Application of zinc ion chelating agent in preparation of medicine for relieving senile pruritus

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of a zinc ion chelating agent in preparation of a medicine for relieving senile itching. The zinc ion chelating agent is made into an injection for intrathecal injection. The senile pruritus can be remarkably improved in an administration mode of injecting the zinc ion chelating agent into the exogenous sheath. Compared with the prior art, according to the scheme, the zinc ion chelating agent is directly injected into the spinal cord cavity through intrathecal injection, the zinc ion chelating agent can act on the central nervous system more directly, and the rapid and local effect is provided. The application of the administration mode in the treatment of chronic pruritus is an innovative attempt.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to the application of a zinc ion chelator in the preparation of a medicine for alleviating senile pruritus. Background Art

[0002] Pruritus is an unpleasant sensation that induces the desire to scratch or the scratching reflex. Clinically, it is divided into acute pruritus and chronic pruritus according to the length of the disease course: acute pruritus generally has a clear cause and is simple to treat; chronic pruritus has a complex cause and currently lacks effective treatment drugs. The incidence of chronic pruritus varies greatly due to factors such as race, age, gender, and nature of work, but the overall incidence in adults is over 10%, and the incidence of senile pruritus is as high as over 60%. The number of patients with chronic pruritus is growing, which has brought a heavy burden to the medical and health system, the country, society, and families, and has also seriously reduced the quality of life of patients. In recent years, great progress has been made in the research on itch, including the establishment of animal models of itch, the identification of itch receptors and the analysis of itch neural circuits. These studies mainly focus on the mechanism of itch when the body is stimulated by acute itch factors under normal physiological conditions. However, there is a lack of research on the mechanism of chronic itch under pathological conditions, such as itch induced by skin diseases, itch induced by systemic diseases, neuropathic itch and psychological itch. These chronic itch are also present in large numbers in clinical practice and need to be treated.

[0003] At present, there are two problems in the treatment of chronic pruritus: first, the mechanism of chronic pruritus is greatly different from that of pruritus induced by acute itch factors under normal physiological conditions, and different types of chronic pruritus have different pathogenesis, so it is necessary to reveal the molecular mechanism of different types of chronic pruritus; second, although the neural circuits formed by itch are gradually analyzed, it is difficult to treat itch patients by manipulating the itch neural circuits in patients with current technical means.

[0004] Therefore, the molecular mechanisms of different types of chronic pruritus still need to be analyzed. In view of the high incidence of chronic pruritus in the elderly, appropriate drugs can be designed for the corresponding molecular mechanisms and ideal drugs for the treatment of senile pruritus can be screened to better solve clinical problems.

[0005] Chinese patent CN116251100B discloses the use of tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or its pharmaceutically or cosmetically acceptable derivatives in the preparation of a composition product for anti-skin aging and / or anti-dermatitis, and an external preparation containing tetrakis(2-pyridylmethyl)ethylenediamine or its pharmaceutically or cosmetically acceptable derivatives. TPEN or its pharmaceutically or cosmetically acceptable derivatives can be used to combat signs of skin aging, and can be used to treat dermatitis, especially senile aseptic dermatitis, and has great application prospects in the fields of pharmacy or cosmetics. The application states that senile dermatitis generally refers to senile skin itching. In this scheme, TPEN is used for external preparations.

[0006] Chinese patent CN116606899A discloses a method for evaluating the efficacy of anti-dandruff based on zinc enzyme homeostasis, including cytotoxicity detection of the test substance; cell culture and grouping, adding TPEN to the model control group, adding TPEN and the test substance at a safe concentration to the experimental group, removing the culture medium after incubation of each group, adding the total RNA extraction reagent to the cells collected by centrifugation and preserving; performing gene expression detection on the cells collected from each group; constructing a zinc-deficient skin model and testing it. This scheme only uses TPEN tool drugs for zinc ion chelation, and the core content of its application is to detect immortalized keratinocytes (HaCaT) and primary isolated keratinocytes after model construction; antioxidant enzymes and cell glycoprotein-related genes are SOD1, CAT, CDH1, VCAN or FBN and KLK5 and KLK7 and other barrier damage target genes for expression evaluation. Summary of the invention

[0007] Based on the current status of the treatment of chronic pruritus, the present invention provides an application of a zinc ion chelator in the preparation of a medicine for alleviating senile pruritus.

