CN116098886A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN116098886A CN116098886A CN202310129329.7A CN202310129329A CN116098886A CN 116098886 A CN116098886 A CN 116098886A CN 202310129329 A CN202310129329 A CN 202310129329A CN 116098886 A CN116098886 A CN 116098886A
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- pharmaceutical composition
- acetylcysteine
- aia
- epal
- pharmaceutically acceptable
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a pharmaceutical composition containing (a) an aldose reductase inhibitor or pharmaceutically acceptable salt thereof and (b) N-acetylcysteine or pharmaceutically acceptable salt thereof and application thereof, wherein the pharmaceutical composition has the advantages of good curative effect, high selectivity and small toxic and side effects.
Description
Technical Field
The invention relates to a pharmaceutical composition and application thereof, in particular to a pharmaceutical composition containing an aldose reductase inhibitor and N-acetylcysteine and application thereof.
Background
Rheumatoid arthritis (rheumatoid arthritis, RA) is a common chronic, systemic autoimmune disease characterized mainly by chronic synovitis and cartilage destruction, and patients often have persistent joint pain, swelling, stiffness, and serious complications such as cardiovascular, pulmonary, skeletal and the like. RA is reported to have a high incidence both worldwide and in our country and can occur at any age. The RA is repeated and is difficult to recover, and the RA does not cause serious threat to the life of the patient, but can seriously affect the daily life and social activities of the patient, thereby bringing heavy mental and economic burden to the patient and the family thereof.
Currently, drugs for treating RA are mainly nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying antirheumatic drugs (DMARDs), biologicals and traditional Chinese herbal medicines.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line drugs for treating RA, which are clinically indispensable nonspecific therapeutic drugs for controlling joint pain and diminishing inflammation by inhibiting Cyclooxygenase (COX) and reducing metabolism of Arachidonic Acid (AA) into Prostaglandins (PGs). Although the medicine can effectively relieve clinical symptoms and physical signs caused by inflammation, the medicine can not radically cure diseases, has obvious toxic and side effects and is mainly characterized by gastrointestinal tract and kidney damage.
The glucocorticoid medicine (GCs) has quick and obvious effect, and the action mechanism is to combine the glucocorticoid with corresponding receptor and enter the cell nucleus, so as to reduce the activity of signal path nuclear factor kappa B (NF-kappa B) and reduce the production of pro-inflammatory cytokines, thereby achieving the aim of reducing inflammation. However, the adverse reaction of the medicines is obvious, the disease progress and joint destruction of RA cannot be blocked, and the adverse reaction such as infection, hypercortical function, osteoporosis and hypertension can be induced after long-term application.
Methotrexate (MTX) in antirheumatic drugs (DMARDs) is used as a first-line drug for treating RA, and can easily cause drug resistance and various side effects such as cardiovascular complications, liver and kidney damage and the like after long-term use.
Biological products, such as rituximab and tolizumab, have been developed that enrich the clinical treatment of RA, but are expensive and create a significant economic strain on patients. It has been reported that about 40% of patients do not respond significantly to treatment with biological products.
In order to improve the quality of life of RA patients and reduce the economic burden thereof, it is necessary to develop low-toxicity and low-cost medicaments.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent, and therefore, the present invention provides a pharmaceutical composition and application thereof.
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising (a) an aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine or a pharmaceutically acceptable salt thereof.
The aldose reductase inhibitor is epalrestat of the formula (I).
The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
The epalrestat and the N-acetylcysteine are administered simultaneously.
The epalrestat is administered before or after the N-acetylcysteine.
The pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, oral liquid, inhalant, cream, ointment, suppository or patch.
The mass ratio of the epalrestat to the N-acetylcysteine is 0.1575:1.
according to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising (a) an aldose reductase inhibitor, or a pharmaceutically acceptable salt thereof, and (b) N-acetylcysteine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis.
According to a further aspect of the present invention there is provided the use of a pharmaceutical composition comprising (a) an aldose reductase inhibitor, or a pharmaceutically acceptable salt thereof, and (b) N-acetylcysteine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetes mellitus in combination with rheumatoid arthritis.
According to a further aspect of the present invention there is provided a kit comprising a pharmaceutical composition comprising (a) an aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and (b) said N-acetylcysteine or a pharmaceutically acceptable salt thereof.
