CN110548150A

CN110548150A - Application of compound pharmaceutical composition in preparation of medicine for treating acute kidney injury

Info

Publication number: CN110548150A
Application number: CN201910796204.3A
Authority: CN
Inventors: 傅继华
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2019-08-27
Filing date: 2019-08-27
Publication date: 2019-12-10
Anticipated expiration: 2039-08-27
Also published as: CN110548150B

Abstract

The invention discloses an application of a compound pharmaceutical composition in preparing a medicine for treating acute kidney injury, wherein the compound pharmaceutical composition takes sarpogrelate and a 5-hydroxytryptamine synthesis inhibitor as active ingredients, and the 5-hydroxytryptamine synthesis inhibitor is carbidopa or benserazide. The sarpogrelate and carbidopa or benserazide can inhibit the synthesis of 5-HT2 receptors and 5-HT of kidney cells, have obvious synergistic effect on treating acute kidney injury, and have obvious effect on treating the acute kidney injury.

Description

application of compound pharmaceutical composition in preparation of medicine for treating acute kidney injury

Technical Field

The invention relates to application of a pharmaceutical composition, in particular to application of a compound pharmaceutical composition in preparing a medicine for treating acute kidney injury.

Background

Acute Kidney Injury (AKI) is a group of clinical syndromes, which refer to sudden (within 1-7 d) and sustained (>24h) sudden decline in renal function, defined as an increase of at least 0.5mg/dl in serum Creatinine (CRE), manifested by azotemia, aqueous electrolyte and acid-base balance, and systemic symptoms throughout the body, which may be accompanied by oliguria (< 400ml/24h or 17ml/h) or anuria (< 100ml/24 h). AKI is a critical kidney disease which is common clinically, and the incidence rate of AKI is still high at present. AKI and its further development leading to Chronic Kidney Disease (CKD) remain a major problem in the current chinese and even world health care industry, mainly because there is no effective targeted treatment for AKI. The mechanisms of AKI caused by various causes such as renal ischemia, nephrotoxic drugs, sepsis and urinary obstruction are different, but basically involve several pathophysiological links including the change of hemodynamics, oxidative stress injury and inflammatory reaction. Xiaoyao et al, in progress of the study of oxidative stress in acute kidney injury, mention that oxidative stress is considered to be one of the most critical direct causative factors of AKI. Oxidative stress occurs primarily in connection with excessive Reactive Oxygen Species (ROS) production in the body, resulting in cell damage. ROS are the major oxidants in the body, and are derived primarily from mitochondrial and non-mitochondrial pathways. The damage of oxidative stress to cells is mainly: DNA damage is caused by modifying bases, causing DNA breakage and the like, and the damage can regulate signal paths of some cells through changes of some RNA and protein expression; by causing a change in the conformation of the protein, its function is activated or inhibited; lipid peroxide is generated by oxidizing lipid, the typical marker of the lipid peroxide is Malondialdehyde (MDA), the lipid peroxide can obviously enhance the toxic effect of low-density lipoprotein on cells, and the permeability of blood vessels can be increased, so that the malignant consequences such as increased leakage of plasma protein and thickening of basement membrane are caused. When oxidative stress occurs in the body, the body regulates by increasing the production of antioxidants. Antioxidants in the body can be classified into antioxidant enzymes and non-enzymatic antioxidants. The antioxidant enzymes include: superoxide dismutase (SOD), Catalase (CAT), glutathione peroxidase (GPx), and the like. The reduction of SOD and CAT content can greatly reduce the oxidation damage resistance of organs, while the reduction of GPx activity can reduce the content of intracellular reduced Glutathione (GSH). GSH can participate in the in vivo oxidation-reduction process, and under the action of glutathione transferase, GSH can combine with peroxide and free radicals to resist the damage of oxidant to sulfhydryl, protect sulfhydryl-containing protein and sulfhydryl-containing enzyme in cell membrane from damage, and resist the damage of free radicals to viscera.

Xiaobiao et al, in progress of research on oxidative stress in acute kidney injury, suggest that oxidative stress is involved in many pathological processes of AKI, including induction of autophagy, mediation of apoptosis of cells and promotion of necrotic apoptosis, interaction with inflammatory responses, causing alterations in renal hemodynamics, etc. As a result, the renal function is reduced, the filtering capability of the kidney on harmful substances such as creatinine, urea nitrogen and the like is reduced, and the concentration of blood creatinine and urea nitrogen is increased; the plasma albumin concentration is reduced because the plasma protein discharge, especially the discharge of plasma albumin with a small molecular weight, is increased due to the damage of the glomerular filtration membrane and the like.