[0008] The present application scheme has been studied and found that spontaneous itching and touch-induced itching behaviors of aged mice can be relieved by intrathecal injection of zinc ion chelators. Based on this, the present invention provides an application of a zinc ion chelator in the preparation of a drug for relieving senile pruritus. Senile pruritus can be significantly improved by the administration of exogenous intrathecal injection of zinc ion chelators.

[0009] The purpose of the present invention can be achieved by the following technical solutions:

[0010] The present invention firstly provides an application of a zinc ion chelator in preparing a medicine for alleviating senile pruritus. The zinc ion chelator is prepared into an injection for intrathecal injection.

[0011] In one embodiment of the present invention, the zinc ion chelating agent is selected from one or a combination of the following substances:

[0012]

[0013] TPEN (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine) is a metal chelator that is highly selective in forming stable complexes with a variety of metal ions. It is mainly used in laboratory research, especially in the fields of cell and molecular biology. ZX1 is also called 2-{[bis(2-pyridylmethyl)amino]ethylamino}benzenesulfonic acid hydrate sodium salt. The following are the main uses of TPEN and ZX1 drugs:

[0014] Metal ion chelation: The main function of TPEN and ZX1 is to form stable complexes with metal ions. It is highly selective for some transition metals such as zinc, nickel, copper and iron ions and can be used to chelate these metal ions and separate them from biological systems.

[0015] Functional studies of metal ions: By using TPEN and ZX1, specific metal ions can be temporarily or reversibly removed from cells to study the role of these metals in cellular function. For example, by removing zinc from cells, researchers can explore the function of zinc in cell growth, differentiation, and signaling.

[0016] Oxidative stress research: TPEN can be used to study processes related to oxidative stress. Some metal ions may cause oxidative stress when they are excessive, and the application of TPEN can help researchers study the interaction between metal ions and oxidative stress.

[0017] Pharmacological studies of metal ions: Since TPEN and ZX1 can regulate the presence of metal ions, it also has potential in studying metal-related pharmacology. For example, TPEN and ZX1 can be used to study the interactions of metal ions on drugs and how these interactions affect the efficacy and toxicity of drugs.

[0018] In conclusion, TPEN and ZX1 are tool compounds for chelating metal ions in cell and molecular biology research. It can provide a better understanding of the functions and effects of metal ions in living organisms and the association of these metals with various biological processes.

[0019] However, there is no related scheme in the prior art regarding the intrathecal injection of zinc ion chelators for relieving senile pruritus.

[0020] In one embodiment of the present invention, the senile pruritus is mainly due to the dehydration and dryness of the skin stratum corneum caused by aging as a clinical feature.

[0021] In one embodiment of the present invention, the senile pruritus includes spontaneous itch and mechanical itch.

[0022] In one embodiment of the present invention, the injection for intrathecal injection further comprises a pharmaceutically acceptable carrier and / or excipient.

[0023] The term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active agent, which is well known in the art and includes, but is not limited to, pH adjusters, surfactants, adjuvants, and ionic strength enhancers. For example, pH adjusters include, but are not limited to, phosphate buffers; surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80; ionic strength enhancers include, but are not limited to, sodium chloride. Pharmaceutically acceptable carriers may include, for example, pharmaceutically acceptable liquids, aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, anesthetics, suspending / dispersing agents, chelating agents, diluents, adjuvants, excipients, or non-toxic auxiliary substances, combinations of various components known in the art, or more.

[0024] In one embodiment of the present invention, the injection for intrathecal injection further contains an adjuvant, and the adjuvant is selected from one or more of the following groups: physiological saline, glucose saline, or a combination thereof.

[0025] The present invention also provides a method for treating senile pruritus, wherein the zinc ion chelator is prepared into an injection for intrathecal injection, and the drug is administered in the form of intrathecal injection.

[0026] The present invention has found that the administration of zinc ion chelators by intrathecal injection can relieve the spontaneous itch and mechanical itch behaviors of aged mice. Therefore, the present invention provides a new idea for treating senile pruritus, and provides a more effective treatment method for the enhancement of chronic itch, itch sensitization and allergic pruritus under pathological conditions such as skin diseases or skin aging.