The invention provides a pharmaceutical composition and application thereof. The medicine composition has the advantages of good curative effect, high selectivity and small toxic and side effects.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention and together with the description serve to explain the invention and do not constitute a limitation on the invention. In the drawings:
FIG. 1 shows the transcript levels of Aldose Reductase (AR) in Peripheral Blood Mononuclear Cells (PBMCs) of RA patients and healthy volunteers;
FIG. 2 shows transcript levels of Aldose Reductase (AR) in synovial tissue of an adjuvant arthritis rat model (AIA) and a healthy control group;
FIG. 3 shows the effect of the Aldose Reductase (AR) inhibitor epalrestat (Epal) on Lipopolysaccharide (LPS) induced inflammatory response;
FIG. 4 shows the effect of different treatment groups on foot swelling;
FIG. 5 shows representative CT images of the foot and ankle of different treatment groups;
FIG. 6 shows the effect of different treatment groups on bone protection;
FIG. 7 shows representative rat knee pathology section images for different treatment groups;
FIG. 8 shows the different treatment groups CD4 + 、CD8 + T cells, CD4 + Foxp3 + T cells (Treg cells), CD4 + IL-17A + T cell (Th 17 cell) subpopulation levels (flow cytometer detection results);
FIG. 9 shows the different treatment groups versus CD4 + /CD8 + Ratio, CD4 + Foxp3 + T cell (Treg cell) ratio, CD4 + IL-17A + Effect of T cell (Th 17 cell) ratio;
FIG. 10 shows the effect of different treatment groups on inflammatory factors in serum;
FIG. 11 shows the effect of different treatment groups on hydroxynonenal (4-HNE) and Malondialdehyde (MDA) in serum.
Detailed Description
The examples set forth below are presented to provide those skilled in the art with a more clear understanding of the present invention. The following examples are not intended to limit the scope of the invention, but are merely illustrative examples. The starting materials, reagents or apparatus mentioned in the examples below are all available commercially, or are obtained by known existing means, unless otherwise specified.
Existing application of Aldose Reductase (AR) inhibitor
The pathogenesis of diabetes is that glucose in the patient's body is abnormally active in the aldose reduction pathway due to the long-term inability to convert normally to glycogen storage. Aldose reductase inhibitors are often used as agents for the prevention and treatment of diabetic sequelae because they are effective in inhibiting abnormal increases in sorbitol levels in many organs of diabetic patients.
A number of aldose reductase inhibitors have been developed to date, with the most currently contemplated inhibitors being of four major classes, representative compounds of which are as follows.
(1) Hydantoin and its analogues:
(2) Carboxylic acids:
(3) Sulfonyl group:
(4) Flavonoids and analogues thereof:
aldose reductase is a key enzyme of the metabolic pathway of polyhydric alcohol, and it can reduce glucose to sorbitol, which in turn is not easy to pass through cell membrane due to its strong polarity, can accumulate in cells, change cell permeability, and make Na in cells + －K + Reduced atpase activity, resulting in the loss of inositol, leading to impairment of cellular metabolism and function. Because of the high levels of aldose reductase in tissues such as the eye and nerve cells, the hyperglycemic environment in diabetic patients makes this pathway very easy to open, causing pathological damage to these tissues, leading to a series of diabetic complications. Drugs that block or attenuate aldose reductase activity may be used to prevent or delay the onset of diabetic complications, and therefore, aldose reductase inhibitors are pharmaceutical therapeutic factors for diabetic complications.
Pathogenesis of rheumatoid arthritis (rheumatoid arthritis, RA)
RA is a chronic autoimmune disease characterized by destructive and symmetrical arthropathy and arthromeningitis, and mainly comprises symptoms such as joint deformity, morning stiffness, ankle, temporomandibular arthritis and the like, which not only can reduce the exercise function of a patient, but also can accumulate respiratory, renal, cardiac and other systems, so that the life and work of the patient are seriously affected. If the illness state of a patient cannot be controlled effectively in time, complications such as sicca syndrome, pericarditis, anemia and necrotizing vasculitis can be caused, the life safety of the patient is threatened, at present, the pathogenesis of the rheumatoid arthritis in the medical field is still in a research stage, but a learner considers heredity and environment to be main factors for causing the rheumatoid arthritis, and meanwhile, more immune cells, immune molecules and other substances exist in synovial tissues and synovial fluid of the patient, which indicates that the occurrence of the rheumatoid arthritis possibly has correlation with the activation or release of the substances, or the progress speed of the illness state of the patient is accelerated under the action of the substances.
