CN103251954A - Diabetes treating compound medicine for reducing side effect of rosiglitazone and preparation method thereof - Google Patents

Diabetes treating compound medicine for reducing side effect of rosiglitazone and preparation method thereof Download PDF

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CN103251954A
CN103251954A CN2013101899250A CN201310189925A CN103251954A CN 103251954 A CN103251954 A CN 103251954A CN 2013101899250 A CN2013101899250 A CN 2013101899250A CN 201310189925 A CN201310189925 A CN 201310189925A CN 103251954 A CN103251954 A CN 103251954A
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rosiglitazone
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罗国安
王义明
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Abstract

The invention discloses a diabetes treating compound medicine for reducing side effect of rosiglitazone and a preparation method thereof, and belongs to the field of medicine preparation. The compound medicine consists of rosiglitazone and a diuretic medicine, wherein the ratio of rosiglitazone to the diuretic medicine by weight is 1:(0.04-1). The diabetes treating compound medicine is compounded and matched with any one of spirolactone, amiloride, compound amiloride, ergosterol, triamterene, ethacrynic acid, hydroflumethiazide and bumetanide which can better eliminate side effect of rosiglitazone with rosiglitazone so as to form the compound medicine which not only can reduce the side effect of rosiglitazone, but also better treats diabetes.

Description

A kind for the treatment of diabetes compound medicine that reduces the rosiglitazone side effect and preparation method thereof
Technical field
The present invention relates to field of medicaments, particularly relate to a kind for the treatment of diabetes compound medicine that reduces the rosiglitazone side effect and preparation method thereof.
Background technology
Rosiglitazone (having another name called Avandia) is that (thiazolidinediones, TZDs) medicine can effectively be treated type 2 diabetes mellitus to a kind of thiazolidinediones.At present, rosiglitazone is unique can also can the use with metformin class compatibility simultaneously at the TZDs of clinical single usefulness class medicine.In JIUYUE, 2010, rosiglitazone is listed in " blacklist " because causing risk of cardiovascular diseases by European Bureau of Drugs Supervision, does not allow it to go on the market again.China Bureau of Drugs Supervision and Ministry of Public Health have announced that portion unites notice subsequently, be illustrated under the prerequisite of " strengthening management ", comprise that 12 kinds of rosiglitazones of this medicine and compound preparation product thereof still can continue the use of having ready conditions in China, but must change its description, can only just can consider to use rosiglitazone and compound preparation thereof using other antidiabetic drugs or using other antidiabetic drugs can't reach under the situation of glycemic control target.
The main target spot of TZDs class medicine is peroxisome proliferation-activated receptors γ (PPAR γ mainly is present in the collecting tubule).Yet experiment in vivo and vitro data show, the heavily absorption that PPAR-γ activator can also promote the distal tubule sodium ion by expression and the migration of rise collecting tubule epithelial sodium ion channel causes water-sodium retention, diluted plasma, body weight increases, and then causes congestive heart failure.There are some researches show also that recently large dose oral administration rosiglitazone or chronic heart failure or hyperpietic take rosiglitazone, can cause serious adverse.Rosiglitazone causes that the reason of heart failure mainly is due to its edema that causes (water sodium pool) is stayed, but not medicine is to the direct toxic action of heart.
Drug side effect is one of main reason of new drug clinical trial failure, and causes a series of serious consequences in treatment clinical course, therefore reduces the important content that side effects of pharmaceutical drugs have been medicament research and development and clinical treatment.At present, clinically rosiglitazone except with the metformin use in conjunction, with the coupling of medicines such as benazepril, insulin and repaglinide the research report is arranged also.Rosiglitazone and metformin synergy can suppress the obesity that occurs in the rosiglitazone therapeutic process, but the side effect of the myocardial hypertrophy that rosiglitazone is caused does not have the effect of alleviating.Although the rosiglitazone compound recipe has many application in clinical treatment, most of compound recipe medications are based on that clinical experience gets, and the molecular mechanism of these compound medicine effects is not fully aware of, and the toxic and side effects of the research and development less relevance medicine of compound medicine.Effectively eliminate the problem that the toxic and side effects of rosiglitazone is individual needs solution and form compound medicine with which kind of medicine and rosiglitazone.
Summary of the invention
Based on above-mentioned prior art problems, the invention provides a kind for the treatment of diabetes compound medicine that reduces the rosiglitazone side effect and preparation method thereof, can effectively eliminate the toxic and side effects of rosiglitazone, thereby solve the bigger problem of present single use rosiglitazone side effect.
Solve the problems of the technologies described above by following scheme:
The present invention provides a kind for the treatment of diabetes compound medicine that reduces the rosiglitazone side effect, and this medicine is made up of rosiglitazone and diuretic, and wherein, the proportioning of rosiglitazone and diuretic is 1: 0.04～1 by weight.
