JP6537064B2 - A remedy for peripheral neuropathy-induced paresthesia - Google Patents

Description

The present invention relates to an agent for improving drug-induced peripheral neuropathic dysesthesia, in particular to iridoid which improves peripheral neuropathic dysesthesia induced by anti-cancer drug.

Cancer chemotherapy is one of the most important treatments for treating cancer patients. However, side effects such as vomiting and peripheral neuropathy that occur when the anticancer drug is administered, in addition to causing a decrease in the QOL of cancer patients, also limit the use of the anticancer drug, Treatment of cancer.

With regard to vomiting of side effects of anticancer drugs, it has become possible to control by preventive pre-administration of a serotonin 5-HT3 receptor antagonist or a tachykinin NK1 receptor antagonist.

On the other hand, with regard to peripheral nerve disorders such as numbness at the extremities of the extremities such as gloves-socks, pain, sensation of cold, hypersensitivity and muscle pain, and peripheral nerve disorders such as movement disorders, control with existing analgesics and analgesic adjuvants difficult. Since such peripheral neuropathies last several months after the end of administration of the anticancer drug, treatment and prevention of peripheral neuropathies are extremely important. However, at present there is no useful therapeutic agent.

Goshajinkigan, a Kampo medicine, is known to improve numbness and painful discomfort such as diabetic peripheral neuropathy, and it is also induced by Pactaxel, a taxane anticancer drug. It is known that Shakuyaku-kanzo-to and a glaze are useful for sensory abnormalities due to peripheral neuropathy at the end of limbs (Non-Patent Document 1).
Iridoid glycosides are found in many medicinal plants. For example, aukvin is contained in plantains, bluefinches, tochus, etc. Hepatitis B treatment (patent document 1), treatment for cranial nerve disorder Applications such as (Patent Document 2) are known.

JP 06-087740 JP 09-095445

Traditional Chinese Medicine, 34 (1), 24-25 (2010) Gauchan et al., J. Pharmacol. Sci., 109, 469-472 (2009). Andoh et al., J. Trad. Complement Med., 4, 293-297 (2014).

The present inventors succeeded in creating a mouse model of peripheral neuropathic pain induced by anticancer drugs (paclitaxel, oxaliplatin, vincristine) having different anticancer effects (Non-patent Document 2), The pain response inhibitory effect of Goshajinkigan, Hachimi-jio-maru, Rokumi-maru and Maobushi-saishinto was examined using a mouse model (Non-patent Document 3).
As a result, in single dose administration, no suppressive effect was observed for paclitaxel and vincristine-induced pain in all the traditional Chinese medicines used. On the other hand, Goshajin-ki-gan, Hachimi-jio-gan and Rokumi-maru showed inhibitory effects on oxaliplatin-induced pain response. However, Maobushi-saishinto did not show any pain suppressive effect.

The anticancer drug administration has a clear time to start its administration. Therefore, it was examined whether pain can be suppressed by repeated administration from the day after initiation of administration of the anticancer drug. As a result, repeated administration of Goshajinkigan reduced paclitaxel-induced pain responses in addition to oxaliplatin. And, the effect of Hachimi-jio-gan, which is obtained by removing cattle knee and car ancestry from Goshajinkigan, reduced the pain suppression effect despite the fact that the dosage of each component crude drug was higher than that of Goshajinkigan.

Under the above-mentioned circumstances, as a result of individually examining paclitaxel-induced pain responses for cattle knees and vehicle ancestry, it was found that carrageenum extract, which is a herbal medicine for plantain, and also vehicle anorexia extract also suppress paclitaxel-induced pain responses, Patent application was filed (Japanese Patent Application No. 2015-020819).
As a result of further search for an active ingredient, the present inventors have found that Aucubin, which is one of the ingredients contained in a vehicle, suppresses the paclitaxel-induced pain response, and completed the present invention.
The present invention will be described in detail below.

