in writing with high molecular weight heparin and the method that belongs to the toxicide enzyme therapeutic alliance retinopathy that obtains the venom of atrox from Brazilian adder Botrhops bothrops jararaca and Brazilian abdomen.

The shortcoming of this method is that toxicide enzyme must at first obtain detoxification then by processing from venom.Only when uniting, just may in zoopery, treat the retinopathy of Cavia porcellus with high molecular weight heparin.Used heparin and venom itself is all invalid to treatment of retinopathy.

The purpose of this invention is to provide the method for treatment retinopathy and/or degeneration of macula, this method does not have above-mentioned shortcoming and can be used for the treatment of retinopathy and degeneration of macula safely, easily.

We find, by using glucosaminoglycan to produce to be used to prevent or the pharmaceutical preparation of the ophthalmic that treatment is relevant with diabetes has reached this purpose.

The invention still further relates to the pharmaceutical preparation that is suitable for treating the ophthalmic relevant with diabetes, said preparation contains the salt of one or more physiologically actives that are selected from glucosaminoglycan, glucosaminoglycan derivant, Hirudoid Cream/gel, these materials or the material of their mixture.

The pharmaceutical preparation of producing for purposes of the present invention can comprise the above-claimed cpd of the combining form of salt, its tautomer and/or the isomeric forms of free cpds or its physiologically active or free cpds and various salt.The example of preferred physiologically active salt comprises sodium salt, calcium salt or magnesium salt.Also can use the salt that forms with organic base such as diethylamine, triethylamine or triethanolamine.This pharmaceutical preparation preferably contains the chemical compound of at least a free material or at least a its salt or its form of mixtures.

The glucosaminoglycan (=mucopolysaccharide) that is used for purposes of the present invention is meant the polysaccharide (polysaccharide) that has negative charge, its disaccharide unit by various connections is formed, wherein, for example, 1 molecular saccharides aldehydic acid such as D-glucuronic acid or L-iduronic acid are connected to amino sugar such as glycosamine or galactosamine 3 or 4 by glycosidic bond.Have at least a kind of sugar to contain electronegative carboxylate radical or sulfate groups in the disaccharide, these groups can connect by oxygen atom or nitrogen-atoms.Because alduronic acid and sulfate group, glucosaminoglycan shows very strong acid reaction.These acidic-groups can be naturally occurring and/or be incorporated in the chemical compound by synthesis example such as sulphation.Its example comprises US 5,013, the process of sulfating of describing in 724.The example of natural glucosamine polysaccharide is heparin, Heparan sulfate (Heparan-sulfat), keratan sulfate, dermatan sulfate, chrondroitin or chondroitin sulfate.Heparan sulfate is equivalent to heparin but its N-and the O-sulfate groups is less and the N-acetyl group is more.The glucosaminoglycan or the Hirudoid Cream/gel that are preferred for purposes of the present invention or pharmaceutical preparation are selected from dermatan sulfate, Heparan sulfate, dextran sulfate (US5,541,166), sulphuric acid xylan (pentosane polysulfate ester for example, EP-A-0184480, FR835170), the derivant of heparin or these materials.These materials are with the effective dose administration of treatment ophthalmic.

Glucosaminoglycan can separate from the mucous membrane of small intestine of animal tissue such as pig or cattle or ear and obtains.Be used in the tissue automatic soup-dissolving that separates glucosaminoglycan and use alkaline extraction.Can make protein coagulating and precipitation by for example acidify then.After joining precipitation in polar nonaqueous solvent such as ethanol or the acetone, remove fat with organic solvent extraction.At last, remove deproteinize by proteolytic digestion and obtain glucosaminoglycan.Charles etc. (journal of biological chemistry (Biochem.J.), 30 (1936) 1927-1933) and Coyne, the chemistry and biology (ElsevierPublishers of E. heparin, North Holland, N.Y., Lunblad, R.L. compile 1981) method of separating heparin described.

These can also carry out derivatization from the isolating glucosaminoglycan of natural origin, and for example according to US 5,013,724 methods of describing are poly-sulfated.Poly-sulfated can to make the sulfur content of glucosaminoglycan be 6-15% (weight), preferred 13-15% (weight).The derivant of material is meant the chemical compound that can improve in use character of glucosaminoglycan (be effect, stability and from intravital elimination).