The typical markers for the occurrence of AKI, discussed in "present research and recent development of biomarkers for acute renal injury" by Chen Mullin et al, are an increase in serum Creatinine (CRE) concentration, and a decrease in serum urea nitrogen (BUN) concentration and albumin (Alb) concentration, which are also one of the obvious features. Therefore, in animal experiments, it can be determined whether the animal has AKI by detecting the change of these indices in blood.

5-hydroxytryptamine (5-HT), also called serotonin, is a small molecule substance existing in the periphery and the center, and the physiological function of 5-HT is complex and is not completely clarified up to now.

The synthesis of 5-HT is carried out in two steps, the first step: tryptophan is converted into 5-hydroxytryptophan under the catalysis of Tryptophan hydroxylase (Tph) (Tph can be divided into two subtypes, i.e., Tph1 and Tph2, wherein Tph1 exists at the periphery and Tph2 exists at the center); the second step is that: 5-hydroxytryptophan is converted to 5-HT under the catalysis of aromatic Amino Acid Decarboxylase (AADC). Thus, inhibition of 5-HT synthesis can be achieved by inhibiting Tph or AADC, respectively.

Although compounds that directly inhibit the activity of Tph have been reported, such compounds are p-chlorophenylalanine (pCPA, alternative name: DL-4-chlorophenylalanine, DL-p-chlorophenylalanine, etc., and the molecular formula: C₉H₁₀ClNO₂) However, the disadvantage of low oral bioavailability is common, so no clinical application report exists.

Carbidopa (Cabidoba, CDP), molecular formula: c₁₀H₁₄N₂O₄(ii) a Benserazide (Bense)razide, BSA), alias: trihydroxyserine hydrazide, salad hydrazine, silk chlorohydrazide and hydroxybenzyl serine, the molecular formula is as follows: c₁₀H₁₅N₃O₅. Both of them are AADC inhibitors and are used clinically in the adjuvant treatment of parkinson's disease, and their combined action features are peripheral AADC inhibitors, which do not easily enter the center, only inhibit the conversion of peripheral levodopa to dopamine, resulting in an increase of the circulating levodopa content, and also inhibit the conversion of 5-hydroxytryptophan to 5-HT, resulting in a decrease of 5-HT production by 5-HT-synthesizing cells. CDP and BSA have also not been reported in studies directed to the treatment of AKI.

The 5-HT receptor (5-HT receptor, 5-HTR) exists on the cell membrane, belongs to the membrane receptor, and the 5-HT receptor subtype is complex, and 7 types of receptors exist, namely 5-HT_1-7R，5-HT_1,4,5r is mainly distributed in the center, 5-HT_2，3,6,7R is mainly distributed on the periphery. These 7 classes of receptors are further divided into several subtypes. 5-HT2 receptor (5-HT)₂R) can be classified as 5-HT_2AR、5-HT_2BR and 5-HT_2CAnd R is shown in the specification. Peripherally and centrally distributed is 5-HT_2AR、5-HT_2BR，5-HT_2CR is mainly present in the central nervous system, kidney, liver, skeletal muscle, etc. with 5-HT distributed therein_2AR、5-HT_2BR, wherein 5-HT_2AR is believed to have a major biological activity.

III.5-HT degradation 5-HT can not only act directly on its receptor to play a biological role, but also be degraded in the mitochondria of cells. The enzyme catalyzing 5-HT degradation is monoamine oxidase A (MAO-A), and the MAO-A can generate A large amount of ROS (reactive oxygen species), mainly H, while catalyzing 5-HT degradation₂O₂. Too much 5-HT will be degraded intracellularly by MAO-A catalysis, generating large amounts of ROS, thereby causing oxidative stress to the cell.

Has the function of selectively blocking 5-HT₂the drugs for R are rare, Sarpogrelate (Sar) is a specific 5-HT₂An R antagonist of the formula: c₂₄H₃₁NO₆Antagonizing mainly 5-HT_2AR, p-5-HT_2BR also has weak antagonistic effect. In clinical applications, Sar inhibits platelet aggregation enhanced by 5-HTIt has effects of inhibiting vasoconstriction, and can be used for improving ischemic symptoms such as ulcer, pain and cold feeling caused by chronic arterial occlusion. Clinically, Sar has been reported to treat diabetic complications, lower extremity atherosclerotic occlusive disease.