The compound to be used for the agent for improving peripheral neuropathy-induced paresthesia of the present invention is one or more compounds selected from Aucubin, analogues of Aucubin or their aglycones.

As analogues of augubin, for example, 6-epiaucubine, 2'-O-benzoyl aukbin, 10-O-foriamain toil aukbin, dehydro aukupin, 10-O-caffeoyl aukbin, 6-O- bear Royl aukin, 10-cinnamoyl aukbin, 6, 10- deoxy aucubin, 10- deoxy aucubin, 10-O- biniloyl aukubin, 6-Op- hydroxy benzoyl aukbin, 6-O- Methyl 6-epi-Akubin, 6-Epi-Akubin, 10-Acetyl-Akuvin, 3,4-Dihydro Akubin, 6'-O-glycosyl-Aukyne, 6-O-β-D-Xylopyranosyl-Aukyne, 10, 6 '-Diamino-10,6'-dideoxy aucuvine, 3,4-dihydroxybenzoyl aukbin, 6- - Echiruaukubin, like 6-O-ethyl -6-epi- aucubin.

  In the present invention, aglycone refers to a non-sugar moiety remaining after a sugar residue such as a glycosyl group in iridoid glycosides, such as alucin and alucin analogue, has been substituted with a hydrogen atom, eg, aukicon of aucuvine, aukubigenin It is.

  Preferred as the compound to be used in the present invention is aukuvine or its aglycone, and more preferred is aukuvine.

  Aucubin, an analog of Aucubin or their aglycone may be isolated or purified from plants or herbal medicines, genetically engineered ones, or chemically synthesized ones.

When used as a peripheral neuropathy-induced paresthesia-improving agent, Aucubin, Aucubin analogues or aglycones thereof may be formulated into tablets, powders, granules, capsules and the like and orally administered. Furthermore, it may be formulated into an external preparation such as a solution, an ointment, a cream, a gel, a patch, an aerosol, etc. and administered parenterally.

An oral preparation can be produced in a conventional manner by adding a binding agent, a lubricant, a disintegrant, a coloring agent, a flavoring agent and the like to tablets, powders, granules and capsules according to need. Further, if necessary, preservatives, antioxidants, stabilizers and the like can be added.

For external use, if necessary, water, lower alcohols, solubilizers, surfactants, emulsion stabilizers, gelling agents, adhesives, and other commonly used base components for obtaining a desired dosage form. Etc., and if necessary, vasodilator, adrenocortical hormone, keratolytic agent, moisturizer, bactericidal agent, antioxidant, refreshing agent, fragrance, pigment, etc. within the range where the effect of the present invention is not impaired It can be blended.
They can be used to produce according to a conventional method.

Although the dose of extract etc. varies depending on the disease, symptoms, age, therapeutic measures to be used in combination, etc., when it is administered to humans as an oral preparation, 0.1 to 100 mg / kg as extract once to several times a day It may be divided and administered. In addition, when administered to humans as external preparations, the extract is usually divided into about 0.1 mg to 1 g per adult, about 1 to 4 times a day, at or around the place where sensory abnormality occurs. It may be applied.

Aucubin, Aucubin analogues or their aglycones can improve sensory abnormalities resulting from peripheral nerve injury such as taxane anticancer agents.

FIG. 5 shows the effect of repeated intraperitoneal administration of Aucubin on paclitaxel induced mechanical allodynia. Values in the figure are mean ± standard error (n = 8). * p <0.05 vs. PTX + VH (Holm-Sidak test). VH (solvent for Aucubin) FIG. 5 shows the effect of repeated skin application of Aucubin on paclitaxel induced mechanical allodynia. The values in the figure are mean ± standard error (n = 8). * p <0.05 vs. PTX + VH (Holm-Sidak test). VH (solvent for Aucubin) FIG. 5 shows the effect of repeated intraperitoneal administration of geniposide acid on paclitaxel induced mechanical allodynia. The values in the figure are mean ± standard error (n = 6). * p <0.05 vs. PTX + VH (Holm-Sidak test). VH (solvent for Aucubin) FIG. 5 shows the effect of repeated intraperitoneal administration of catapol on paclitaxel induced mechanical allodynia. The values in the figure are mean ± standard error (n = 6). * p <0.05 vs. PTX + VH (Holm-Sidak test). VH (solvent for Aucubin)

Hereinafter, the present invention will be described by way of examples and reference examples, but the present invention is not limited thereto.
The evaluation of sensory hypersensitivity (allodynia) using von Frey filaments was used as an index of sensory abnormalities.