Preferred glucosaminoglycan is heparin and/or dermatan sulfate, and its mean molecule quantity is 1000-20000 dalton, preferred 1500-9000 dalton, preferred especially 2000-6000 dalton.The low molecular weight heparin and/or the dermatan sulfate (can be poly-sulfated) of the form of mixtures of preferred especially free acid form or the salt that forms with alkali that physiology can tolerate or these chemical compounds.

Low-molecular-weight glucosaminoglycan such as low molecular weight heparin and/or dermatan sulfate can prepare by several different methods.Method by depolymerization prepares low molecular weight heparin with nitrous acid and is recorded in for example EP-B-0037319 or biochemistry 15 (1976) 3932.Low molecular weight heparin and low-molecular-weight glucosaminoglycan can also be used enzyme (journal of biological chemistry, 108 (1968) 647), (FR 2 for sulphuric acid and chlorosulfonic acid, 538,404), periodic acid or physical method or γ-radiation (EP-A-0269937) or ultrasonic (Fuchs etc., Lebensm.Unters.Forsch.198 (1994) 486-490) preparation.

The invention still further relates to by containing glucosaminoglycan such as low molecular weight heparin and/or dermatan sulfate and at least a medicine that can bring high blood pressure down or at least a medicine or the compound product formed of the pharmaceutical preparation of its combination that can blood sugar lowering.

The medicine that can bring high blood pressure down is meant, for example inhibitor or its combination of endothelin-converting enzyme (ECE) inhibitor, endothelin antagonists or renin-angiotensin system.

The inhibitor of renin-angiotensin system is renin inhibitor, Angiotensin II antagonist, particularly angiotensin converting enzyme (ACE) inhibitor.The combination of medicine can reach the beneficial effect that brings high blood pressure down.

The hypoglycemic drug that the example of medicine that can blood sugar lowering is insulin, be used to orally use, for example solsonylurea compounds or α-glucosidase inhibitor.

The combination of described medicine (glucosaminoglycan, can bring high blood pressure down and/or the medicine of blood glucose) can with single medicament forms or on time or space isolating form administration.

About dosage and administering mode, must consider the factor that corresponding one matter is considered.

Produced according to the present invention and the pharmaceutical preparation used can be in the mode of routine oral or parenteral (subcutaneous, intravenous, intramuscular, intraperitoneal) administration, preferred oral or intravenous administration.

Dosage depends on patient's age, disease and body weight and administering mode.

Glucosaminoglycan is preferably with the dosed administration of 0.1-500mg/kg body weight/day.Under the situation that parenteral uses, preferably with the dosed administration of 0.1-30mg/kg body weight/day, under situation about orally using, its dosage is the 0.2-500mg/kg body weight/day to glucosaminoglycan, can be with described dosage with single dose or the dosed administration that separates.The mixture of at least a low molecular weight heparin and/or its poly-sulfated derivant and/or at least a low-molecular-weight dermatan sulfate and/or its poly-sulfated derivant is also with the dosage parenteral of 0.1-30mg/kg body weight/day or with the oral dose administration of 0.2-500mg/kg body weight/day.

In theory, the pharmaceutical preparation that is used for the treatment of the compound recipe that contains glucosaminoglycan or these polysaccharide and above-mentioned other medicines of the ophthalmic that is caused by diabetes can be all medicament forms that can be used for oral or parenteral, no matter be solid or liquid, for example coating or (thin film) coating tablet, capsule, powder, granule, suppository, solution or suspensoid.These preparations prepare in the mode of routine.Also can be with medicine with conventional pharmaceutical adjuvant such as tablet binder, extender, antiseptic, tablet disintegrant, flowing regulator, plasticizer, wetting agent, dispersant, emulsifying agent, solvent, delayed discharge agent, antioxidant and/or the processing of propellant gas (referring to Sucker etc.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991).The dosage form that obtains in this mode contains the medicine of 0.1-90% (weight) usually.

Because the reinforcement of each composition effect, the combination of various effects is a kind of ideal additions.