[0027] The incidence of chronic pruritus varies greatly due to factors such as race, age, gender, and nature of work, but the overall incidence in adults is more than 10%, while the incidence in the elderly is as high as more than 60%. Traditional treatments for skin pruritus mostly use ointments for local application, which have limited effects and are therefore not good for treating chronic pruritus caused by some systemic diseases (such as age). The solution of the present invention can solve senile pruritus.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0029] The present invention has concluded through experimental studies on aged mice that intrathecal injection of zinc ion chelators TPEN and ZX1 can significantly reduce the spontaneous itching and touch-induced itching behaviors of aged mice and improve the symptoms of pruritus. The administration method adopted by the present invention is intrathecal injection, which is systemic administration and has a wider mode of action, making up for the deficiency that local administration of ointment cannot quickly relieve the patient's itching symptoms, and has no effect on the motor ability of mice after administration, and the injection method is easy to operate, and the drug technology used is mature and easy to obtain. The present application scheme directly injects the zinc ion chelator into the spinal cavity through intrathecal injection, which can act more directly on the central nervous system and provide rapid and local effects. The application of this administration method in the treatment of chronic pruritus is an innovative attempt. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Spontaneous itch was significantly relieved after intrathecal injection of zinc ion chelator TPEN or ZX1 in aged mice.

[0031] Figure 2 After intrathecal injection of zinc ion chelator TPEN or ZX1 into aged mice, touch-induced itch behind the ear was significantly relieved. DETAILED DESCRIPTION

[0032] The present invention provides an application of a zinc ion chelator in preparing a medicine for alleviating senile pruritus, wherein the metal ion chelator is TPEN or ZX1.

[0033] The zinc ion chelator is prepared into an injection for intrathecal injection.

[0034] In the following examples, it was verified that intrathecal injection of zinc ion chelators TPEN and ZX1 could significantly reduce the itch behavior of aged mice.

[0035] Intrathecal injection (IFI) in mice is an experimental technique that directly injects drugs, pathogens or other substances into the brain ventricles of mice.

[0036] The specific method of intrathecal injection in mice is as follows:

[0037] 1. Select C57BL / 6 mouse strain, the age of mice is usually 6-8 weeks, and the age of old mice is over 18 months. Anesthetize the mice by inhalation anesthesia.

[0038] 2. Anesthetize the mouse using inhalation anesthesia. Fix the mouse's head after anesthesia, remove the hair on the mouse's waist and back, and disinfect it with a 75% alcohol cotton ball.

[0039] 3. Fix the mouse with your left hand, expose the back of the iliac spine, hold the insulin syringe with your right hand, and find the anterior superior iliac crest after the mouse is quiet. The horizontal distance between the L5 intervertebral space and the iliac spine of C57BL / 6 mice is about 1.5mm, and the horizontal distance between the L6 intervertebral space and the iliac spine is about 4mm.

[0040] 4. Insert the needle into the midline skin at an angle of about 30°, about 4 mm caudal to the iliac crest. If the needle cannot be inserted into the L6 intervertebral space, slowly lower the needle insertion angle while moving the needle tip forward along the groove between the spinous process and mastoid process until it is inserted into the L5 intervertebral space.

[0041] (4) After the needle tip entered the spinal canal, 10 μL of TPEN (100 μM) or ZX1 (100 μM) was pushed in. The trembling or sudden shaking of the mouse's tail indicated successful needle insertion.

[0042] (5) Monitoring and behavioral experiments: Observe the behavior and health status of mice by detecting the number of spontaneous itch behaviors and touch-induced behaviors of mice and making statistics.

[0043] This method is mature and stable, has no influence from anesthetics, does not affect the subsequent behavioral results detection, produces less stimulation to mice, and can minimize the impact on the experimental results.

[0044] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0045] Embodiment 1:

[0046] Six male 6-8W C57 mice were used to establish the xeroderma model for 7 days. After 7 days, the behavior of the mice was recorded, and the number of spontaneous itching was about 60 times / hour, indicating that the model was successfully established. Zinc ion chelator TPEN (100μM, 10μL) or ZX1 (100μM, 10μL) was injected intrathecally into the xeroderma model mice, and then spontaneous itching behavior was detected.

