WO2022174743A1 - Utilisation d'extrait de peau de lapin enflammée par le virus de la vaccine dans le traitement d'une maladie démyélinisante du système nerveux - Google Patents

Utilisation d'extrait de peau de lapin enflammée par le virus de la vaccine dans le traitement d'une maladie démyélinisante du système nerveux Download PDF

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WO2022174743A1
WO2022174743A1 PCT/CN2022/075464 CN2022075464W WO2022174743A1 WO 2022174743 A1 WO2022174743 A1 WO 2022174743A1 CN 2022075464 W CN2022075464 W CN 2022075464W WO 2022174743 A1 WO2022174743 A1 WO 2022174743A1
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nervous system
vaccinia virus
rabbit skin
disease
extract
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PCT/CN2022/075464
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English (en)
Chinese (zh)
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刘承鑫
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骏运投资有限公司
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Priority to CN202280015598.4A priority Critical patent/CN117355317A/zh
Publication of WO2022174743A1 publication Critical patent/WO2022174743A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/275—Poxviridae, e.g. avipoxvirus
    • A61K39/285—Vaccinia virus or variola virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention belongs to the field of medicine.
  • the present invention relates to novel therapeutic uses of vaccinia virus-inflamed rabbit skin extracts.
  • the present invention relates to the therapeutic use of vaccinia virus-inflamed rabbit skin extracts.
  • the present invention relates to the medicinal use of vaccinia virus-inflamed rabbit skin extracts for the treatment of demyelinating diseases of the nervous system, especially demyelinating diseases of the central nervous system.
  • the demyelinating disease of the nervous system can be multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica.
  • Nerve fibers are divided into unmyelinated nerve fibers and myelinated nerve fibers.
  • Myelinated nerve fibers such as autonomic preganglionic fibers and larger somatic nerve fibers have an outer sheath on their axons called myelin.
  • Myelin is made up of the cell membrane of myelin cells.
  • the myelinating cells of the central nervous system are oligodendritic cells.
  • the myelin sheath of peripheral nerve fibers consists of the cell membrane of Schwann cells.
  • Myelin sheath is composed of lipids and proteins, which protect the axon and insulate nerve impulses and accelerate the conduction of nerve impulses. Fibers with thick myelin sheaths also conduct faster impulses. When the myelin sheath is destroyed, conduction slows down. Nerve conduction is also affected by temperature, and an increase in body temperature during demyelination can cause conduction block.
  • Demyelinating diseases can include demyelinating diseases of the central nervous system and demyelinating diseases of the peripheral nervous system.
  • Common clinical demyelinating diseases of the central nervous system include multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, etc. It has serious impact and poses a serious threat to the physical and mental health of patients.
  • MS Multiple sclerosis
  • the most frequently involved parts of the disease are the white matter, optic nerve, spinal cord, brain stem and cerebellum.
  • the main clinical features are the scattered distribution of white matter in the central nervous system and the remission and recurrence in the course of the disease, and the spatial multiple and course of symptoms and signs. temporal multiplicity. Multiple sclerosis was included in China's "First List of Rare Diseases" in 2018.
  • ADEM Acute disseminated encephalomyelitis
  • IPMSSG International Pediatric MS Study Group
  • ADEM is an acute or subacute onset with encephalopathy (abnormal behavior or disturbance of consciousness) that affects multiple regions of the central nervous system. The first occurrence of demyelinating disease.
  • Neuromyelitis optica is an acute or subacute demyelinating disease with simultaneous or sequential involvement of the optic nerve and spinal cord.
  • the disease first described by Devic (1894), is clinically characterized by acute or subacute onset blindness in one or both eyes, preceded or followed by transverse or ascending myelitis for days or weeks, and later this disease It's called Devic's disease or Devic's syndrome.
  • Neuromyelitis optica was also included in China's "First List of Rare Diseases" in 2018.
  • Glucocorticoids have been used in the treatment of multiple sclerosis and acute disseminated encephalomyelitis.
  • Representative glucocorticoids include methylprednisolone and prednisone (see Myhr KM et al., Corticosteroids in the treatment of multiple sclerosis, Acta Neurol Scand 2009: 120 (Suppl. 189): 73-80).