The use of the 5-hydroxytryptamine 2 receptor antagonist sarpogrelate and/or 5-hydroxytryptamine synthesis inhibitors for the treatment of acute kidney injury has not been reported.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to disclose application of a compound pharmaceutical composition in treating acute kidney injury.

The technical scheme is as follows: the invention discloses application of a compound pharmaceutical composition taking sarpogrelate and a 5-hydroxytryptamine synthesis inhibitor as active ingredients in preparation of a medicine for treating acute kidney injury.

The 5-hydroxytryptamine synthesis inhibitor is carbidopa or benserazide; wherein the carbidopa is carbidopa or a pharmaceutically acceptable salt of carbidopa, and the benserazide is benserazide or a pharmaceutically acceptable salt of benserazide.

The sarpogrelate ester is sarpogrelate ester or a pharmaceutically acceptable salt of sarpogrelate ester.

The compound pharmaceutical composition is in the dosage form of tablets, capsules, granules, powder, syrup, oral liquid or injection.

The weight ratio of the sarpogrelate ester to the 5-hydroxytryptamine synthesis inhibitor is 15: 1-1: 15, preferably 8: 1-1: 6.

The weight ratio of sarpogrelate to carbidopa is 8: 1-1: 5, preferably 2:1

The weight ratio of the sarpogrelate ester to the benserazide is 7: 1-1: 6, preferably 5: 3.

We found in the study:

Expression of 5-HT synthetase system, tryptophan hydroxylase 1(Tph1) and aromatic Amino Acid Decarboxylase (AADC), 5-HT2A receptor (5-HT) in Cisplatin (Cisplatin) -induced Acute Kidney Injury (AKI) model in renal tissue_2AR) and monoamine oxidase A (MAO-A) were both significantly up-regulated. Suggesting that 5-HT synthesis and 5-HT2A receptor in renal tissues are involved in AKI induced by cisplatinIs significantly activated and 5-HT degradation catalyzed by MAO-A is also activated, possibly associated with the occurrence of AKI, oxidative stress of renal tissues.

In the cisplatin-induced mouse AKI model, sarpogrelate (Sar) (inhibition of 5-HT)_2AR) and Carbidopa (CDP) or Benserazide (BSA) (inhibiting 5-HT synthesis) to form a compound, and Sar + CDP or Sar + BSA are formed into different compounds according to different weight ratios of the two medicines to treat the model. The results indicate that the pathological manifestations of AKI are significantly reversed, appearing as: the drug treatment obviously improves serum AKI indexes (CRE, BUN and Alb) of model animals, and also obviously improves oxidative stress indexes (MDA, SOD, CAT and GSH) of kidney tissues. In addition, the two compounds of Sar + CDP and Sar + BSA are mixed according to a certain weight ratio of the medicine, and show obvious synergistic effect on treating AKI, and the combined use of the medicines can obviously improve the curative effect of the medicine.

Has the advantages that: the compound pharmaceutical composition can inhibit 5-HT synthesis and 5-HT2 receptors of kidney cells, specifically, the compound is formed by combining sarpogrelate and a 5-hydroxytryptamine synthesis inhibitor such as carbidopa or benserazide in a certain weight ratio range, has obvious synergistic effect on treating acute kidney injury, and has obvious effect on treating the acute kidney injury.

Drawings

FIG. 1 shows that after Cisplatin (Cisplatin) induces mouse AKI, kidney tissue Tph1, AADC, 5-HT_2Ar, MAO-A expression detection result (protein expression is detected by a Western blot method);

Figure 2 is a graph of the effect of Sar + CDP combination drug treatment on cisplatin-induced acute kidney injury-a serum Creatinine (CRE) b, serum urea nitrogen (BUN) c, serum albumin (Abl) P < 0.05, P < 0.01, NS: P >0.05, N < 12 in mice;

FIG. 3 shows the effect of Sar + CDP combination drug therapy on cisplatin-induced acute kidney injury-kidney related markers in mice A. kidney tissue Malondialdehyde (MDA) B. kidney tissue superoxide dismutase (SOD) C. kidney tissue Catalase (CAT) D. kidney tissue reduced Glutathione (GSH) P < 0.05P < 0.01, NS: P >0.05, N ═ 12;