Example 1
<Experimental animal>
Sixteen C57 BL / 6 NCr 6 week old male mice were used.
<Reagent used and administration method>
(a) Paclitaxel (SIGMA / SLBB4755V) or solvent adjusted to 5 mg / kg was intraperitoneally administered at 0.1 mL per 10 g of mouse weight.
(b) The solvent composition of paclitaxel used what mixed 100% ethanol: CremophorEL (Fluka / 1048604): saline (Otsuka Pharmaceutical / M2J98) by 1: 1: 8.
(c) Aucubine was intraperitoneally administered at 1 mg per animal (1 mg × 8 animals × 1 group × 13 days). In addition, the solvent of Aucubine was saline, and 0.1 mL / body weight 10 g was administered.
<Classification of group>
Group A: Paclitaxel + Aucubin administration group
Group B: Paclitaxel + Aucubin solvent administration group <index of pain occurrence>
The mouse responses when pressing a 0.69 mN vFF into the hind footpad for 3 seconds are classified and counted as follows. This operation is performed six times, one for each foot three times.
0 point: No response / Move foot horizontally
1 point: lift the hind limb
2 point: shake the hind limbs / lick the hind limbs <break-in operation>
Place the mouse in the observation container for 30 minutes before conducting the experiment in order to make the mouse get used to the environment in the observation container.
The results are shown in FIG.

Example 2
<Experimental animal>
Sixteen C57 BL / 6 NCr 6 week old male mice were used.
<Reagent used and administration method>
(a) Paclitaxel (SIGMA / SLBB4755V) or solvent adjusted to 5 mg / kg was intraperitoneally administered at 0.1 mL per 10 g of mouse weight.
(b) The solvent composition of paclitaxel used what mixed 100% ethanol: CremophorEL (Fluka / 1048604): saline (Otsuka Pharmaceutical / M2J98) by 1: 1: 8.
(c) In 28 mL of 100% ethanol was dissolved 28 mg of aukubin, and 20 μL was applied per animal. Application was to the right foot (vFF stimulation described below was to both feet). Moreover, the prepared solution was wrapped in aluminum foil and stored in a light-shielded and refrigerated manner.
<Classification of group>
Group A: Paclitaxel + Aucubin application group
Group B: Paclitaxel + Aucubin solvent application group <Indicator of pain occurrence>
The mouse responses when pressing a 0.69 mN vFF into the hind footpad for 3 seconds are classified and counted as follows. Perform this operation a total of 12 times, one for each foot 6 times.
0 point: No response / Move foot horizontally
1 point: lift the hind limb
2 point: shake the hind limbs / lick the hind limbs <break-in operation>
Place the mouse in the observation container for 30 minutes before conducting the experiment in order to make the mouse get used to the environment in the observation container.
The results are shown in FIG.

Reference Example A test was carried out in the same manner as in Example 1 using geniposidic acid and catalpol instead of Aucubin. The results are shown in FIG. 3 and FIG.

The agent for improving sensory abnormalities due to peripheral neuropathy according to the drug of the present invention is useful for the prevention and treatment of sensory abnormalities such as numbness and pain due to peripheral neuropathy which is one of the side effects of anticancer agents.

Claims (1)

An agent for improving peripheral nerve disorder-induced paresthesia caused by a taxane-based anticancer agent, which comprises auguvin as an active ingredient .