  • hormonal drugs glucocorticoids can cause allergic reactions when used in large quantities in a short period of time; while long-term use of glucocorticoids has greater side effects, including muscle atrophy, obesity, hypertension, hyperlipidemia, elevated urine sugar, and osteoporosis. Therefore, there is still a need to develop other drugs instead of glucocorticoids for the treatment of central nervous system demyelinating diseases that do not produce the side effects of glucocorticoids.
  • Vaccinia virus-inflamed rabbit skin extract is an active substance extracted from the skin of rabbits inflamed by vaccinia virus.
  • This vaccinia virus-inflamed rabbit skin extract is commercially available under the trade name Lepalvir for pain treatment.
  • Vaccinia virus-inflamed rabbit skin extract has been shown to be clinically safe and does not produce the aforementioned side effects.
  • WO2020/211009 discloses the use of vaccinia virus-induced inflammatory rabbit skin extracts for the treatment of hematopoietic system damage;
  • WO 2020/248240 discloses vaccinia virus-induced inflammatory rabbit skin extracts for use in the treatment of cancer. Reference is incorporated herein.
  • EAE Experimental autoimmune encephalitis
  • TNF- ⁇ and IL-6 are important inflammatory factors in the body, which can be produced by T cells, B cells, dendritic cells, fibroblasts and smooth muscle cells, but mainly monocytes-macrophages. .
  • IL-6 as an early inflammatory acute protein, induces T cells to differentiate towards Th17 and initiates chronic tissue damage.
  • IL-6 and TNF- ⁇ act synergistically to participate in and aggravate the inflammatory response of EAE.
  • Studies have shown that at active MS lesions, the levels of a series of inflammatory cytokines are elevated, including IL-1 ⁇ , TNF- ⁇ , and IL-6 (Schonrock LM et al., Interleukin-6 expression in human multiple sclerosis lesions. Neurosci Lett.
  • Natalizumab approved for the treatment of MS, significantly reduces the levels of various inflammatory cytokines such as IL-6 and TNF- ⁇ in the cerebrospinal fluid of MS patients (J et al, Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid, Multiple Sclerosis, 2010 Feb;16(2)208-217).
  • Objects of the present invention include providing medicaments for preventing, alleviating or treating demyelinating diseases of the nervous system. More specifically, the object of the present invention includes providing a medicament for preventing, alleviating or treating multiple sclerosis or acute disseminated encephalomyelitis.
  • the technical problem of the present invention is solved by providing an extract of vaccinia virus-inflamed rabbit skin, preferably immediately.
  • vaccinia virus-inflamed rabbit skin extract can effectively prevent, treat or alleviate demyelinating diseases of the nervous system, especially central nervous system demyelinating diseases, such as multiple sclerosis or acute disseminated disease. Encephalomyelitis. Furthermore, the inventors unexpectedly found that the vaccinia virus-inflamed rabbit skin extract was more effective than the approved prednisone in treating the disease. Such an effect is surprising since prednisone therapy is already widely used in the clinical treatment of multiple sclerosis.
  • the present invention relates to the use of a vaccinia virus inflamed rabbit skin extract in the manufacture of a medicament for the prevention or treatment of demyelinating diseases of the nervous system in a patient.
  • the present invention relates to a vaccinia virus-inflamed rabbit skin extract for use in the prevention or treatment of a demyelinating disease of the nervous system in a patient.
  • the present invention relates to a method of preventing or treating a demyelinating disease of the nervous system in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a vaccinia virus inflamed rabbit skin extract.
  • the present invention relates to the use of a vaccinia virus-inflamed rabbit skin extract in the manufacture of a medicament for restoring nerve function in a patient suffering from a demyelinating disease of the nervous system.
  • the present invention relates to a vaccinia virus-inflamed rabbit skin extract for use in restoring neurological function in a patient suffering from a demyelinating disease of the nervous system.
  • the present invention relates to a method of restoring neural function in a patient suffering from a demyelinating disease of the nervous system, the method comprising administering to the patient a therapeutically effective amount of a vaccinia virus inflamed rabbit skin extract.