The present invention provides novel therapeutic combinations of the AR inhibitor epalrestat (Epal) in combination with N-acetylcysteine (NAC) for the treatment or co-treatment of rheumatoid arthritis, particularly in RA patients with complications of diabetes. More specifically, the epalrestat is a marketed drug, is widely used as an AR inhibitor in clinic for treating diabetic complications, has low toxicity and good patient tolerance, and is very suitable for treating rheumatoid arthritis requiring long-term intervention. The N-acetylcysteine (NAC) of the present invention is a dietary supplement, and is clinically used for dyspnea caused by phlegm obstruction and detoxification of acetaminophen poisoning. The therapeutic combination of the invention is effective in RA treatment, where epalrestat is administered in an adult recommended dose (150 mg/d) compared to the equivalent dose in rats (15.75 mg/kg/d) and the dietary supplement N-acetylcysteine is administered in a dose (100 mg/kg/d) lower than the adult recommended intake dose (1.2 g/d) compared to the equivalent dose in rats (126 mg/kg/d), as a potential therapeutic or adjuvant therapeutic combination for RA. For RA patients with complications of diabetes, supplementation with NAC may have a positive therapeutic effect on RA while treating the complications of diabetes with epalrestat.
According to an embodiment of the present invention, a pharmaceutical composition is provided comprising (a) an aldose reductase inhibitor and (b) N-acetylcysteine, wherein the active ingredient is present in each case in free form or in the form of a pharmaceutically acceptable salt thereof, and wherein the aldose reductase inhibitor is epalrestat of the structure as in formula (I).
The mass ratio of epalrestat to N-acetylcysteine is 0.1575:1.
another aspect relates to the use of an inhibitor of aldose reductase or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of rheumatoid arthritis.
Another aspect relates to the use of an inhibitor of aldose reductase or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetes mellitus together with rheumatoid arthritis.
In another aspect, the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, oral liquid, inhalant, cream, ointment, suppository or patch. The dosage form of the pharmaceutical composition of the present invention for oral administration may be, for example, a solid preparation such as a tablet, capsule, granule, powder, etc. Examples of the dosage forms for parenteral administration include injections, suppositories, sublingual tablets, and the like. In addition, for example, a dosage form for sublingual, subcutaneous, intramuscular, or the like administration may be a sustained-release preparation such as sublingual tablet, microcapsule, or the like.
According to another embodiment of the present invention, there is provided a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are used, for example, as excipients, lubricants, binders, disintegrants, thickeners in solid formulations using various organic or inorganic carrier substances commonly used as formulation materials; the composition can be formulated into liquid preparation as solvent, dispersant, solubilizer, suspending agent, tonicity agent, buffer, analgesic, etc. In addition, additives such as preservatives, antioxidants, colorants, sweeteners, and the like may be used according to conventional methods, as needed.
Preferred examples of the excipient may be exemplified by lactose, white sugar, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant may be exemplified by magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Preferred examples of the binder include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, polyvinylpyrrolidone, and the like. Preferable examples of the disintegrant may be exemplified by starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, and the like. Preferred examples of the thickener may be exemplified by natural gums, cellulose derivatives, acrylic polymers, and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and the like. Preferable examples of the dispersing agent include tween 80, HCO 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, and the like. Preferred examples of the solubilizing agent may be exemplified by polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Preferred examples of the suspending agent include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, and the like. Preferable examples of the surfactant include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose. Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer may be exemplified by phosphate, acetate, carbonate, citrate, and the like. Preferred examples of the analgesic agent include benzyl alcohol and the like. Preferable examples of the preservative include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid.