Figure 4 is a graph of the effect of Sar + BSA combination drug treatment on cisplatin-induced acute kidney injury-a serum Creatinine (CRE) b, serum urea nitrogen (BUN) c, serum albumin (Abl): P < 0.05,: P < 0.01, NS: P >0.05, N ═ 10;

Figure 5 is the effect of Sar + BSA combination drug treatment on cisplatin-induced acute kidney injury-kidney related indices in mice a. kidney tissue Malondialdehyde (MDA) b. kidney tissue superoxide dismutase (SOD) c. kidney tissue Catalase (CAT) d. kidney tissue reduced Glutathione (GSH): P < 0.05,: P < 0.01, NS: P >0.05, N ═ 10.

Detailed Description

Example 1

Cisplatin-induced alterations in renal 5-HT synthetase, 5-HT2A receptor and MAO-A expression in mice with acute renal injury

1.1 Experimental methods

The male ICR mice for the experiment are 20-28 g in weight, the animals are cultivated in common mouse cages, the room temperature is kept at 24 +/-2 ℃, the illumination control is carried out to ensure the light and dark conditions for 12 hours, and the mice are fed with common water. An Acute Kidney Injury (AKI) animal model is established by intraperitoneal injection (i.p.) of Cisplatin (Cisplatin, 25mg/kg), and a control group is i.p. normal saline with equal volume. The animals were sacrificed 72 hours after cisplatin injection, blood was taken, and relevant indices were examined by kidney.

Extracting protein after homogenizing kidney tissue, detecting 5-HT synthetase Tph1, AADC, 5-HT2A receptor (5-HT) of kidney tissue by Western blot method_2AR) and the 5-HT degrading enzyme monoamine oxidase A (MAO-A). After cisplatin-induced AKI in mice, the expression of 5-HT synthetase, 2A receptor and degrading enzyme MAO-A in kidney tissues was examined to be changed (N ═ 4, compared with the control group).

1.2 results of the experiment

Comparing with control group, serum Creatinine (CRE) and urea nitrogen (BUN) test prove that mouse AKI induced by cisplatin has been obviously formed, kidney tissue of these animals is taken, and Tph1, AADC, 5-HT are tested_2AR, MAO-A, with an internal reference to GAPDH, the results are shown in FIG. 1. The results show that after cisplatin induces mouse AKI, the kidney tissue Tph1, AADC and 5-HT_2AR, MAO-A protein expression was all significantly up-regulated, and the expression level was much higher than that of control (Ctrl) animals.

Example 2

Therapeutic effect of medicine on cisplatin-induced acute kidney injury of mice

The synergistic effect of sarpogrelate (Sar) in combination with CDP or BSA on AKI treatment was verified by comparing the therapeutic effect of sarpogrelate (Sar) in combination with Carbidopa (CDP) or Benserazide (BSA), and each alone on cisplatin-induced Acute Kidney Injury (AKI) in mice.

2.1 Experimental methods

(1) Animal treatment

The experimental male ICR mice are 18-28 g in weight, and the animals are cultivated in common mouse cages, kept at room temperature of 24 +/-2 ℃, and kept under the condition of illumination control for 12 hours of light and dark, and fed with common water.

The experiment was completed in two batches. The first animals were randomized into 8 groups (12 per group): a control group, a Cisplatin (cissplatin) induced AKI model group, an AKI model Sar treatment group, an AKI model Sar + CDP compound treatment group (Sar: 4 compounds with different weight ratios of CDP), and an AKI model CDP treatment group. In the experiment, four compounds of Sar + CDP according to different weight proportions are: sar + CDP-1-Sar: CDP ═ 8: 1; sar + CDP-2-Sar: CDP ═ 2: 1;

Sar+CDP-3—Sar:CDP＝1:2；Sar+CDP-4—Sar:CDP＝1:5。

The second batch of animals was randomly divided into 8 groups (10 animals per group): a control group, a Cisplatin (cissplatin) induced AKI model group, an AKI model Sar treatment group, an AKI model Sar + BSA compound treatment group (Sar: 4 compounds of BSA in different weight ratios), and an AKI model BSA treatment group. In the experiment, four compounds of Sar + BSA compound according to different weight ratios are:

Sar+BSA-1—Sar:BSA＝7:1；Sar+BSA-2—Sar:BSA＝5:3；

Sar+BSA-3—Sar:BSA＝1:2；Sar+BSA-4—Sar:BSA＝1:6。

(2) Dosage to be administered

Control group-0.20 ml/10g body weight/time of 0.5% sodium carboxymethylcellulose (CMC-Na) solution administered orally (p.o.);

Model group-p.o.0.5% CMC-Na 0.20ml/10g body weight/time;

The drug treatment groups-p.o. each group of drugs, all administration groups are the same in administration dose: 40.0 mg/kg/time.