  • the present invention relates to the use of a vaccinia virus-inflamed rabbit skin extract in the manufacture of a medicament for alleviating or reducing inflammation or reducing the level of inflammatory cytokines in a patient suffering from a demyelinating disease of the nervous system.
  • the present invention relates to a vaccinia virus-inflamed rabbit skin extract for use in alleviating or reducing inflammation or reducing inflammatory cytokine levels in a patient suffering from a demyelinating disease of the nervous system.
  • the present invention relates to a method of alleviating or reducing inflammation or reducing the level of inflammatory cytokines in a patient suffering from a demyelinating disease of the nervous system, the method comprising extracting a therapeutically effective amount of vaccinia virus inflamed rabbit skin administered to the patient.
  • the extract can reduce the level of inflammatory cytokines in the patient's blood, spleen, lesion or cerebrospinal fluid.
  • alleviation or reduction of inflammation is achieved or achieved by reducing inflammatory cytokines, such as reducing inflammatory cytokine levels in the patient's blood, spleen, lesion or cerebrospinal fluid
  • a demyelinating disease of the nervous system may be a demyelinating disease of the nervous system that is characterized by or accompanied by elevated levels of inflammatory cytokines, such as elevated levels of IL-6 or TNF-alpha.
  • Inflammatory cytokines inflammatory cytokines and pro-inflammatory cytokines are used interchangeably and are a general term for a series of cytokines that can promote inflammation.
  • the inflammatory cytokine can be interleukin (IL) or tumor necrosis factor (TNF), such as IL-6 or TNF-alpha.
  • IL interleukin
  • TNF tumor necrosis factor
  • the treatment of a demyelinating disease of the nervous system is accomplished by alleviating or reducing inflammation in the patient. In one aspect, the treatment of demyelinating diseases of the nervous system is achieved by reducing the levels of inflammatory cytokines such as IL-6 or TNF-alpha levels.
  • the demyelinating disease of the nervous system is multiple sclerosis.
  • the demyelinating disease of the nervous system comprises demyelinating disease of the central nervous system or demyelinating disease of the peripheral nervous system, preferably demyelinating disease of the central nervous system.
  • the demyelinating disease of the nervous system comprises multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, diffuse sclerosis (Schilder disease) or concentric sclerosis (Balo disease) ), preferably multiple sclerosis or acute disseminated encephalomyelitis, more preferably multiple sclerosis.
  • the disease is multiple sclerosis.
  • the disease is acute disseminated encephalomyelitis.
  • the site of lesions in a demyelinating disease of the nervous system includes the white matter, optic nerve, spinal cord, brain stem, or cerebellum.
  • restoring nerve function includes ameliorating, alleviating, or eliminating the following symptoms: loss or abnormality of sensation, muscle weakness, blurred vision, increased reflexes, spasticity, dyskinesia, ataxia, limb tremor, dysphonia, dysphagia, nystagmus , ophthalmoplegia, optic neuritis, fatigue, diplopia, incontinence, impaired thinking or cognitive impairment.
  • the demyelinating disease of the nervous system is multiple sclerosis selected from the group consisting of clinically single syndrome (CIS), relapsing remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS) or progressive relapsing (PRMS).
  • CIS clinically single syndrome
  • RRMS relapsing remitting
  • SPMS secondary progressive
  • PPMS primary progressive
  • PRMS progressive relapsing
  • vaccinia virus inflamed rabbit skin extract can be used as the sole active ingredient for the treatment of demyelinating diseases of the nervous system.
  • the vaccinia virus inflamed rabbit skin extract can be used as the sole active ingredient in the preparation of a medicament for the treatment of, or in a patient with, a demyelinating disease of the nervous system Restore nerve function.
  • the vaccinia virus inflamed rabbit skin extract can be administered as the sole active ingredient. patient.
  • “Sole Active Ingredient” means that the Vaccinia Virus Inflammatory Rabbit Skin Extract is not to be used, administered to a patient, or prepared in combination with other drugs for the treatment of demyelinating diseases of the nervous system.
  • the other drug for treating demyelinating diseases of the nervous system may be glucocorticoid drugs, such as methylprednisolone or prednisone.
  • the use of the extract of the present invention together with glucocorticoid drugs may lead to an increase in the efficacy of glucocorticoid drugs, but this does not mean that the extract of the present invention itself will be expected to have therapeutic effects by those skilled in the art.