The mode of administration of the aldose reductase inhibitor and N-acetylcysteine of the present invention is not particularly limited, and the aldose reductase inhibitor and N-acetylcysteine may be combined at the time of administration. Examples of such administration modes include (1) administration of a single preparation obtained by simultaneously preparing an aldose reductase inhibitor and N-acetylcysteine, (2) administration of 2 preparations obtained by separately preparing an aldose reductase inhibitor and N-acetylcysteine by the same administration route, (3) administration of 2 preparations obtained by separately preparing an aldose reductase inhibitor and N-acetylcysteine by the same administration route interval time difference, (4) administration of 2 preparations obtained by separately preparing an aldose reductase inhibitor and N-acetylcysteine by different administration routes, (5) administration of 2 preparations obtained by separately preparing an aldose reductase inhibitor and N-acetylcysteine by different administration route interval time difference (for example, administration of an aldose reductase inhibitor→n-acetylcysteine in the order of administration, or administration in reverse order).
The use of the above therapeutic combination for the treatment of rheumatoid arthritis, in particular rheumatoid arthritis with complications of diabetes. Experiments show that the therapeutic combination can obviously improve the relevant indexes such as foot swelling degree, arthritis score, bone destruction degree, immune overactivation and the like of a rheumatoid arthritis rat model (AIA) induced by complete Freund's adjuvant.
Compared with the prior art, the invention has the following beneficial effects:
(1) Rheumatoid arthritis and diabetes are risk factors for each other, and many patients suffer from the two diseases simultaneously; epalrestat (Epal) is widely used for clinically treating diabetic complications, but the single use of epalrestat (Epal) can aggravate the pathological process of RA, and the combined use of epalrestat (Epal) and N-acetylcysteine (NAC) can obviously relieve arthritis.
(2) Compared with antirheumatic drugs (DMARDs) for treating rheumatoid arthritis, the therapeutic combination of the invention has the advantages of lower toxicity, low price, reduced burden on patients and reduced social medical expenditure.
(3) Compared with non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids and the like used for controlling inflammation and immune response in rheumatoid arthritis, the therapeutic combination of the invention has fewer side effects and no dependence, and can effectively control the rheumatoid arthritis response.
(4) The medicines for the treatment combination are all medicines for clinical treatment, and have definite action and high safety.
Example 1
Transcript levels of Aldose Reductase (AR) in Peripheral Blood Mononuclear Cells (PBMCs) of RA patients and healthy volunteers.
Human peripheral blood has a variety of immune cells including neutrophils, lymphocytes, monocytes, among which monocytes are a very important type of immune cells, presenting antigen, activating autoreactive T cells, and migrating to synovial tissue to differentiate into macrophages, producing pro-inflammatory factors and further converting into osteoclasts, involved in joint destruction in rheumatoid arthritis patients. Monocytes can also serve as precursor cells for vascular endothelial cells and participate in the formation of synovial neovasculature.
To study the heterogeneity of immune cell phenotypes in RA patients, peripheral Blood Mononuclear Cells (PBMCs) were isolated from healthy volunteers and RA patients, respectively, using Ficoll cell separation fluid. Total RNA from peripheral blood mononuclear cells was extracted using total RNA extraction reagent (TRIzol) (Invitrogen, USA) and reverse transcribed into cDNA using Master Mix kit (Roche, switzerland). cDNA was bound by fluorochromes FastStart Universal SYBR-Green Master Rox (Roche Diagnostics, indianapolis, IN, USA), wherein the RT-PCR mixture included 0.5. Mu.L of total cDNA, 0.5. Mu.L each of forward and reverse primers, 10. Mu.L of SYBR Master Mix reagent and 8.5. Mu.L of sterile water, and a total volume of 20. Mu.L. Real Time-PCR program (ViiA 7Real-Time PCR system, USA) was run, and the results were processed using the DeltaCT method for data analysis.
As shown in FIG. 1, transcript levels of Aldose Reductase (AR) were significantly elevated in PBMCs of RA patients (P < 0.05) compared to healthy volunteers.
Example 2
Transcript levels of Aldose Reductase (AR) in synovial tissue of the adjuvant arthritis rat model (AIA) and healthy control group.
The pathogenesis of AIA models is mainly molecular modeling theory. The bacillus tuberculosis in bacillus calmette-guerin as antigen enters the organism to sensitize and differentiate and proliferate popliteal lymph node T cells, release lymphokines including TNF-alpha and IFN-gamma, cause joint mononuclear macrophage infiltration, further release IL-6, IL-1 beta and TNF-alpha cytokines to directly kill target cells. Thus, AIA immunology is characterized by a T cell mediated chronic systemic inflammatory response in which a balance disorder between T cell subsets in helper T cells (Th) is one of the important features of AIA rat immune dysfunction.