The present invention gives a kind of preparation method that reduces the treatment diabetes compound medicine of rosiglitazone side effect, comprising:
The screening drug candidate:
Make up the network screening model of side effect-path-drug candidate according to the side effect of rosiglitazone, the drug candidate that screening determines to eliminate the side effect of described rosiglitazone is diuretic;
Be that 1: 0.04～1 proportioning is made treatment diabetes compound medicine by weight with rosiglitazone and diuretic.
The present invention by with can fine elimination rosiglitazone the diuretic of side effect cooperate with the rosiglitazone compound recipe, form the treatment diabetes compound medicine that a kind of side effect of eliminating rosiglitazone again can fine performance rosiglitazone drug effect.
Description of drawings
Side effect-path the network diagram of Fig. 1 for making up in the preparation method provided by the invention;
Medicine-path the network diagram of Fig. 2 for making up in the preparation method provided by the invention;
Side effect-path-drug candidate the network diagram of Fig. 3 for making up in the preparation method provided by the invention;
Fig. 4 irritates stomach packed cell volume (HCT, %) change curve (n=10) figure after 21 days for the rosiglitazone of the present invention experiment;
Fig. 5 is situation of change (n=10) curve chart of the red blood cell count(RBC) of the present invention's experiment;
Fig. 6 is situation of change (n=10) curve chart of the hemoglobin of the present invention's experiment.
The specific embodiment
A kind for the treatment of diabetes compound medicine that reduces the rosiglitazone side effect that the embodiment of the invention provides, this medicine is made up of rosiglitazone and diuretic, and the proportioning of rosiglitazone and diuretic is 1: 0.04～1 by weight.Wherein, diuretic is any in spironolactone, amiloride, compound recipe amiloride, ergosterol, triamterene, etacrynic acid, hydrogen fluorine first thiophene, the bumetanide, wherein, the compound recipe amiloride is to be made up of at 1: 1 amiloride and hydrochlorothiazide by mass ratio.Cooperating with in spironolactone, amiloride, compound recipe amiloride, ergosterol, triamterene, etacrynic acid, hydrogen fluorine first thiophene, the bumetanide any by 4～300mg with measuring of rosiglitazone.
The preparation method of the treatment diabetes compound medicine of above-mentioned reduction rosiglitazone side effect specifically may further comprise the steps:
The screening drug candidate:
Make up the network screening model of side effect-path-drug candidate according to the side effect of rosiglitazone, the definite drug candidate that can eliminate the side effect of described rosiglitazone of screening is diuretic, wherein, diuretic is any in spironolactone, amiloride, compound recipe amiloride, ergosterol, triamterene, etacrynic acid, hydrogen fluorine first thiophene, the bumetanide, wherein, the compound recipe amiloride is to be made up of at 1: 1 amiloride and hydrochlorothiazide by mass ratio;
Be that 1: 0.04～1 proportioning is made treatment diabetes compound medicines (being the rosiglitazone compound medicine) by weight with rosiglitazone and diuretic.
In the said method, the network screening model that makes up side effect-related pathways-drug candidate according to the side effect of rosiglitazone comprises:
According to the side effect (as causing edema) of rosiglitazone, make up the network model of the side effect-path of rosiglitazone, make up the network model of the side effect drug candidate-path for the treatment of rosiglitazone again;
With the network model of the side effect-path of described rosiglitazone and the network model of the side effect drug candidate-path for the treatment of rosiglitazone, by the signal path that analysis relates to, integrate the network screening model that obtains between side effect-path-drug candidate.
In the said method, according to the side effect of rosiglitazone, the network model that makes up the side effect-path of rosiglitazone comprises:
To cause and the disease gene of the rosiglitazone side effect same disease potential pathogenetic gene as the rosiglitazone side effect;
Extract described disease gene from GAD data base (Genetic Association Database);
Described disease gene note to the KEGG data base, is chosen the path of significant enrichment under P＜0.05 condition, determine each path relevant with side effect, utilize these paths to make up the network model that obtains side effect-path.
In the said method, the network model that makes up the side effect drug candidate-path for the treatment of rosiglitazone comprises:
Extract the medicine that is used for the treatment of the rosiglitazone side effect from the SIDER data base, choose the medicine that wherein is used for the treatment of edema;
From the DRUGBANK data base, extract selected medicine-target spot information;
Gather each drug target respectively by the DAVID annotation system note, then is linked at this medicine as if on target spot note to a path of certain drug candidate to the KEGG path with corresponding path;
Relation between the drug candidate-path of drug candidate and path generation is configured to the network model of drug candidate-path.
In the said method, screening determines that the drug candidate that can eliminate the side effect of described rosiglitazone comprises:
The network path relation that provides in the network screening model according to side effect-path-drug candidate is estimated based on the path relation, determines to share the drug candidate of eliminating the rosiglitazone side effect with rosiglitazone.