  • the combined use of the two drugs still cannot solve the side effects of glucocorticoid drugs themselves.
  • the inventors have surprisingly found that the single use of the vaccinia virus-inflamed rabbit skin extract can achieve better efficacy than the single use of glucocorticoid drugs, while avoiding the significant side effects of glucocorticoid drugs.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a vaccinia virus inflamed rabbit skin extract and optionally a pharmaceutically acceptable carrier, adjuvant or excipient.
  • the pharmaceutically acceptable carriers, adjuvants or excipients are those for formulating the drug into oral preparations or injections.
  • the vaccinia virus inflammatory rabbit skin extract is formulated into an oral preparation or an injection, preferably an intramuscular injection or an intravenous injection.
  • the vaccinia virus-inflamed rabbit skin extract is Lizaizhi.
  • the present invention also relates to the use of the pharmaceutical composition for treating demyelinating diseases of the nervous system, or restoring nerve function in patients suffering from demyelinating diseases of the nervous system.
  • the present invention also relates to the use of the vaccinia virus-induced inflammatory rabbit skin extract in preparing the pharmaceutical composition.
  • the vaccinia virus-inflamed rabbit skin extract is Lizaizhi.
  • the vaccinia virus-inflamed rabbit skin extract is formulated into oral preparations or injections, preferably intramuscular injections or intravenous injections.
  • the patient is a mammal, preferably a human.
  • the vaccinia virus inflamed rabbit skin extract is administered to the patient in an amount of 0.05 U/kg to 50 U/kg, preferably 0.1 U/kg to 10 U/kg, more preferably 0.5 U/kg to 5 U/kg, e.g. people.
  • the prepared medicament comprises 3U to 3000U, preferably 6U to 600U, more preferably 30U to 300U of the vaccinia virus inflamed rabbit skin extract.
  • the vaccinia virus inflamed rabbit skin extract (preferably Lizaizhi) is 0.05U/kg to 50U/kg, preferably 0.1U/kg to 10U/kg, more preferably 0.5U/kg to 5U/kg is administered to a patient, preferably a human.
  • the vaccinia virus-inflamed rabbit skin extract is administered to a patient, preferably a human, in an amount selected from: 0.05 U/kg, 0.06 U/kg, 0.07 U/kg, 0.08 U/kg, 0.09 U/kg, 0.1 U/kg U/kg, 0.2U/kg, 0.3U/kg, 0.4U/kg, 0.5U/kg, 0.6U/kg, 0.7U/kg, 0.8U/kg, 0.9U/kg, 1U/kg, 1.5U /kg, 2U/kg, 2.5U/kg, 3U/kg, 3.1U/kg, 3.2U/kg, 3.3U/kg, 3.4U/kg, 3.5U/kg, 3.6U/kg, 3.7U/kg , 3.8U/kg, 3.9U/kg, 4U/kg, 4.5U/kg, 5U/kg, 5.5U/kg, 6U/kg, 6.5U/kg, 7U/kg, 7.5U/kg, 8U/kg , ,
  • the above doses may be effective amounts to treat the above-mentioned diseases in a patient.
  • the vaccinia virus-inflamed rabbit skin extract is administered by injection, eg, intramuscularly or intravenously, at the above doses.
  • the prepared medicament or pharmaceutical composition comprises 3U to 3000U, preferably 6U to 600U, more preferably 30U to 300U of the vaccinia virus inflamed rabbit skin extract.
  • the medicament or pharmaceutical composition is for administration to a human, eg, an adult.
  • the average weight of an adult is, for example, 60 kg.
  • the amount of the vaccinia virus inflammatory rabbit skin extract contained in the medicine prepared by the present invention is, for example, 3U, 4U, 5U, 6U, 7U, 8U, 9U, 10U, 15U, 20U, 25U, 30U, 35U, 40U, 42U, 44U, 45U, 46U, 47U, 48U, 49U, 50U, 55U, 60U, 65U, 70U, 80U, 90U, 100U, 120U, 150U, 160U, 170U, 180U, 190U, 192U, 194U, 195U, 196U, 198U, 200U, 220U, 240U, 260U, 280U, 300U, 350U, 400U, 500U, 600U, 700U, 800U, 900U, 1000U, 1500U, 2000U, 2500U, 3000U and ranges bounded by these numbers.