Freund's Adjuvant is classified into complete Adjuvant (CFA) and incomplete Adjuvant (Incomplete Freund's Adjuvant, IFA), and complete Freund's Adjuvant is used in this example. The method comprises adding 1ml mineral oil into 5mg heat-inactivated tubercle bacillus inactivated at 80deg.C for 1 hr, and grinding. The method for injecting the AIA model comprises injecting the hindfoot plantar part or the tail root part into the skin, and injecting CFA 0.1mL into the skin once to prepare the model AIA.
Synovial tissue was taken from healthy control and AIA rat knee joints, triturated using liquid nitrogen, total RNA of the synovial tissue was extracted using TRIzol (Invitrogen, USA), and Real Time-PCR was performed to detect mRNA levels of AR as described in "example 1".
As shown in fig. 2, the transcription level of AR in the synovial tissue of the AIA model rats was significantly up-regulated compared to the healthy control group.
Example 3
The effect of Aldose Reductase (AR) inhibitor epalrestat (Epal) on Lipopolysaccharide (LPS) induced inflammatory response.
TNF- α: TNF- α is an important cytokine involved in the development of rheumatoid arthritis, and overexpression of TNF- α can promote the onset of rheumatoid arthritis, and the level of this cytokine can reflect the severity of arthritis in patients.
IL-6: IL-6 always keeps rising trend in synovial fluid and serum of rheumatoid arthritis patients, and can be used as a B cell differentiation factor to induce high-y globulin and autoantibodies to be produced, wherein the produced autoantibodies contain a certain rheumatoid factor. Meanwhile, IL-6 can accelerate the formation rate of osteoclasts in the metabolism process, and IL-6mRNA is limited in a synovial lining layer formed by synovial A cells and synovial B cells, so that a learner believes that IL-6 is mainly generated in local lesions of a human body.
IL-1. Beta: IL-1β is currently considered to be one of the most important cytokines in the pathogenesis of rheumatoid arthritis, and in particular, exacerbates the degree of joint destruction in patients during the progressive phase of the disease.
Lipopolysaccharide (LPS) is the main cell surface antigen of gram negative bacteria and the main biological effector for stimulating the host to react with bacterial infection, belongs to pathogen related molecular pattern (PAMP), and has strong immunostimulation effect. It has been shown that LPS can bind to various cell surface TLR4 and that once TLR4 recognizes LPS, it activates receptor-related kinases and NF- κB, which translocate into the nucleus to induce pro-inflammatory cytokine production.
Fibroblast-like synoviocytes (RAFLS) from RA patients were treated with 20. Mu.M, 40. Mu.M, 60. Mu.M epalrestat (Epal) for 2 hours, and then with 100ng/mL LPS for 4 hours. Total RNA of the cells was extracted using TRIzol reagent. The transcription levels of AR and proinflammatory cytokines (TNF-. Alpha., IL-1. Beta., IL-6) were detected by Real Time-PCR as described in "example 1".
As shown in FIG. 3, mRNA levels of TNF- α, IL-1β, IL-6 and AR were significantly increased (P < 0.05) after LPS stimulation, and Epal inhibited LPS-induced expression of inflammatory factors in a dose-dependent manner.
The structural formula of epalrestat is shown below.
Example 4
Effect of pharmaceutical composition comprising epalrestat (Epal) and N-acetylcysteine (NAC) on adjuvant arthritis rat model (AIA) foot swelling.