The invention will be further described below in conjunction with specific embodiment.
Present pharmaceutical field, the toxic and side effects of medicine is the serious problems that drug development and application face, rosiglitazone is the active drug for the treatment of type 2 diabetes mellitus clinically, but there are side reactions such as edema (and then can cause congestive heart failure), anemia, liver toxicity in it, threatens diabetics life.Rosiglitazone is because its serious adverse faces " quitting listing " risk, and the present invention eliminates the side effect of rosiglitazone for addressing this problem by the form of compound medicine.The present invention analyzes the network forecast model of foundation " side effect-path-drug candidate " by the network pharmacology, and screening can be formed the potential drug that compound medicine alleviates its edema side effect with rosiglitazone; And adopt the type 2 diabetes mellitus rat model, by classical evaluating drug effect index, quantitatively metabolism group and related gene quantitative analysis, the drug effect of checking and evaluation rosiglitazone compound recipe reaches the improvement degree to the edema side effect; Network pharmacology data and experimental data are carried out confluence analysis, inquire into the molecular mechanisms of action that the rosiglitazone compound recipe overcomes the edema side effect from the angle that whole (metabolic profile spectrum) changes and specific target spot (biomarker) changes.The present invention is not only for being that the compound medicine research and development of target provide a kind of research thinking to solve drug side effect, and screening obtains truly having the Lie Gelie ketone compound medicine of curative effect.
Preparation process to treatment diabetes compound medicine of the present invention (being the rosiglitazone compound medicine) specifies below:
Set up " side effect-path-drug candidate " network forecast model:
Side effect (namely causing edema) according to rosiglitazone, make up the network forecast model of rosiglitazone " side effect-path-drug candidate ", at first to make up " side effect-path " network and " medicine-path " network, integrate this two networks again, make up the cyberrelationship between " side effect-path-drug candidate ".The back is based on the evaluation of path relation, and the potential drug that prediction can be share with rosiglitazone obtains forming with the rosiglitazone compatibility potential drug of compound recipe.
Step 1 makes up " side effect-path " network:
Edema is one of common symptoms, mainly is to produce owing to excess body fluid accumulates in the extravascular tissue space.It also is a kind of common clinical picture of the drug-induced side effect of rosiglitazone.Because side effect is as a kind of clinical manifestation, therefore with the potential pathogenetic gene of disease gene as side effect.These disease genes can extract by the GAD data base, based on side effect gene and KEGG path information, make up side effect-path-network.At first, obtain rosiglitazone edema related gene by the GAD data base." Type2Diabetes (2-type diabetes)/edema (edema)/Rosiglitazone (rosiglitazone) " is used for extracting the gene information that rosiglitazone is induced edema as key word.Finally extracting 2435 from 130653 records of GAD data base removes redundant edema gene.Secondly, 2435 nonredundancy edema gene annotations to the KEGG pathway database, are chosen the path (P＜0.05) of significant enrichment then.Analyze last determine 72 and edema related pathways by enrichment.These paths are induced the potential morbidity path of edema as rosiglitazone, have finally made up " side effect-path " network (see figure 1).Among Fig. 1, the central circular node represents the edema that Rosiglitazone induces; Square nodes represents path.If a certain path of edema disease gene significant enrichment (P＜0.01 and Fold＞2) so just links edema and this path.
Step 2 makes up " medicine-path " network:
At first, extract the medicine that is used for the treatment of side effect based on the SIDER data base.Key word " Oedema " is used for determining corresponding indication medicine that we obtain 31 kinds of medicines with edema indication.Choose the medicine that wherein is mainly used in administering edema by the manual synchronizing method, finally this research is chosen 15 kinds of medicines as uniting the drug candidate of use with Rosiglitazone.For each medicine in the drug candidate, we extract medicine-target spot information from the DRUGBANK data base.The DRUGBANK data base is contained abundant drug resource information, comprises medicine name, information such as drug target.By this step, we determine 56 kinds of medicines-target spot relation, wherein comprise 15 kinds of medicines and 30 target spots.For each drug candidate, based on the drug target set, we determine the corresponding path information of drug candidate.We gather difference note to the KEGG path with each drug target by the DAVID annotation system.If the corresponding target spot gene annotation of medicine is to some paths, this path is just relevant with medicine so.In this research, in 15 kinds of medicines, have 4 kinds of drug targets not have the path annotation information, finally our 30 target spots obtaining 11 kinds of medicine correspondences are annotated on 28 paths.These drug candidates and path common property are given birth between 77 drug candidate-paths and are concerned.Finally, relation is used for making up treatment " medicine-path " network struction between these drug candidate-paths.If on target spot note to a path of certain medicine, so just this medicine is linked at (see figure 2) with corresponding path.Among Fig. 2, the circular node representative is applicable to the medicine of edema symptom; Square nodes represents path.If the target spot of a certain medicine correspondence can a certain path of note, so just this medicine and this path are interlinked.
