CN115607533A - Application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia - Google Patents
Application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia Download PDFInfo
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- CN115607533A CN115607533A CN202211204298.9A CN202211204298A CN115607533A CN 115607533 A CN115607533 A CN 115607533A CN 202211204298 A CN202211204298 A CN 202211204298A CN 115607533 A CN115607533 A CN 115607533A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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Abstract
The invention discloses application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia. The invention increases the clinical indication of tranilast and fills the blank that tranilast is used for preventing and treating CIPN. The tranilast specifically inhibits the TRPV2 pathway, has certain correlation and causal relationship with mitochondrial injury and epidermal nerve fiber loss, and provides a feasible way for preventing and treating the diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of tranilast in prevention and treatment of chemotherapy-induced peripheral neuralgia.
Background
Chemotherapy-induced peripheral neuralgia (CIPN) is clinically manifested by pain, numbness and tingling, seriously affects the quality of life of patients, is a main cause of hindering cancer treatment, and is imminent for prevention and treatment of peripheral nerve endings. Therefore, the research on the pathogenesis of the CIPN and the research and development of CIPN prevention and treatment medicines have important scientific significance and clinical practical value. Research shows that the target TRPV2 has certain prevention and treatment effect on chemotherapy-induced peripheral neuralgia.
Tranilast, an analogue of a tryptophan metabolite. Originally, tranilast was considered an antiallergic agent for the treatment of inflammatory diseases such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Meanwhile, the beneficial effects of tranilast are also seen in various disease states such as fibrosis, proliferative diseases, cancer, cardiovascular problems, autoimmune diseases, ocular diseases, diabetes and kidney diseases (Koda A, nagai H, watanabe S, yanagihara Y, sakamoto K.1976; azuma H, banno K, yoshimura T.1976; shioda H.1979; isaji M, nakajoh M, naito J.1987; konneh M. Tranilast Kissei Phacenter. Idrugs 1998). With the progress of research, tranilast has also been found to effectively block TRPV2 (Santoni, g., c.amantini, f.maggi, et al., 2020), which TRP channels are involved not only in pain, taste, heat and mechanical reactions, but also in a variety of pathological conditions, such as neurodegenerative diseases, neuropathic pain, cardiac diseases, renal diseases and cancer (Vaidya B, sharma SS..2020;
m, braidy n.2017; hof T, chaigne S, rcalde a, et al nat Rev cardio.2019; tomilin V, mamenko M, zaika O, et al.2016may), provides a powerful scientific basis for tranilast to treat CIPN.
Disclosure of Invention
The invention aims to provide application of tranilast in prevention and treatment of chemotherapy-induced peripheral neuralgia, aims to solve the problems in the background technology and defines application of tranilast in prevention and treatment of chemotherapy-induced peripheral neuralgia. In order to realize the purpose, the invention adopts the technical scheme that:
application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia is provided.
The tranilast has the following planar structure:
the invention has the beneficial effects that:
1. the tranilast for blocking the TRPV2 has certain control effect on CIPN, and the old drug (tranilast) can be rapidly popularized and applied to clinic;
2. increases the clinical indications of tranilast and fills the blank that tranilast is used for preventing and treating CIPN. The tranilast specifically inhibits the TRPV2 pathway, has certain correlation and causal relationship with mitochondrial injury and epidermal nerve fiber loss, and provides a feasible way for preventing and treating the diseases.
Drawings
FIG. 1 is a graph showing the results of clinical drug tranilast as a TRPV2 pathway specific inhibitor for prevention and treatment of chemotherapy-induced peripheral neuropathic pain.
Fig. 2 is a graph showing the protection results of clinical drug tranilast as TRPV2 pathway specific inhibitor against chemotherapy-induced DRG neuronal mitochondrial loss, provided by an embodiment of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The technical solution of the present patent will be described in further detail with reference to the following embodiments.
1. Material
Tranilast (from MCE MK-341).
2. Administration and grouping
The preparation method is characterized in that the preparation method is dissolved in dimethyl sulfoxide (DMSO) for standby, and DMSO mother liquor containing tranilast is diluted into physiological saline before injection and is injected according to a certain concentration.
The mice were divided into 4 groups:
(1) Blank group (n = 10);
(2) Paclitaxel (n = 10);
(3) Low dose group (n = 10) at 5mg/kg/d;
(4) High dose group (n = 10) at 10mg/kg/d.
2, 3, and 4 groups of mice were intraperitoneally injected with 2.0mg/kg paclitaxel (cumulative dose of 8 mg/kg) on days 1, 3, 5, and 7, respectively, while tranilast was administered, and CIPN-related pain behavior peaked 14-21 days after the first administration.
3. Observation index
3.1 behavioral observations of mechanical pain
The Von Frey method is adopted to detect the mechanical pain behaviors of the mice: the VonFrey acupuncture tactile measurement kit is composed of 20 nylon fiber yarns and is mainly used for evaluating the tactile sensation of skin. It can provide 0.008g-300g of stimulating power. The thickness and extension of the nylon thread determine the amount of stimulation provided. In the experiment, the nylon wire with proper thickness is selected according to the actual situation, the skin is vertically stimulated by adjusting the proper extension length, and the stimulation force can be adjusted by adjusting the extension and replacing the nylon wire until the nylon wire is bent. When the rodent paws are subjected to a mechanical stimulus, they retract into the reflex. The tactile test can be applied to the soles of large and small mice, and the stimulation force when the mice retract to the reflex is recorded as the pain threshold value of the mice.