A model was constructed using 110-130 g SPF grade male SD rats (all animal care and experiments were approved by the animal ethics Committee of the national institute of health and administration, australian university of science and technology, animal Care and use Committee directive) obtained from hong Kong Chinese university, and 36 rats were randomly divided into 6 groups (health control group, AIA model group, methotrexate (MTX) treatment group, epalrestat (Epal) treatment group, N-acetylcysteine (NAC) treatment group, epalrestat (Epal) +N-acetylcysteine (NAC) treatment group), and the other animals except for the health control group were subjected to model making, 0.1mL complete Freund's adjuvant was injected intradermally into the tail root portion, and the health control group was injected with an equivalent amount of physiological saline as a control in the same manner. The epalrestat (Epal) treatment group was gavaged 15.75mg/kg of Epal daily, the N-acetylcysteine (NAC) treatment group was intraperitoneally injected daily with 100mg/kg of NAC, epalrestat (Epal) +n-acetylcysteine (NAC) treatment group was administered in combination with the above doses and dosing regimen for 27 consecutive days, the Methotrexate (MTX) treatment group was gavaged weekly at a dose of 7.6mg/kg/week, the rat foot volumes were measured every 3 days and scored for arthritis according to the following criteria, (1) no signs of erythema and swelling were scored as 0; (2) Only tarsal bones or ankle joints had erythema and mild swelling, a score of 1; (3) There were erythema and mild swelling from ankle to tarsal bones, score 2; (4) There were erythema and moderate swelling of the joints from ankle to plantar, score 3; (5) Erythema and severe swelling surrounded ankle, foot and finger, or limb stiffness, scoring 4.
As shown in fig. 4, the AIA model group showed significant foot swelling from day 12 and significantly increased arthritis scores (P < 0.01) compared to the healthy control group, the NAC treatment failed to effectively relieve the AIA rat foot swelling level and the arthritis scores, whereas the Epal treatment group had foot swelling levels more severe than the AIA model group and the arthritis scores were also higher than the AIA model group, but Epal significantly reduced the AIA rat foot swelling and decreased the arthritis scores (P < 0.05) in combination with NAC, and the combination group effect was comparable to the MTX positive drug treatment group, which relieved foot swelling levels even better than the MTX treatment group.
Example 5
Effect of pharmaceutical composition comprising epalrestat (Epal) and N-acetylcysteine (NAC) on bone protection in rat model of adjuvant arthritis (AIA).
The rats in example 4 were euthanized after day 27, left legs were fixed in 4% PFA, and microCT scans were performed on SkyScan 1176 using the following parameters: 35 μm resolution, 85kV, 385. Mu.A, 65ms exposure time, 360 scan with 0.7℃rotation using a 1mm Al filter. The 3D reconstructed image was then performed with NRecon software. Obtaining CT
As shown in fig. 5, the bones of the healthy control group are clear and complete, the metatarsals of the AIA group are corroded to a certain extent, part of the bone joints only keep part of the contours, the bone corrosion after molding is obviously aggravated by the Epal single-use group, the bone corrosion degree of the NAC group is equivalent to that of the AIA group, but the bone damage caused by the AIA molding is almost reversed by combining the Epal and the NAC, and obvious bone corrosion is rarely seen in appearance.
The rat calcaneus part is subjected to micro CT analysis, and the bone density, the bone volume fraction, the cortical bone density, the bone trabecular number and the total pore volume are calculated, and the micro CT score is calculated from the five data.
As shown in fig. 6, the Epal treatment group showed more serious bone destruction compared with the AIA model group, the microCT score was also lower (P < 0.01) than that of the AIA group, the NAC group-related score was comparable to that of the AIA group, but the combination of Epal and NAC significantly increased the microCT score and reduced bone destruction (P < 0.05). The results show that the single use of Epal aggravates the bone erosion degree of AIA rats, NAC has no obvious effect on bone damage caused by AIA molding, and the combination of Epal and NAC can effectively reduce bone damage after molding and play a role in bone protection.
Example 6
Effect of a pharmaceutical composition comprising (a) epalrestat (Epal) or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof on joint pathology in a rat model of adjuvant arthritis (AIA).
The rats in example 4 were euthanized after day 27 and knee joint tissue was fixed in 4% pfa for 24 hours. And (3) performing decalcification treatment after trimming, and then performing gradient dehydration by using alcohol, paraffin embedding and slicing. And then dewaxing the paraffin sections to water, hematoxylin staining, eosin staining and dewatering the sections. Relevant pathology pictures were taken using a Leica DM2500 fluorescence microscope.
As shown in FIG. 7, AIA model was compared to healthy control groupThe group can see obvious synovial hyperplasia (marked by the symbol → in the figure), accompanied by inflammatory cell infiltration, narrowing of the tibial and femoral space, and joint surface roughness, osteoporosis destruction due to cartilage erosion and synovial hyperplasia. The Epal single drug group can be seen with obvious pannus (marked with the symbol in the drawing
) The synovial hyperplasia is more serious than that of AIA group, and obvious synovial hyperplasia and bone destruction (marked by +.>
) But the combination of Epal and NAC obviously reduces the proliferation of synovium, the joint surface is smooth, and the bone tissue is complete. The results above demonstrate that Epal alone aggravates AIA rat arthropathy and NAC alone does not have a significant effect on its pathology, but Epal in combination with NAC significantly reverses AIA rat arthropathy and reduces bone damage.