Step 3 makes up " side effect-path-drug candidate " network:
For obtain can with the medicine of rosiglitazone compatibility, at first our network of obtaining by integration step 2 and step 3 makes up the relation between side effect-path-drug candidate, wherein path is as the connecting path of step 2 and step 3 gained network.Can realize like this seeking the potential drug of forming compound recipe with the rosiglitazone compatibility, this medicine should be relevant with the edema pathology path that rosiglitazone is induced.Therefore, if a certain path namely is edema relevant disease path, be again the treatment path of medicine simultaneously, we can determine side effect-path-drug candidate relation so.Finally, 7 paths interconnect with edema and 7 kinds of medicines simultaneously, and common property is given birth to 12 kinds of side effect-path-drug candidates and concerned (see figure 3).Among Fig. 3, lower floor's circular node representative is applicable to the medicine of edema symptom; Square nodes represents path.The dependency that is used for the edema that evaluate candidate medicine and rosiglitazone cause based on the Co-occurrence score method of path; The random disturbance method is used for the reliability of test score.By the said method analysis, tentatively obtain 7 kinds of drug candidates: triamterene, etacrynic acid, hydrochlorothiazide, amiloride, hydrogen fluorine first thiophene, spironolactone, bumetanide.
Record determines that amiloride and spironolactone are the medicine that acts on tubular distal and collecting tubule according to prior art; has diuresis; and have the hepatic fibrosis of preventing, the protection heart reduces the function of cardiac load, namely has the effect of protection liver function and cardiac function.In view of the clinical amiloride compound recipe that all uses, namely compound hydrochloric acid amiloride sheet comprises amiloride hydrochloride and hydrochlorothiazide, and hydrochlorothiazide acts on the diuretic of renal tubules near-end, and diuresis is better than singly using amiloride.Consider that the selected result of forecast model is Western medicine, though there are many Chinese medicines also to have good diuretic effect, because its study on mechanism is less, obtain based on very difficult focusing of the network pharmacology of path target spot.Therefore, select the diuresis composition ergosterol in the Chinese medicine diuretic Polyporus commonly used among the present invention, as a kind of potential drug candidate.Final selected ergosterol, spironolactone, amiloride and compound recipe amiloride are formed compound medicine as potential drug and rosiglitazone, have carried out next step experiment.
The following aspects is determined in experiment:
(1) determine that rosiglitazone causes the edema dose relationship:
Adopt rosiglitazone injury rats model, determine that tentatively it causes dosage and the administration time of edema.The effect dosage of rosiglitazone is 300mg/kgd, and be 2 weeks action time, and rat behavior is learned and observed obviously visible limb edema, and in conjunction with the measurement result analysis of indexs such as body weight, urine amount, plasma volume, significant edema appears in rat, and model stability.Fig. 4 is that packed cell volume (HCT) is schemed with the change curve (n=10) of administration time after the rosiglitazone intervention.Packed cell volume refers to anticoagulated whole blood after centrifugal, records the ratio that the erythrocyte of precipitation occupies in whole blood, points out in the document to descend 〉=0.5% the time when the HCT value, is considered as edema.Among Fig. 4, # represents to compare P＜0.05 with same time point matched group; * expression is organized the 0th day and is compared P＜0.05 with each.
When edema takes place, blood volume increases, the Hct value descends, under the constant situation of erythrocyte volume, red blood cell count(RBC) also can descend, and hemoglobin is erythrocytic main component, also decreases, as shown in Figure 5 be situation of change (n=10) curve chart of red blood cell count(RBC), shown in Figure 6 is situation of change (n=10) curve chart of hemoglobin.
(2) determine that compound medicine is to the influence of edema:
(2.1) grouping of laboratory animal:
9 the week age SD rat, male and female half and half.Adaptability was fed after four days, weighed, and received urine, measured routine blood test, was guaranteeing to be divided into 7 groups under each index zero difference prerequisite, and 10 every group, male and female half and half: (1) rosiglitazone group (300mg/kg/d); (2) rosiglitazone+ergosterol group (300mg/kg/d+20mg/kg/d); (3) rosiglitazone+spironolactone group (300mg/kg/d+10.8mg/kg/d); (4) rosiglitazone+amiloride (300mg/kg/d+20mg/kg/d amiloride) (5) rosiglitazone+compound recipe amiloride (300mg/kg/d+20mg/kg/d amiloride+20mg/kg/d hydrochlorothiazide); (5) matched group (only giving solvent).Urine is collected in administration 14 days weekly, weighs.After administration finishes, 10% chloral hydrate intraperitoneal injection of anesthesia, anesthesia back hepatic portal vein is got blood, collects pancreas, heart, renal tissue simultaneously.Hepatic portal vein blood plasma aldosterone (heparin sodium anticoagulant), Plasma Atrial Natriuretic Peptide (the ETDA-2K anticoagulant, and add aprotinin), serum creatinine, serum N a+, K+, Cl-value.