Compound recipe of the present invention (Kombination) is usually with for example form oral administration of the tablet of coating or (lacquer) coating, dragee, hard and Perle, solution, emulsion or suspension not.But, the also form rectally of suppository for example, or with the form parenteral of solution or injection.Can be with product form such as tablet or the capsule administration of medicine to contain two kinds of medicines simultaneously, perhaps with the form administration respectively of the special combination of one matter, can be simultaneously or administration successively with it.

In order to produce the tablet and the hard gelatin capsule of coating not or (lacquer) coating, can be with compound recipe of the present invention with the inert inorganic or organic excipients processing of medicine.The excipient that can be used for coating not or coated tablet and hard gelatin capsule is lactose, corn starch or derivatives thereof, Talcum, stearic acid or its salt.The excipient that is applicable to Perle is vegetable oil, wax, fat, semisolid and liquid polyol.

Be suitable for producing solution and the syrup excipient is, for example water, polyhydric alcohol, sucrose, Nulomoline, glucose etc.The excipient that is suitable for injection solution is water, alcohol, polyhydric alcohol, glycerol, vegetable oil.The excipient that is applicable to suppository is natural or fixed oil, wax, fat, semiliquid or liquid polyol etc.

Pharmaceutical preparation also can contain salt, buffer agent, " coating materials and/or the antioxidant of antiseptic, solubilizing agent, stabilizing agent, wetting agent, emulsifying agent, sweeting agent, coloring agent, correctives, adjusting osmotic pressure.

The research of embodiment retinopathy is preclinical study a)

Carry out animal experiment study and compare with placebo, with various glucosaminoglycans (Reviparin particularly with investigation ^) development of diabetic retinopathy when treating.

In order to induce diabetes and the sequela (for example retinopathy, nephropathy) relevant, once to administration 60mg/kg streptozotocin in the rat vein with it.This processing causes the destruction of beta Cell of islet.After a couple of days, compare with the animal of not handling with streptozotocin, the blood sugar level of these rats obviously raises, and the weight of animals reduces, this is can't utilize glucose caused owing to what insulin deficit caused, and insulin is that cell ingestion of glucose from blood is necessary.

Compare with placebo, every day is with the dosage intravenous of 1mg/kg or with the oral dose administration Reviparin of 5mg/kg ^(=low molecular weight heparin, mean molecule quantity 4000 dalton) obviously stop the development of diabetic retinopathy, and in rat, this can be by the sxemiquantitative measurement is carried out in the scoring of the vascular permeability increase of morning as far as possible.

Material and method

Animal: rat

Kind: Sprague Dawley, Janvier, France

Sex: male

Body weight: 220-240g

40 animals are used in experiment.To all animals with the dosage intravenous of 60mg/kg (=i.v.) the administration streptozotocin (=STZ) once.This processing causes the destruction of beta Cell of islet.After a couple of days, compare with the animal of not handling with streptozotocin, (all animals all＞25mmol/l) obviously raise the blood sugar level of these rats, and the weight of animals reduces, this is can't utilize glucose caused owing to what insulin deficit caused, and insulin is that cell ingestion of glucose from blood is necessary.

In s.c. test (s.c.=is subcutaneous), to the Reviparin of animal with the volume subcutaneous administration 1mg/kg of 1ml/kg ^Corresponding matched group is accepted the placebo (=isotonic saline solution) of respective amount.

In p.o. test (p.o.=is oral), by the Reviparin of tube feed to animals administer 5mg/kg ^The administration volume is 5ml/kg.Corresponding matched group is accepted the placebo (=isotonic saline solution) of respective amount.

Group	Number of animals	Induce diabetes	Treatment
				????1	????10	The 60mg/kg streptozotocin	Placebo, 8-28 days s.c.
????2	????10	The 60mg/kg streptozotocin	1mg/kg?Reviparin , 8-28s.c.
				????3	????10	The 60mg/kg streptozotocin	Placebo, 8-28 days p.o.
????4	????10	The 60mg/kg streptozotocin	5mg/kg?Reviparin , 8-28p.o.

On weekdays animal is treated.Animal is not treated on Saturday and Sunday.