3.2 behavioral observations of thermal pain
Hot plate method for detecting mouse hot pain behavior: the mice are placed on a hot plate at 55.0 +/-0.5 ℃, and the feet of the mice are thermally stimulated to generate pain reaction, namely licking reaction. The time effect of the mouse licking is taken as the index of the hot pain response.
3.3 test the effect of tranilast on the number of mitochondria and mitochondrial DNA of DRG neurons in paclitaxel treated mice.
Selecting a drug-adding group mouse with excellent experimental phenotype, and detecting the influence of the tranilast on the mitochondrial quality in the DRG neuron of the mouse treated by the paclitaxel by adopting a mitochondrial fluorescent probe combined with a flow cytometry technology.
Detecting the plantar epidermal nerve fibers of the mice by an immunofluorescence staining method: anesthetizing and perfusing the mouse, taking the skin with the foot far away from the heel and near the sole protrusion, fixing, embedding, and freezing into 10-15 μm slice. After the sections were sealed, they were stained with an axon protein PGP9.5 antibody and a secondary antibody, and subcutaneous nerve fibers connected to the epidermis were observed under a confocal microscope.
Detecting the morphology and the number of mitochondria of sciatic nerve cells of mice by an electron microscope: anesthetizing and perfusing the mice, taking 5mm sciatic nerve at the middle part of thigh, fixing for 4 hours, dehydrating with ethanol and propylene oxide, and embedding with epoxy resin. And (3) manufacturing an ultrathin section with the thickness of 70nm by using an ultrathin slicer, dyeing the ultrathin section by using lead citrate and uranyl acetate, and detecting the ultrathin section under an electron microscope.
3.3 results
3.3.1 Effect on mechanical pain in mice
| Group of | Dosage/mg.kg -1 | Threshold value of mechanical pain |
| Blank control group | _ | 15.3±1.8 |
| Paclitaxel group | _ | 5.2±0.6 |
| |
5 | 8.4±0.9 |
| |
10 | 12.6±0.8 |
3.3.2 Effect on Hot pain in mice
3.3.3 Effect on mitochondrial number
| Group of | Fluorescence intensity (10) 5 ) |
| Blank control group | 2.4±0.26 |
| Paclitaxel group | 1.3±0.24 |
| Group of paclitaxel + tranilast | 2.1±0.28 |
3.3.4 Effect on mitochondrial DNA
| Group of | Relative content of mitochondrial DNA |
| Blank control group | 1.05±0.13 |
| Paclitaxel group | 0.46±0.12 |
| Group of paclitaxel + tranilast | 0.81±0.18 |
The results are shown in fig. 1, and it can be seen that the tolerance threshold for pain in mice is significantly higher during tranilast administration than the threshold affected by paclitaxel, indicating that tranilast acts to raise the pain threshold in mice during normal administration. Meanwhile, as shown in fig. 2, in the tranilast administration process, the influence of both mitochondrial number and mitochondrial DNA in mice is higher than that of paclitaxel, which indicates that in the normal administration process, tranilast plays a role in protecting mitochondria of mouse DRG neurons, i.e., tranilast blocks TRPV2 and has a certain prevention and treatment effect on CIPN.
The above embodiments are only for illustrating the invention and are not to be construed as limiting the invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention, therefore, all equivalent technical solutions also belong to the scope of the invention, and the scope of the invention is defined by the claims.
Claims (1)
1. Application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia is provided.
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| CN202211204298.9A CN115607533A (en) | 2022-09-29 | 2022-09-29 | Application of tranilast in preventing and treating chemotherapy-induced peripheral neuralgia |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101222918A (en) * | 2005-05-16 | 2008-07-16 | 安吉奥根制药控股有限公司 | Methods and compositions for the treatment of pain |
| CN101730467A (en) * | 2007-07-06 | 2010-06-09 | 努恩治疗学股份有限公司 | Treatment of neuropathic pain |
| CN108578403A (en) * | 2018-01-31 | 2018-09-28 | 南京中医药大学 | Jamaicin is used to prepare the purposes of the peripheral neuropathy drug of prevention chemotherapy induction |
| CN108938617A (en) * | 2017-05-23 | 2018-12-07 | 中国科学技术大学 | The new opplication of tranilast |
| US20220259144A1 (en) * | 2019-07-16 | 2022-08-18 | Virginia Commonwealth University | Compounds as nlrp3 inflammasome inhibitors and compositions and uses thereof |
-
2022
- 2022-09-29 CN CN202211204298.9A patent/CN115607533A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101222918A (en) * | 2005-05-16 | 2008-07-16 | 安吉奥根制药控股有限公司 | Methods and compositions for the treatment of pain |
| CN101730467A (en) * | 2007-07-06 | 2010-06-09 | 努恩治疗学股份有限公司 | Treatment of neuropathic pain |
| CN108938617A (en) * | 2017-05-23 | 2018-12-07 | 中国科学技术大学 | The new opplication of tranilast |
| CN108578403A (en) * | 2018-01-31 | 2018-09-28 | 南京中医药大学 | Jamaicin is used to prepare the purposes of the peripheral neuropathy drug of prevention chemotherapy induction |
| US20220259144A1 (en) * | 2019-07-16 | 2022-08-18 | Virginia Commonwealth University | Compounds as nlrp3 inflammasome inhibitors and compositions and uses thereof |
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