(2.2) biochemical indicator measurement result
(2.2.1) body weight and urine amount
Each body weight of organizing rat is all increasing, though data statistics does not have significant difference between each group, on variation tendency, the body weight increase of compound medicine RSG+ spironolactone, RSG+ compound recipe amiloride group rat is less relatively.Table 1 is 14 days rat body weight change of administration situation.
Each time point weight ratio of table 1 (g, m ± sd, n=10)
Grouping The 0th day The 7th day The 14th day
RSG 298.5±76.7 350.1±93.6 364.0±98.9
The RSG+ ergosterol 299.0±76.0 345.4±87.8 357.6±98.1
The RSG+ spironolactone 295.6±75.9 333.8±87.4 345.0±97.7
The RSG+ amiloride 295.6±72.1 320.5±78.3 347.4±90.2
RSG+ compound recipe amiloride 299.6±74.2 318.5±80.2 344.2±91.9
Matched group 302.3±77.2 338.1±86.5 356.4±94.0
Before grouping, the amount of urine is irritated the stomach screening.After irritating stomach normal saline 25ml/kg, collect urine amount in the 2h, total volume of urine reaches the rat of filling stomach amount more than 40% and is selected into formal experiment.When carrying out the diuresis experiment, at first will guarantee the homogeneity into the group laboratory animal, the homogeneity of the aspect of particularly urinating avoids the individual variation of the aspect because animal urinates to have influence on the diuresis experimental result.Table 2 is the urine quantitative determination result of an administration time point.From the urine amount as can be seen, compare with matched group, two groups of urine amounts that give rosiglitazone reduce but difference not to some extent; Give compound recipe amiloride group simultaneously relatively with giving rosiglitazone, only give rosiglitazone and also give three groups of folic acid simultaneously that there were significant differences. illustrate that the potential compound drug that screens can promote to urinate.
Each time point urine amount comparison of table 2 (mL, m ± sd, n=10)
Grouping The 0th day The 7th day The 14th day
RSG
18±6.9 32.7±4.9 # 30.5±13.4 #
The RSG+ ergosterol 19.7±7.3 40.3±23.9 37.7±20.1
The RSG+ spironolactone 18.5±7.1 44.8±22.6 45.3±21.4
The RSG+ amiloride 18.8±5.6 48.2±19.6 53.3±14.2
RSG+ compound recipe amiloride 17.8±7.9 53.0±18.7 54.3±14.0
Matched group 14.5±2.2 33.7±11.3 34.0±8.7
What # indicated is: compare P＜0.05. with RSG+ compound recipe amiloride group
(2.2.2) the edema related biochemical indicator is measured
Packed cell volume (HCT) refers to anticoagulated whole blood after centrifugal, records the ratio that the erythrocyte of precipitation occupies in whole blood, points out in the document to descend 〉=0.5% the time when the HCT value, is considered as edema.Rosiglitazone can cause that blood volume increases as can be seen from Table 3, and then causes that HCT value descends, and has corrected well and take the HCT value reduction that RSG causes by giving diuretic compound recipe amiloride simultaneously.Compound recipe amiloride and rosiglitazone are formed compound drug can resist the blood volume increase that rosiglitazone causes, avoids water-sodium retention.
Each time point HCT comparison of table 3 (%, m ± sd, n=10)
m±sd(％) The 0th day The 7th day The 14th day
RSG 49.1±2.5 42.3±2.0 43.6±2.6 *
The RSG+ ergosterol 48.1±2.4 44.9±2.1 45.6±2.8 *
The RSG+ spironolactone 48.1±2.0 43.1±3.7 44.5±1.6 *
The RSG+ amiloride 48.5±2.8 46.9±3.8 47.8±3.5
RSG+ compound recipe amiloride 47.5±3.9 46.1±3.2 48.2±3.0
Matched group 48±2.9 47.9±1.2 48.5±1.9
What * indicate is: relatively have with this time point matched group to show poor, P＜0.05.
Simultaneously, the increase of blood volume also can cause RBC number, hemoglobin, sero-abluminous reduction.RBC number, hemoglobin, serum albumin have been measured in this research simultaneously, the results are shown in Table shown in the 4-table 6, rosiglitazone and compound recipe amiloride compound recipe can be corrected the water-sodium retention that rosiglitazone causes well, the compound medicine that rosiglitazone and spironolactone are formed also has better action, but its effect is not as the former.