Therapeutic scheme

The 0th day: induce diabetes with streptozotocin

The 7th day: measure blood sugar level

The 28th day: vascular permeability was measured in injection macromole label (FITC-Dextran 150 000=FDex) back

Marking system:

0: seepage FDex not

1: from the slight increase of≤2 breakthrough seepages and/or background fluorescence

2: from the increase greatly of＞2 breakthrough seepages and/or background fluorescence

3: after administration FDex5 minute, from a large amount of seepages of all blood vessels

The result:

In all 40 animals that institute is used, 5 animals in experimental session dead (1 group: 1 animal, 3 groups: 2 animals, 4 groups: 2 animals) are arranged.

Subcutaneous administration is after 3 weeks, administration Reviparin ^Caused that fluorescently-labeled macromole oozes out obvious minimizing (referring to Fig. 1).Fig. 1 has illustrated Reviparin ^(1mg/kg subcutaneous administration) in the STZ diabetes rat to the influence of vascular permeability.At oral administration Reviparin ^After also can cause the reduction (Fig. 2) of the degree of oozing out.Fig. 1 has illustrated Reviparin ^(5mg/kg oral administration) in the STZ diabetes rat to the influence of vascular permeability.B) clinical research

There are 11 I types or type ii diabetes patient to participate in research.The purpose of research is the Reviparin of every morning to one time 4200 unit of patient's subcutaneous injection ^, carried out for 12 weeks altogether.Then, the patient was followed up a case by regular visits to for 12 weeks (the total inspection phase was 24 weeks).

Main observation variable during with the Reviparin treatment in the specificity change on eye optical fundus.

Research keeps and exclusion standard is defined as follows:

Retention criteria:

I type or type ii diabetes, non-proliferative retinopathy weak or moderate, age 18-80 year

Exclusion standard:

Serious non-proliferative diabetic retinopathy, the proliferative diabetic retinopathy, before 3 months, carry out the laser coagulation of focus, carried out full optical fundus laser coagulation (a variety of causes) in the past, because serious non-proliferative or proliferative diabetic retinopathy needs laser coagulation clinically, with known can with hemostasis or the interactional medicine (NSAID of platelet function, prostaglandin synthesis inhibitors, anticoagulant [ASA＞100mg], glucosan) treatment, treat with steroidal compounds, the thrombocytopenia that known heparin causes, known to heparin and sulfate allergy, gastrointestinal hemorrhage (having the patient of gastrointestinal hemorrhage medical history to use H2 blocker or omeprazole treatment), anemia of pregnant woman or prepare conceived person, the women of child-bearing age of (hormonal contraceptive or intrauterine pessulum) reliably must practise contraception, HbAlc is greater than 9%, Arterial Hypertention out of control.

According to this standard, 11 patients finally from 36 patients, have been selected.

Patient's consensus data is as follows: 4 women and 7 male, age is 52.45 ± 18.73 (31-74) year (M ± SE[scope]), suffer from I type (n=6) and II type (n=5) diabetes, the self diagnosis time up till now is 21.73 ± 10.53 years (3-42), height 167 ± 11.3 (150-186) cm, body weight 79.3 ± 11.3 (57-97.7) kg, body-mass index 28.8 ± 4.83 (24.1-38.2) kg/m ², mean blood pressure 125/75 ± 13/7 (100/58-150/82) mmHg that measured in 24 hours, heart rate 77.4 ± 12.2 (54-89) is inferior/minute.

The disease that occurs together:

In the patient, found following secondary and the disease that occurs together:

Arterial Hypertention (n=7), coronary heart disease (n=5), arteriosclerosis obliterans (n=2), situation behind the apopiecticus insultus (n=1), property diabetic insanity (n=4), diabetic retinopathy (n=5 on every side, have 4 patients that the microalbuminuria of just sending out is arranged, 1 patient has albuminuria), chronic kidney deficiency (n=4; A patient is the chronic glomerulonephritis that the nephropathy symptom is arranged), epilepsy (n=1), lichen ruber planus (n=1).

All patients all do not have allergy.4 patient's smokings are arranged, and 6 patients have hyperlipemia.

The Drug therapy of carrying out simultaneously:

Table I has been listed the long-term Drug therapy that the patient accepts.During treating, do not give new medicine or stop administration.It is constant that the patient's of insulin injection insulin dose keeps.A patient is because allergic rhinitis needs the administration antihistaminic.Three patients are arranged with carrying out long-term treatment in aspirin 100mg/ days.