Example 7
An immunomodulatory effect of a pharmaceutical composition comprising (a) epalrestat (Epal) or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof on an adjuvant arthritis rat model (AIA).
Research has demonstrated that T cells of various subtypes are involved in the pathological process of RA, CD4 + T cells and CD8 + T cells are two important T cell subsets, CD4 found in RA autoimmune disease + /CD8 + The ratio is adjusted up. In CD4 + Among T cells, th17 cells and Treg cells are two representative cell subsets. Pathogenic Th17 cells excessively differentiate in RA process, promote secretion of proinflammatory factors such as IL-17A, IL-21 and the like, and aggravate autoimmune reaction; while the differentiation and function of Treg cells that regulate immune tolerance are inhibited, treg cells can exert anti-inflammatory effects by secreting IL-10 and TGF- β.
The rats in example 4 were euthanized on day 27 and peripheral blood mononuclear cells were collected. Collected peripheral blood mononuclear cells were stained with anti-CD 45 antibody coupled to APC-Cy7, anti-CD 3 antibody coupled to FITC, and anti-CD 4 antibody coupled to PerCP-Cy 5-5. After staining, part of the cells are stained with a fixed membrane-disrupting solution, washed with a buffer solution, stained with an anti-Foxp 3 antibody coupled to PE-a, and part of the cells are stained with a fixed membrane-disrupting solution, washed with a buffer solution, and then flow analyzed with a BD FACSAria III four-way flow cell sorter using an anti-IL-17A antibody coupled to PE-Cy7, and the relevant data are processed on FlowJo software.
As shown in fig. 8 and 9, AIA model group CD4 compared to the healthy control group + /CD8 + Up-regulation of the ratio, CD4 + Foxp3 + T cells (Treg cells) decreased in proportion, while CD4 + IL-17A + The proportion of T cells (Th 17 cells) increases; compared to the AIA model group, the NAC single-drug group had no significant effect on T cell differentiation, and the Epal single-drug group significantly upregulated the proportion of Th17 cells, although it was on CD4 + /CD8 + The ratio and Treg cell ratio have no obvious effect; while the combination of Epal and NAC significantly down-regulates CD4 + /CD8 + Ratio and Th17 cell ratio, while Treg cell ratio was up-regulated. The above results demonstrate that NAC alone had no significant effect on the in vivo immune response in AIA rats, epal alone promoted Th17 differentiation exacerbating the immune response, and Epal and NAC combined significantly reduced the immune response in AIA rats.
Example 8
Effects of pharmaceutical compositions comprising (a) epalrestat (Epal) or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof on inflammatory factors in serum of an adjuvant rat model of arthritis (AIA).
In the pathological course of RA, pro-inflammatory factors are overproduced and anti-inflammatory factor secretion is inhibited. To examine the effect of the therapeutic combination on the production of inflammatory-related factors in AIA rats, peripheral blood from the rats in example 4 was taken at day 27, coagulated at room temperature for at least 30 minutes, centrifuged at 2000g for 10 minutes, and the supernatant serum was stored at-80℃for use. The concentration of each inflammatory factor in serum was measured using the LEGENDplexTM kit (Customer panel,10 cytokins) from BioLegend. The centrifuged serum is added into a V-shaped bottom plate, and the serum is combined with micromagnetic beads, antibodies and the like in an incubation manner according to the specification steps of a company kit. Detection was performed using a BD FACSAria III four-way flow cytometer, and the relevant data was processed on LEGENDplexTM Data Analysis Software software.