Each time point RBC of table 4 compares (10 12Individual/L, m ± sd, n=10)
Grouping The 0th day The 7th day The 14th day
RSG 8.1±0.3 6.9±0.4 * 7.1±0.6 *
The RSG+ ergosterol 7.9±0.6 7.1±0.4 7.4±0.5 *
The RSG+ spironolactone 7.8±0.3 6.7±0.7 * 7.0±0.5 *
The RSG+ amiloride 7.8±0.5 7.3±0.6 7.6±0.4
RSG+ compound recipe amiloride 7.7±0.6 7.4±0.7 7.8±0.8
Matched group 7.8±0.6 8.0±0.5 8.3±0.6
What * indicate is: relatively have with this time point matched group to show poor, P＜0.05.
Each time point HGB comparison of table 5 (g/L, m ± sd, n=10)
Figure BSA00000898831100121
What * indicate is: relatively have with this time point matched group to show poor, P＜0.05.
Each time point serum albumin of table 6 contain and survey relatively (g/L, m ± sd, n=10)
Grouping The 0th day The 7th day The 14th day
RSG 35.3±6.7 25.7±2.4 * 30.3±4.2 *
The RSG+ ergosterol 35.8±4.0 33.1±3.1 * 30.8±4.1 *
The RSG+ spironolactone 36.3±5.1 31.7±3.1 * 34.2±8.2
The RSG+ amiloride 35.7±5.1 34.8±3.2 34.2±3.3
RSG+ compound recipe amiloride 34.6±5.3 34.2±2.4 35.5±3.8
Matched group 35.1±2.3 36.3±3.7 35.3±2.7
What * indicate is: relatively have with this time point matched group to show poor, P＜0.05.
Serum albumin is the main protein composition of total serum protein, accounts for 60% of blood plasma total protein., synthetic by liver.It all plays a part very important at aspects such as keeping blood colloid osmotic pressure, the transportation of internal metabolism material, nutrition.It is closely bound up to keeping with the increase of plasma volume of plasma colloid osmotic pressure.If albumin obviously reduces, colloid osmotic pressure of serum also will obviously reduce, because moisture is to flow to osmotic pressure by hyperosmosis, thereby plasma volume will increase, this has also further explained the reason that HCT descends. while compound medicine (RSG+ spironolactone, RSG+ compound recipe amiloride) intervention group serum albumin levels and matched group there was no significant difference illustrates the edema that compound medicine can avoid list to cause with rosiglitazone.
(2.2.3) serum glutamic pyruvic transminase (ALT) changes of contents situation
ALT is present in each histiocyte, and is maximum with liver content, secondly is in the myocardial cell, and enzymatic activity is very low in the serum.When these lesion tissues, when necrocytosis or permeability strengthened, desmoenzyme was released into blood, and the serum alt activity is increased.Serum ALT is measured the diagnosis that is mainly used in hepatopathy.This research reflects that by measuring ALT medicine is to the influence of liver.
Each time point serum glutamic pyruvic transminase content comparison of table 7 (U/L, m ± sd, n=10)
Grouping The 0th day The 7th day The 14th day
RSG 33.2±3.4 19.4±8.1 9.8±2.7 *
The RSG+ ergosterol 32.5±4.0 24.7±6.3 13.8±1.9 *
The RSG+ spironolactone 32.1±4.1 23.6±6.5 15.4±4.3 *
The RSG+ amiloride 33.0±4.7 20.1±8.6 19.3±5.1
RSG+ compound recipe amiloride 32.5±5.8 17.1±9.6 * 18.7±6.0
Matched group 30.4±1.7 24±5.5 21.6±10.2
What * indicate is: relatively have with this time point matched group to show poor, P＜0.05.
Generally pass judgment on liver function with the content increase of glutamate pyruvate transaminase, the ALT value does not only increase in this research, descends on the contrary, illustrates that RSG influences liver function, but influence mechanism is also indeterminate, this change that the compound medicine that RSG+ compound recipe amiloride is formed can antagonism RSG causes.
(3) hepatic portal vein obtains serum creatinine, Na +, K +, Cl -Value relatively
Table 8 serum creatinine, Na +, K +, Cl -Measurement result (m ± sd)
Figure BSA00000898831100141
Figure BSA00000898831100151
What * indicate is: relatively have with matched group to show poor, P＜0.05.
Creatinine is micromolecule, discharge with urine, during renal dysfunction, serum creatinine raises, from tabulation, find out, spironolactone group serum creatinine value maximum, creatinine fail to discharge with urine well, illustrate that glomerular filtration rate reduces, renal function generation obstacle. since the front has proved that rosiglitazone causes the urine sodium retention, serum N a+ content should increase so, but has reduced herein, and this phenomenon can't be explained; Spironolactone group K+ content maximum illustrates that spironolactone has good diuresis, but compound recipe amiloride group K+ concentration should be not low, and this can't explain; Rosiglitazone can cause the urine sodium retention, thereby follows the Cl-output to reduce, and the blood chlorinity increases, and compound recipe amiloride group can be corrected the side effect of its water-sodium retention, thereby chloride ion content reduces.