Physical examination:

The clinical examination that keeps the patient is not found to get rid of the pathology situation (concrete outcome: two patients suffer from chronic foot ulcer, and a patient suffers from influences the left side of arm hemiparesis) that the patient studies.Physical examination result is relevant with the disease of knowing in the past.

The investigation of security parameters

Will be before the treatment phase, the following parameter of investigation in (after 24 weeks) after (12 week back) and the follow-up period after the process neutralization:

In the blood: retention value (carbamide, kreatinin), serum electrolyte (sodium, potassium, chlorine), liver function test result (alkali phosphatase, gGT, ASAT, ALAT, bilirubin), cholesterol, triglyceride, serum glucose, HbAlc, total protein, albumin, blood picture (leukocyte, erythrocyte, hemoglobin, platelet), coagulation parameters (ATIII, aPTT, HEP test)

In the urine: kreatinin, total protein, albumin, creatinine clearance

In addition by 24 hours blood pressure measurements before the treatment phase and when finishing and follow-up period checked blood pressure when finishing.

Table II has provided the definite time to each parameter investigation.

The investigation of rendeing a service

Begin treatment research is to reach the improvement that changes with the optical fundus specificity relevant with diabetic retinopathy.For this reason, beginning to use Reviparin ^Before the treatment, carry out fluorogaphy with Heidelberger fluorescein angiographic photo, the maximum image sector is 30 a °/egative film.Disk fixed with the nose edge labelling so that the identical image fragment in can relatively all are checked.Possible area coverage with the best is taken pictures, and considers best picture quality.In this research, the specificity that the treatment in 12 weeks finishes to pass through the detected slight non-proliferative retinopathy of fluorogaphy in the back when comparing in the treatment beginning on two fluorescence photos changes (the particularly quantity and the degree of microaneurysm, petechia and hard exudate in the retina).The Reviparin that 2 patients are arranged ^Fluorescence photo and the fluorescence photo of all patients when follow-up period finishes when treatment finishes do not obtain as yet.

With fluorescence photo by qualitative standard (microaneurysm, inter-retinal hemorrhage) and following scoring (++ be clearly better ,+slight the improvement ,=constant ,-slight deterioration,--obviously worsen) assess.

Treat the term results after 12 weeks

The safety variable: in the treatment phase, retention parameter and serum electrolyte concentration and liver power checking result are all less than changing.Serum level of glucose has very big-difference, because when blood sampling, the patient does not have fasting usually.

Using Reviparin ^During the treatment, have a patient slight leukocytosis to occur, maximum is 13300[x 10 ⁹/ l] m, leukopenia has appearred in another patient, and minima is 3.31[x 10 ⁹/ l].Do not observe leukocytic other variation.On red blood cell concentration, hemoglobin, hematocrit and PC, do not change.

Other parameter of checking is anti-xa activity and creatinine clearance.Do not find to worsen.For PE, there are two type i diabetes patients in the treatment phase, to demonstrate the minimizing (Reviparin of microalbuminuria ^Before the treatment is 34.7mg/ days, is 730mg/ days after 12 weeks).Table III has been summarized laboratory result.On blood pressure regulating, do not change.

Efficacy variable: in 20 eyes altogether that detect (female patient has stopped treatment), 16 eyes have been carried out half-quantitative detection and assessment by above-mentioned standard.Only when beginning, detected the optical fundus by fundus photography.Therefore, use this appraisal procedure, can only sxemiquantitative the degree of investigation and harder exudate.In 10 eyes, the detection of hard exudate is not demonstrated variation.In fundus observation, there are 3 eyes to improve (+), other 3 eyes deteriorations (-).There are not eyes to demonstrate tangible improvement or deterioration.Have the eyes of two improvement to belong to the type ii diabetes patient, the eyes of remaining improvement belong to the type i diabetes patient.The eyes of all slight deterioration all belong to the type ii diabetes patient.

For the specificity at the bottom of the evaluate ocular changes, in this research, carried out fluorogaphy first.This method can detect amphiblestroid typical case in more detail and change, for example microaneurysm, inter-retinal hemorrhage or-in serious non-proliferative retinopathy case-intraretinal microvascular abnormality (=IRMA).Therefore, this diagnostic method is the golden standard that detects the optical fundus blood vessel pathological change.After treating for 12 weeks, the result of this method shows the trend that retinopathy improves.But, the final assessment of all eyes is not carried out as yet.