  • the drug or pharmaceutical composition is prepared as an injection, such as an intramuscular injection or an intravenous injection.
  • the medicament or injection is an indivisible fixed dose.
  • the drug or injection cannot be divided into smaller doses within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.
  • the drug or injection is administered only once within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.
  • the vaccinia virus inflamed rabbit skin extract is administered to the patient every 6-72 hours, preferably 12-48 hours, more preferably 24-36 hours, more preferably 24 hours.
  • the dosing regimen to the patient is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks Once, once a month.
  • the extract of the present invention can be administered to a patient once a day.
  • the extract of the invention is administered to a patient for at least 24 months, at least 12 months, at least 6 months, at least 2 months, at least 1 month, at least 3 weeks, at least 2 weeks, at least 10 days, At least 7 days, at least 5 days, at least 2 days, or at least 1 day.
  • the "vaccinia virus-inflamed rabbit skin extract (extract from rabbit skin inflamed by vaccinia virus)" described herein refers to a kind of extract from the inflamed rabbit skin inoculated with vaccinia virus, such as through extraction, purification, purification and other procedures. Extracts of active substances. This extract is usually a yellow or pale yellow liquid, but can also be made into a solid by drying.
  • the injection of the vaccinia virus-inflamed rabbit skin extract is commercially available under the trade name Lepalvir.
  • the vaccinia virus-inflamed rabbit skin extract of the present invention may contain peptides. For example, it has been found that the extract may contain naturally occurring peptides (ie not additionally added peptides).
  • the peptides may be short peptides.
  • WO2013173941 describes short peptides isolated from vaccinia virus inflamed rabbit skin extracts. Therefore, in this aspect, the vaccinia virus inflamed rabbit skin extract of the present invention may not be a non-protein extract.
  • the preparation method includes extracting the inflamed rabbit skin fragments after vaccinia virus inoculation with an aqueous solution of phenol, wherein preferably the concentration of phenol is about 1%-10%, preferably about 2%-5%, more preferably about The 2% or about 3% phenol in water is carried out below about 12°C, eg, about 0-10°C, preferably about 2-8°C, more preferably about 3-6°C, more preferably about 4°C.
  • the preparation method also includes adsorbing the extract treated with the aqueous phenol solution with an adsorbent (eg, activated carbon), and performing desorption under alkaline conditions, wherein the adsorption is preferably performed under acidic conditions (eg, about pH 3-6, more preferably about pH 3-6). pH 4-5, more preferably about pH 4.5), and the basic conditions for desorption are about pH 9-12, preferably about pH 10 or pH 11.
  • an adsorbent eg, activated carbon
  • a vaccinia virus-inflamed rabbit skin extract or anisotropy can be prepared by a method comprising the steps of:
  • solution A (1) collecting the inflamed rabbit skin after inoculation with vaccinia virus, fragmenting the rabbit skin, and extracting it with an extraction solvent to obtain solution A;
  • the extract is mixed with a pharmaceutically acceptable carrier, adjuvant or excipient.
  • a rabbit is inoculated with vaccinia virus, the skin of the pox is collected, the skin is fragmented, an aqueous solution of phenol is added, and the temperature is lower than about 12°C (eg, about 0-10°C, Preferably about 2-8°C, more preferably about 3-6°C, more preferably about 4°C) for at least about 12 hours (eg about 24-90 hours, preferably about 48-72 hours, more preferably about 70 or about 72 hours) ), centrifuged to obtain supernatant, and filtered to obtain solution A.
  • the phenol concentration in the phenol aqueous solution is about 1%-10%, preferably about 2%-5%, more preferably about 2% or about 3%.
  • solution A is made acidic (eg, about pH 4-6, more preferably about pH 4.5-5.5, more preferably about pH 5) with an acid (eg, hydrochloric acid), heated (eg, at about pH 5).
  • an acid eg, hydrochloric acid
  • 90-100°C preferably about 95°C for at least about 10 minutes, such as about 20-50 minutes, preferably about 30-40 minutes
  • a lower temperature eg, to below about 50°C, preferably below about 30°C
  • the step (2) can be carried out in a nitrogen atmosphere.