(4) rats'liver portal vein blood plasma aldosterone (ALD), atrial natriuretic peptide (ANP) changes of contents situation are relatively
Table 9ALD and ANP measurement result (m ± sd)
Grouping ALD(ng/mL) ANP(ng/mL)
RSG 0.33±0.15 * 0.56±0.11
The RSG+ ergosterol 0.35±0.22 0.52±0.07
The RSG+ spironolactone 0.35±0.14 0.91±0.69 *
The RSG+ amiloride 1.2±0.88 * 0.68±0.35
RSG+ compound recipe amiloride 1.8±0.93 * 0.59±0.11
Matched group 0.49±0.18 0.61±0.13
What * indicate is: relatively have with matched group to show poor, P＜0.05.
Contain amiloride and hydrochlorothiazide in the compound recipe amiloride, amiloride acts on aldosterone receptor and then produces diuretic effect.The diuresis of compound recipe amiloride should reduce the content of serum aldosterone, increases on the contrary herein, can't explain.The water-sodium retention of rosiglitazone initiation simultaneously is to have increased aldosterone receptor, and then the increase of the amount of heavy absorption of N a+, but RSG group ALD content reduces herein, needs further explanation.When heart failure took place, ANP content can increase in the blood plasma, and when it can be seen from the table having only spironolactone and RSG to share, the ANP amount increases, and the heavy dose of RSG of possibility and spironolactone share, and cardiac function is caused unexpected influence.
Rosiglitazone and single diuretic spironolactone, amiloride and compound recipe amiloride can be formed compound medicine, and this compound recipe can alleviate the edema side effect that rosiglitazone causes.
(3) compound medicine efficacy enhancing and toxicity reducing effect research
Feed the 2-type diabetes rat model that causes in conjunction with the streptozotocin injection by setting up long-term high glucose and high fat, investigate the efficacy enhancing and toxicity reducing effect of compound recipe rosiglitazone.
(3.1) zoopery and grouping
After male SD rat, adaptability raised for 1 week, give the high glucose and high fat feedstuff 5 weeks, the low dose of streptozotocin of continuous two all tail vein injections, weekly.Blood sugar level 〉=16.8mmol/L is the modeling success.The rat of modeling success is divided into 3 groups at random: model group, rosiglitazone treatment group and compound recipe rosiglitazone treatment group, every group of 8 rats.Administration the 0th day, 56 days, measure blood glucose and edema index of correlation (body weight, urine amount, packed cell volume, plasma aldosterone, blood Na+, K+, Cl-concentration etc.).
(3.2) measurement result
Table 10 is pharmaceutical intervention each experimental group changes of blood glucose situation after 56 days, visible rosiglitazone and compound recipe rosiglitazone group, and blood sugar level significantly descends, and the model group blood sugar level rises.
Table 10 blood sugar detection value (mmol/l, m ± sd, n=8)
Time Model group The rosiglitazone group Compound recipe rosiglitazone group
The 0th day 18.8±2.4 21.9±2.8 24.2±8.4
The 56th day 24.9±1.6 18.3±6.3 * 18.8±5.3 *
Rate of change (%) ↑2.4 ↓6.4 ↓2.3
What * indicate is: compare P=＜0.05 with model group
The index determining that edema is relevant, body weight and urine amount do not have the variation of significance, and all the other index tools have some improvement, and table 11 is the situation of change of packed cell volume.
Table 11 respectively organize the packed cell volume measured value (%, m ± sd, n=8)
What * indicate is: compare P=＜0.05 with model group; What # indicated is: compare P=＜0.05 with the RSG group
Rosiglitazone and compound recipe rosiglitazone all can effectively improve the hyperglycemia of 2-type diabetes, and long-term large dose oral administration rosiglitazone can cause the generation of edema, and compound recipe rosiglitazone group edema relevant parameter is compared with model group, no significant change.Illustrate that the compound recipe rosiglitazone eliminated single edema that causes with rosiglitazone in the blood glucose in control.By blood plasma superoxide dismutase (SOD) and alanine aminotransferase (ALT) level (seeing Table 12), compound medicine does not cause the significantly unusual of heart and liver, can not cause heart or liver toxicity simultaneously.
The measured value of table 12 experimental group SOD and ALT (m ± sd, n=8)
Grouping SOD(U/mL) ALT(IU/L)
Model group 141.8±26.1 122.7±26.4
The rosiglitazone group 111.1±21.1* 77.3±45.1
Rosiglitazone compound recipe group 117.7±19.4 87.7±42.2
More than be preferred embodiment of the present invention, protection scope of the present invention is not limited to these embodiment, is familiar with those skilled in the art in the present invention discloses technical scope, and the variation of expecting easily and replacement all are encompassed in the protection domain of the present invention.Therefore, protection domain of the present invention should be as the criterion with the protection domain of claims.