Table I: participate in Reviparin ^The patient's of treatment research long-term Drug therapy

Substance classes	Prescription	Individual substance
			Anticoagulant	????3	Aspirin (maximum dosage 100mg every day)
ACE inhibitor	????6	Captopril, enalapril, Fosinopril, ramipril
			Diuretic	????7	Hydrochlorothiazide, furosemide, Torasemide
Beta-Blocking agent	????2	Metoprolol
			Other antihypertensive	????2	Moxonidine, nisoldipine
Cardiac drug	????5	Digoxin, sorbitrate, molsidomine
			Insulin	????17	Insulin regular, NPH insulin, compound insulin
Antilipemic	????3	Fluvastatin, lovastatin, simvastatin
			Antidepressants	????1	Amitriptyline
Antuepileptic	????2	Carbamazepine, lamotrigine
			Antianxiety drugs	????1	Lorazepam
Gastrointestinal drug	????1	Omeprazole
			Inorganic matter	????1	Calcium

Table II: flow chart (evaluation time of safety variable)

	It is 0 years old	They are 3 years old	Week 1	They are 10 years old	Week	2	Week 4	Week 8	Week 12	Week 16	Week 20	Week 24
													Medical history	??X		??X			??X	??X	??X	??X	??X	??X
Clinical examination	??X							??X			??X
												BP	??X		??X			??X	??X	??X	??X	??X	??X
24hBP	??X							??X			??X
												FAG	??X							??X			??X
Blood picture	??X	??X	??X	??X	??X	??X	??X	??X	??X	??X	??X
												The HEP test	??X					??X	??X	??X	??X	??X	??X
aPPT	??X
												ATIII	??X
S.Na	??X		??X			??X	??X	??X	??X	??X	??X
												S.K	??X		??X			??X	??X	??X	??X	??X	??X
S.chl.	??X		??X			??X	??X	??X	??X	??X	??X
												S.prot.	??X							??X			??X
S.alb.	??X							??X			??X
												S.crea.	??X		??X			??X	??X	??X	??X	??X	??X
Crea.Cl.	??X					??X	??X	??X	??X	??X	??X
												U.alb.	??X					??X	??X	??X	??X	??X	??X
U.TP	??X					??X	??X	??X	??X	??X	??X
												S.glu.	??X		??X		??X	??X	??X	??X	??X	??X	??X
HbAlc	??X					??X	??X	??X	??X	??X	??X
												S.chol.	??X							??X			??X
S.trigl.	??X							??X			??X
												gGT	??X							??X			??X
ALAT	??X							??X			??X
												ASAT	??X							??X			??X
S.bili	??X							??X			??X

S.=serum bili=bilirubin U.=urine prot.=protein HEP test=heparin test BP=blood pressure alb.=albumin TAG[sic]=the part thrombus fibrinolytic solution time glu. of fluorogaphy crea.=kreatinin chl.=chlorine Crea.Cl.=creatinine clearance TP=total protein aPPT=activation=glucose ATIII=Antithrombin III HbAlc=glycosylated HbAlc chol.=cholesterol MAU=microalbuminuria trigl.=triglycerides gGT[sic]=gamma-glutamic acid transferase [sic] ALAT=ALT ASAT=aspartate aminotransferase

Table III: with the reality of (T0) and treatment 12 week backs (T1) before the Reviparin treatment beginning

Test the chamber result, provided meansigma methods (M) and standard deviation (SE).