Each drug was suspended with 0.5% CMC-Na at the same concentration: 2.0mg/ml, and the p.o. administration volume of each group of the medicines is 0.20ml/10g body weight/time; the medicine is taken twice a day, once every morning and afternoon, so the daily dosage is as follows: 80 mg/kg.

(3) Method for inducing mouse AKI by cisplatin

After each group was continuously administered for 5 days, except for the control group which was injected with i.p. normal saline, the other groups were uniformly administered with i.p. cisplatin 25mg/kg to establish an AKI animal model. And each administration group was administered once 3 hours before i.p. cisplatin, and thereafter, three days (72 hours) were continued with the original administration dose and administration method after i.p. cisplatin.

(4) Test index detection method

animals were sacrificed 72 hours after cisplatin, serum was obtained from blood, and kidneys were taken and stored frozen for future use. Detection by a kit spectrophotometry method: serum Creatinine (CRE), urea nitrogen (BUN), albumin (Alb) concentrations; the kit spectrophotometry detects the contents of Malondialdehyde (MDA), superoxide dismutase (SOD), Catalase (CAT) and reduced Glutathione (GSH) in kidney tissues.

2.2 results of the experiment

Statistical tests among multiple groups of data are carried out by single-factor analysis of variance (LSD) detection, and statistical tests among two groups of data are carried out by student-T detection. P < 0.05 indicates significant statistical difference, and P < 0.01 indicates very significant statistical difference. Mean. + -. standard deviation of data in the plotAnd (4) showing.

(1) Treatment effect of Sar + CDP compound on cisplatin-induced acute kidney injury of mice

1) Serum index test results

The results are shown in FIG. 2. Compared with a control group (Ctrl), the concentrations of serum Creatinine (CRE) and urea nitrogen (BUN) of a cisplatin injection model group (Mod) are obviously increased, and the concentration of serum albumin (Abl) is obviously reduced, which indicates that Mod animals have obvious Acute Kidney Injury (AKI); in comparison with the Mod group, four formulations of Sar, CDP, Sar + CDP were administered at the same dose (80 mg/kg/day): the Sar + CDP-1, Sar + CDP-2, Sar + CDP-3 and Sar + CDP-4 can obviously reduce serum CRE and BUN. In addition, the administration groups of Sar, Sar + CDP-1, Sar + CDP-2 and Sar + CDP-3 all obviously increase the concentration of serum Alb, but the administration groups of Sar + CDP-4 and CDP do not obviously increase the Alb; the compound Sar + CDP-2 treatment group has the best effect, and is remarkably better than the single treatment of Sar or CDP, which prompts the generation of good synergistic effect; the treatment effect of the compound Sar + CDP-1, Sar + CDP-3 and Sar + CDP-4 is better than or equal to that of the single treatment of CDP and Sar, and the suggestion also generates synergistic effect. The results show that the Sar and the CDP form a compound with a certain proportion, have obvious synergistic effect on treating AKI, and the proportion range of Sar to CDP is as follows according to the weight proportion: 8: 1-1: 5, the best curative effect is achieved by taking Sar: CDP ═ 2:1 (compound Sar + CDP-2) in the experiment.

2) Renal tissue index detection results

The results are shown in FIG. 3. The detection results of the kidney tissue AKI related indexes of the AKI model and each drug treatment group are consistent with those of the serum AKI related indexes. Compared with a control group, the kidney tissue MDA content of the Mod group is obviously increased, the SOD activity, the CAT content and the GSH content are obviously reduced, and the obvious oxidative stress appears and the kidney has obvious renal function injury. Four combinations of Sar, CDP, Sar + CDP were administered at the same dose (80 mg/kg/day): the treatment of Sar + CDP-1, Sar + CDP-2, Sar + CDP-3 and Sar + CDP-4 can obviously reduce the oxidative stress index of the kidney and reduce the injury of the kidney function. However, CDP alone has poor curative effect, and shows no obvious improvement in renal tissue SOD and GSH. The results also show that the compound of Sar and CDP in a certain proportion has obvious synergistic effect on reducing the oxidative stress of the kidney and improving the renal function, and the proportion range of Sar to CDP is as follows according to the weight proportion: the ratio of Sar to CDP is 8: 1-1: 5, and the best curative effect is Sar to CDP 2:1 (compound Sar + CDP-2).