Claims (10)

1. a treatment diabetes compound medicine that reduces the rosiglitazone side effect is characterized in that this compound medicine is made up of rosiglitazone and diuretic, and wherein, the proportioning of rosiglitazone and diuretic is 1: 0.04～1 by weight.
2. compound medicine according to claim 1, it is characterized in that, described class diuretic is any in spironolactone, amiloride, compound recipe amiloride, ergosterol, triamterene, etacrynic acid, hydrogen fluorine first thiophene, the bumetanide, wherein, the compound recipe amiloride is to be made up of at 1: 1 amiloride and hydrochlorothiazide by mass ratio.
3. compound medicine according to claim 1 and 2 is characterized in that, the consumption of described rosiglitazone is 4～300mg.
4. a preparation method that reduces the treatment diabetes compound medicine of rosiglitazone side effect is characterized in that, comprising:
The screening drug candidate:
Make up the network screening model of side effect-path-drug candidate according to the side effect of rosiglitazone, the drug candidate that screening determines to eliminate the side effect of described rosiglitazone is diuretic;
Be that 1: 0.04～1 proportioning is made treatment diabetes compound medicine by weight with rosiglitazone and diuretic.
5. method according to claim 4, it is characterized in that, described diuretic is any in spironolactone, amiloride, compound recipe amiloride, ergosterol, triamterene, etacrynic acid, hydrogen fluorine first thiophene, the bumetanide, wherein, the compound recipe amiloride is to be made up of at 1: 1 amiloride and hydrochlorothiazide by mass ratio.
6. method according to claim 4 is characterized in that, the consumption of described rosiglitazone is 4～300mg.
7. according to each described method of claim 4 to 6, it is characterized in that the network screening model that described side effect according to rosiglitazone makes up side effect-path-drug candidate comprises:
According to the side effect of rosiglitazone, make up the network model of the side effect-path of rosiglitazone, make up the network model of the side effect drug candidate-path for the treatment of rosiglitazone again;
With the network model of the side effect-path of described rosiglitazone and the network model of the side effect drug candidate-path for the treatment of rosiglitazone, by the signal path that analysis relates to, integrate the network screening model that obtains between side effect-path-drug candidate.
8. method according to claim 7 is characterized in that, described side effect according to rosiglitazone, and the network model that makes up the side effect-path of rosiglitazone comprises:
To cause and the disease gene of the rosiglitazone side effect same disease potential pathogenetic gene as the rosiglitazone side effect;
Extract described disease gene from the GAD data base;
Described disease gene note to the KEGG pathway database, is chosen the path of significant enrichment under P＜0.05 condition, determine each path relevant with side effect, utilize these paths to make up the network model that obtains side effect-path.
9. according to each described method of claim 4 to 6, it is characterized in that the network model of the side effect drug candidate-path of described structure treatment rosiglitazone comprises:
Extract the medicine that is used for the treatment of the rosiglitazone side effect from the SIDER data base, choose the medicine that wherein is used for the treatment of edema;
From the DRUGBANK data base, extract selected medicine-target spot information;
Gather each drug target respectively by the DAVID annotation system note, then is linked at this medicine as if on target spot note to a path of certain drug candidate to the KEGG path with corresponding path;
Relation between the drug candidate-path of drug candidate and path generation is configured to the network model of drug candidate-path.
10. according to each described method of claim 4 to 6, it is characterized in that described screening determines that the drug candidate that can eliminate the side effect of described rosiglitazone comprises:
The network path relation that provides in the network screening model according to side effect-path-drug candidate is estimated based on the path relation, determines that can share the drug candidate of eliminating the rosiglitazone side effect with rosiglitazone is diuretic.
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WO2014187250A1 (en) * 2013-05-22 2014-11-27 Luo Guoan Compound medicine for reducing side effects of resiglitazone and treating diabetes and preparation method thereof
CN105012353A (en) * 2015-08-05 2015-11-04 中南民族大学 Medicine for preventing and treating diabetes

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CN101396560A (en) * 2007-09-28 2009-04-01 上海迈欣医药科技有限公司 Medicine composition for treating polycystic kidney disease and use thereof
CN101664410A (en) * 2009-06-30 2010-03-10 中国人民解放军第二军医大学 Medicine composition of rosiglitazone and amiloride and application thereof
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WO2014187250A1 (en) * 2013-05-22 2014-11-27 Luo Guoan Compound medicine for reducing side effects of resiglitazone and treating diabetes and preparation method thereof
CN105012353A (en) * 2015-08-05 2015-11-04 中南民族大学 Medicine for preventing and treating diabetes
CN105012353B (en) * 2015-08-05 2018-09-28 中南民族大学 Tabasheer acetic acid ethyl ester extract is used to prepare the purposes of prevention diabetes medicament

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