	????T0 ????M±SE	????TI[sic] ????M±SE
1. blood picture
			Leukocyte [x10 9/l]	????7.5±2.5	????7.5±2.3
Hemoglobin [g/dl]	????14.0±1.8	????14.2±1.4
			Platelet [x10 9/l]	????265±36	????252±36
			2. blood coagulation
??aPPT[s]	????25.4±1.6
			??AT?III[％]	????90.1±7.7
Hep tests [s]	????21.1±2.1	????73.2±27.1
3. renal function
			??Na[mmol/l?]	????137±2	????139±1
??K[mmol/l]	????4.5±0.5	????4.3±0.3
			??Cl[mmol/l]	????95±4	????95±4
??S.TP[g/l]	????70.8±5.6	????70.0±7.2
			??s.alb[g/l]	????44.1±5.0	????43.2±8.0
??S.crea.[mg/dl]	????1.5±1.1	????1.3±0.9
			??Crea.Cl.	????91±68	????95±63
??MAU[mg/d]	????740±1518	????856±1971
			??U.TP[mg/d]	????1261±2019	????1394±2454
			4. metabolism
Glucose [mg/dl]	????211±83	????148±55
			??HbAlc[％9]	????7.3±0.8	????7.4±1
??chol.[mg/dl]	????221±42	????218±31
			??trigl.[mg/dl]	????266±255	????241±251
			5. liver is moving
??gGT[U/l]	????12±6	????16±11
			??ALAT[U/l]	????10±4	????19±6
??ASAT[U/l]	????9±3	????10±3
			??bili[mg/dl]	????0.5±0.1	????0.5±0.1

Table IV: with 24 hours motion blood pressure measurements of (T0) and treatment 12 week backs (T1) before the Reviparin treatment beginning.Provided the record meansigma methods of contraction and phase diastolic blood pressure; The meansigma methods and the standard deviation of all measurements have been provided below.

Patient's code	Average systolic	AvDP	Heart rate [sic]	Average systolic	AvDP	Heart rate
							Time	????T0	????T0	????T0	???TI[sic]	????T1	????T1
2R1	????128	????80	????84	????127	????76	????81
							2R2	????115	????72	????82
2R3	????100	????58	????54	????109	????64	????86
							1R1	????131	????82	????67	????124	????78	????69
1R2	????124	????81	????87	????116	????76	????95
							1R3	????119	????78	????89	????126	????83	????85
1R4	????119	????71	????89	????122	????74	????83
							1R6	????151	????78	????77	????129	????73	????81
1R7	????133	????66	????62
							1R9	????138	????78	????89
1R12	????122	????73	????76
							Mean	????125	????74	????78	????122	????74	????83
SE	????13	????7	????12	????7	????6	????9

Studies show that, can be by administration Reviparin ^Improve patient's retinopathy.

Claims (12)

Claims 1. Use of glycosaminoglycans in the manufacture of a medicament for the prevention or treatment of eye diseases associated with diabetes. 2. The purposes of the described glucosaminoglycan of claim 1, wherein, at least one is selected from dermatan sulfate, heparan sulfate, dextran sulfate, xylan sulfate, heparin or the derivatives of these substances. Glycosaminoglycans are administered in effective amounts. 3. The use of the glycosaminoglycan according to claim 1 or 2, wherein low molecular weight heparin, heparan sulfate, dermatan sulfate or a mixture thereof is administered. 4. The use of the glycosaminoglycan according to any one of claims 1-3, wherein the glycosaminoglycan is administered orally or parenterally. 5. The use of the glycosaminoglycan according to any one of claims 1-4, wherein the glycosaminoglycan is administered parenterally at a dose of 0.1-30 mg/kg body weight/day. 6. The use of the glycosaminoglycan according to any one of claims 1-4, wherein the glycosaminoglycan is orally administered at a dose of 0.2-500 mg/kg body weight/day. 7. The use of the glycosaminoglycan according to any one of claims 1-6, wherein the sulfur content of the glycosaminoglycan is 6-15% by weight. 8. The use of the glycosaminoglycan according to any one of claims 1-7, wherein the average molecular weight of the glycosaminoglycan is 1000-20000 Daltons. 9. The use of the glycosaminoglycan according to any one of claims 1-8, wherein the glycosaminoglycan, its derivative or mixture is used in the form of free acid, its physiologically active salt or its mixture . 10. A pharmaceutical preparation suitable for the treatment of eye diseases associated with diabetes, containing one or more substances selected from the group consisting of glycosaminoglycans, glycosaminoglycan derivatives, physiologically active salts of these substances or mixtures thereof. 11. A compound of the pharmaceutical preparation according to claim 10 and at least one drug capable of lowering blood pressure or at least one drug capable of lowering blood sugar or a combination thereof. 12. Combination as claimed in claim 11, which contains ACE inhibitor as blood pressure lowering drug.

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