(2) Treatment effect of Sar + BSA compound on cisplatin-induced acute kidney injury of mice

1) Serum index test results

The results are shown in FIG. 4. The cisplatin injection model group (Mod) had developed significant AKI; compared with the Mod group, the same administration dose (80 mg/kg/day) of the four compounds of Sar, BSA and Sar + BSA are used: the serum CRE and BUN can be obviously reduced by treating Sar + BSA-1, Sar + BSA-2, Sar + BSA-3 and Sar + BSA-4. Moreover, the administration groups of Sar, Sar + BSA-1, Sar + BSA-2, Sar + BSA-3 and Sar + BSA-4 all obviously increase the serum Alb concentration, but the Alb increasing effect of the BSA administration group is not obvious; the compound Sar + BSA-2 treatment group had the best effect and was significantly better than either Sar or BSA alone, suggesting a good synergistic effect; the treatment effect of the compound Sar + BSA-1, Sar + BSA-3 and Sar + BSA-4 is better than or equal to that of the BSA and Sar which are treated independently, and the synergistic effect is also prompted. The result shows that the compound of Sar and BSA in a certain proportion has obvious synergistic effect on treating AKI, and the proportion range of Sar to BSA is as follows according to the weight ratio: 7: 1-1: 6, and the curative effect of Sar, BSA-5: 3 (compound Sar + BSA-2) is the best in the experiment.

2) Renal tissue index detection results

The results are shown in FIG. 5. The kidney of the AKI model animal has obvious oxidative stress and renal function injury, and compared with a control group, the kidney tissue MDA content of the Mod group is obviously increased, and the SOD activity, CAT and GSH content are obviously reduced. Four formulations of Sar, BSA, Sar + BSA were administered at the same dose (80 mg/kg/day): the treatment of Sar + BSA-1, Sar + BSA-2, Sar + BSA-3 and Sar + BSA-4 obviously reduces the oxidative stress index of the kidney and reduces the renal function injury. However, the curative effect of BSA single administration is poor, and the SOD and GSH of kidney tissues are not obviously improved. The result also shows that the compound of Sar and BSA in a certain proportion has obvious synergistic effect on reducing the oxidative stress of the kidney and improving the renal function, and the proportion range of Sar to BSA is as follows according to the weight ratio: 7: 1-1: 6, and the curative effect of Sar, BSA-5: 3 (compound Sar + BSA-2) is best.

Claims

1. An application of a compound pharmaceutical composition taking sarpogrelate and a 5-hydroxytryptamine synthesis inhibitor as active ingredients in preparing a medicine for treating acute kidney injury.

2. Use according to claim 1, characterized in that the inhibitor of 5-hydroxytryptamine synthesis is carbidopa or benserazide; wherein the carbidopa is carbidopa or a pharmaceutically acceptable salt of carbidopa, and the benserazide is benserazide or a pharmaceutically acceptable salt of benserazide.

3. use according to claim 1, characterized in that the sarpogrelate is sarpogrelate or a pharmaceutically acceptable salt thereof.

4. the use of claim 1, wherein the compound pharmaceutical composition is in the form of tablet, capsule, granule, powder, syrup, oral liquid or injection.

5. Use according to claim 1, characterized in that the weight ratio of sarpogrelate to the inhibitor of 5-hydroxytryptamine synthesis is from 15:1 to 1: 15.

6. Use according to claim 5, characterized in that the weight ratio of sarpogrelate to the inhibitor of 5-hydroxytryptamine synthesis is from 8:1 to 1: 6.

7. Use according to claim 5, characterized in that the weight ratio of sarpogrelate to carbidopa is from 8:1 to 1: 5.

8. Use according to claim 5, characterized in that the weight ratio of sarpogrelate to benserazide is 7:1 to 1: 6.

9. Use according to claim 7, characterized in that the weight ratio of sarpogrelate to carbidopa is 2: 1.

10. Use according to claim 8, characterized in that the weight ratio of sarpogrelate to benserazide is 5: 3.