[0047] Embodiment 2:

[0048] Six male aged mice (C57; more than 1.5 years old) were tested for spontaneous itch behavior. The number of spontaneous itch in aged mice was about 40 times / hour, indicating that itch behavior increases with age. Zinc ion chelator TPEN (100μM, 10μL) or ZX1 (100μM, 10μL) was injected intrathecally in aged mice, and then spontaneous itch behavior was tested.

[0049] Embodiment 3:

[0050] Six male aged mice (C57, more than 1.5 years old) were subjected to touch-induced itch behavior test, and 0.07g Von Frey fiber hair was used to stimulate the back of the ear and the back of the neck of the mice for five times, and the number of times of itch was counted. Zinc ion chelator TPEN (100μM, 10μL) or ZX1 (100μM, 10μL) was injected intrathecally into the aged mice, and touch-induced itch behavior was tested at the same time.

[0051] Statistical analysis of Examples 1, 2, and 3

[0052] The itch behavior data were expressed as mean ± SD and analyzed by One-way ANOVA for comparison between groups and Two-way ANOVA for comparison between two groups, and post-analysis was performed if differences were shown.

[0053] The experimental results of Examples 1, 2, and 3 are as follows:

[0054] 1. In the spontaneous itch behavior experiment, intrathecal injection of zinc ion inhibitor TPEN (100μM, 10μL) or ZX1 (100μM, 10μL) significantly alleviated the spontaneous itch behavior of aged mice. Figure 1 , Figure 1 The results in the left figure show that the spontaneous itch behavior of aged mice was significantly reduced 1 hour after intrathecal injection of zinc ion chelator TPEN. Figure 1 The results in the right figure show that the spontaneous itch behavior of aged mice was significantly reduced 1 hour after intrathecal injection of zinc ion chelator ZX1.

[0055] 2. In the experiment of touch-induced itch behavior, intrathecal injection of zinc ion inhibitors TPEN and ZX1 can significantly alleviate the touch-induced itch behavior of chronic itch model mice and aged mice. Figure 2 , Figure 2 The results in the left figure show that intrathecal injection of zinc ion chelator TPEN 1 hour after injection can significantly alleviate the touch-induced itch behavior behind the ear of aged mice. Figure 2 The results in the right figure show that intrathecal injection of zinc ion chelator ZX1 can significantly alleviate touch-induced itch behavior behind the ear of aged mice 1 hour after injection.

[0056] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. Use of a zinc ion chelator in the preparation of a drug for alleviating senile pruritus, characterized in that: The zinc ion chelator is prepared into an injection for intrathecal injection.

2. The use of a zinc ion chelator according to claim 1 in the preparation of a drug for alleviating senile pruritus, characterized in that: The zinc ion chelating agent is selected from one or a combination of the following substances: N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine 2-{[Bis(2-pyridylmethyl)amino]ethylamino}benzenesulfonic acid hydrate sodium salt.

3. Use of a zinc ion chelator according to claim 1 in the preparation of a drug for alleviating senile pruritus, characterized in that: The senile pruritus is characterized by the dehydration and dryness of the stratum corneum of the skin as the age increases.

4. Use of a zinc ion chelator according to claim 1 in the preparation of a drug for alleviating senile pruritus, characterized in that: The senile pruritus includes spontaneous itch and mechanical itch.

5. Use of a zinc ion chelator according to claim 1 in the preparation of a drug for alleviating senile pruritus, characterized in that: The injection for intrathecal injection also includes a pharmaceutically acceptable carrier and / or excipient.

6. Use of a zinc ion chelator according to claim 1 in the preparation of a drug for alleviating senile pruritus, characterized in that: The injection for intrathecal injection further contains an adjuvant, and the adjuvant is one or more selected from the following group: physiological saline, glucose saline, or a combination thereof.

7. A method for treating senile pruritus, characterized in that: The zinc ion chelator is made into an injection for intrathecal injection and administered by intrathecal injection.

8. A method for treating senile pruritus according to claim 7, characterized in that: Zinc ion chelators are injected directly into the spinal cavity via intrathecal injection, acting directly on the central nervous system.

9. A method for treating senile pruritus according to claim 7, characterized in that: The zinc ion chelating agent is selected from one or a combination of the following substances: N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine 2-{[Bis(2-pyridylmethyl)amino]ethylamino}benzenesulfonic acid hydrate sodium salt.

10. A method for treating senile pruritus according to claim 7, characterized in that: The senile pruritus includes spontaneous itch and mechanical itch.

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