As shown in FIG. 10, compared with the healthy control group, the AIA model group has significantly increased inflammatory factor content (P < 0.05), and significantly decreased anti-inflammatory factor IL-4 content (P < 0.05), and the Epal single drug treatment has significantly higher TNF-alpha and IL-17A content than the AIA model group, and significantly lower IL-4 content than the AIA model group (P < 0.05); each inflammatory factor of the NAC single drug group was comparable to the model group, but the combination treatment of Epal and NAC significantly reversed the inflammatory response in AIA rats, with significant decrease in the concentrations of pro-inflammatory factors in the serum of the combination group and significant increase in the concentrations of anti-inflammatory factors. The above results demonstrate that the use of Epal alone promotes the inflammatory response in AIA rats and that NAC alone has no significant effect on the inflammatory response in AIA rats, whereas the use of Epal in combination with NAC significantly reduces the inflammatory response in AIA rats.
Example 9
NAC significantly reversed epalrestat (Epal) -induced accumulation of hydroxynonenal (4-HNE) and MDA in AIA rat serum.
Rat serum from example 8 was taken on day 27 and Malondialdehyde (MDA) content was determined using the Lipid Peroxidation (MDA) Assay kit (ab 118970) from Abcam corporation; the content of hydroxynonenal (4-HNE) was measured using the Lipid Peroxidation (4-HNE) Assay Kit (ab 238538) from Abcam. And (3) operating according to the specification steps and requirements of the company kit, and detecting the fluorescence intensity or absorbance on an enzyme-labeled instrument respectively.
As shown in fig. 11, the MDA and 4-HNE levels in the AIA model group were only slightly up-regulated (no significant difference) compared to the healthy control group, and the MDA and 4-HNE concentrations in the serum of the Epal single drug group were significantly increased compared to the AIA model group, whereas the two index concentrations in the serum of the NAC single drug group were comparable to the AIA model group, but the MDA and 4-HNE concentrations in the serum of the Epal and NAC combination treatment group were significantly lower than the Epal single drug group, comparable to the AIA model group. The above results demonstrate that Epal causes the accumulation of 4-HNE toxic aldehydes, which in turn aggravates the autoimmune response, whereas NAC significantly reverses the 4-HNE elevation caused by Epal, which in turn inhibits the side effects caused by Epal alone (accumulation of 4-HNE and other toxic aldehydes), resulting in better action of Epal.
In the specific embodiment of the present invention, the model building agent used for building the AIA rat model was complete freund's adjuvant (prepared by mixing heat-inactivated tubercle bacillus with liquid MINERAL OIL), tubercle bacillus (m.turciculosis des.h37ra) was purchased from DIFCO corporation of america, and MINERAL OIL (milneal OIL) was purchased from Sigma corporation of america. Methotrexate is methotrexate tablet (national drug standard H31020644) produced by Shanghai pharmaceutical company, yipanstat is epalrestat tablet (national drug standard H20040012) produced by Nanjing Haolin pharmaceutical company, yangtze river pharmaceutical company, N-acetylcysteine is purchased from Shanghai Han Xiang Biotechnology Co., ltd (purity > 98%). Foot swelling was determined on a Ugo basic foot volume measuring instrument, bone joint scanning was performed using micro CT software using SkyScan 1176 instrument (Bruker, belgium), analysis software was performed using NRecon software (Bruker-micro CT, belgium), real-time fluorescent quantitative PCR was performed on Life Technologies ViiA-7 instrument, treg to Th17 cell ratio was performed using BD FACSaria III four-way flow cytometer, and cytokine content in serum was determined using Legendplex customer panel (Biolegend, USA).
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition comprising (a) an aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and (b) N-acetylcysteine or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1, wherein the aldose reductase inhibitor is epalrestat of formula (I).
3. The pharmaceutical composition of claim 2, further comprising one or more pharmaceutically acceptable carriers.
4. The pharmaceutical composition of claim 2, wherein the epalrestat and the N-acetylcysteine are administered simultaneously.
5. The pharmaceutical composition of claim 2, wherein the epalrestat is administered before or after the N-acetylcysteine.
6. The pharmaceutical composition according to claim 2, in the form of a capsule, powder, tablet, granule, pill, injection, oral liquid, inhalant, cream, ointment, suppository or patch.
7. The pharmaceutical composition according to claim 2, the mass ratio of epalrestat to N-acetylcysteine being 0.1575:1.
8. use of a pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of rheumatoid arthritis.
9. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of diabetes combined with rheumatoid arthritis.
10. A kit comprising (a) an aldose reductase inhibitor or a pharmaceutically acceptable salt thereof of any one of claims 1-7 and (b) N-acetylcysteine or a pharmaceutically acceptable salt thereof.
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