  • step (3) solution B is adjusted to alkaline (eg, about pH 8-10, more preferably about pH 8.5-9.5, more preferably about pH 9 or about pH 9.5) with a base (eg, sodium hydroxide). 2), heating (for example at about 90-100°C, preferably about 95°C for at least 10 minutes, for example about 30-50 minutes, preferably about 30-40 minutes), optionally cooling (for example to below about 50°C, Preferably below about 30°C), solution C is obtained after filtration.
  • the step (3) can be carried out in a nitrogen atmosphere.
  • step (4) solution C is made acidic (eg, about pH 3-6, more preferably about pH 4-5, more preferably about pH 4.5) with an acid (eg, hydrochloric acid), and the adsorbent is added thereto (eg activated carbon) is soaked (eg, with agitation for at least about 1 hour, preferably about 2-10 hours, more preferably about 4 hours), after which the solution is removed and the adsorbent containing the active ingredient is collected.
  • an acid eg, hydrochloric acid
  • the adsorbent eg activated carbon
  • the above adsorbent is added to the eluent (eg, water), and the pH is adjusted to basic (eg, about pH 9-12, preferably about pH 10 or pH 11) with a base (eg, sodium hydroxide) to remove the active ingredient from the adsorbent.
  • a base eg, sodium hydroxide
  • Separation eg, stirring for at least about 1 hour, preferably 2-10 hours, more preferably 4 hours, followed by filtration, and washing of the adsorbent with water
  • the step (4) can be carried out in a nitrogen atmosphere.
  • step (5) solution D is neutralized to weakly acidic (eg, about pH 5.5-6.6, preferably about pH 6) with an acid (eg, hydrochloric acid) to obtain solution E.
  • acid eg, hydrochloric acid
  • the step (5) can be performed under sterile conditions.
  • step (6) solution E is concentrated (eg, concentrated under reduced pressure, preferably concentrated by evaporation under reduced pressure, eg, at about 50°C-70°C, preferably about 54°C-56°C), followed by filtration, An extract containing the active ingredient is obtained.
  • the step (6) can be carried out in a nitrogen atmosphere.
  • the extracts of the present invention can also be obtained by inoculating other animal tissues with vaccinia virus.
  • extracts of inflamed tissues inoculated with vaccinia virus can be used.
  • the tissue may be derived from mammalian tissue, which may include companion animals, laboratory animals, livestock animals, such as rabbits, cows, horses, sheep, goats, monkeys, mice, pigs.
  • the tissue can be skin.
  • mice SPF grade C57BL/6 mice, 18-22g, 250, male.
  • All the other mice were injected with 0.2 mL of Mog35-55 emulsifier antigen at 3 points on the back skin (the injection volume of MOG35-55 was 200ug/mice), and 1/3 of each site was injected. .
  • the pertussis toxin was injected intraperitoneally at 200 ng per animal.
  • Mice with a neurological function score of about 2 were randomly divided into the model control group, the prednisone acetate group, and the "Lizaishi" low, medium and high dose groups, 16 mice/group.
  • mice in each group were randomly selected for testing.
  • LZS Rabbit skin extract caused by vaccinia virus
  • Prednisone acetate injection (referred to as PA).
  • mice with a neurological function score of about 2 were screened and randomly divided into model control group, prednisone acetate group, "Lizaixi” low (10U/Kg), medium (20U/Kg), and high-dose group (40U/Kg) /Kg), 16/group.
  • MOG35-55 Dissolve 5 mg of MOG35-55 dry powder in PBS to 2.5 mL to obtain a solution with a concentration of 2 mg/mL.
  • the MOG35-55 solution was mixed with the same volume of complete Freund's immune adjuvant (1:1), and the adjuvant added Mycobacterium tuberculosis 10 mg/mL to form an emulsifier.
  • PTX was dissolved in physiological saline, and the concentration was adjusted to 2 ⁇ g/mL.
  • mice were injected with 0.2 mL of emulsifier (ie, the injection volume of MOG35-55 was 200 ug/mice).
  • 0.2 mL of the antigen formulation was injected subcutaneously at 3 points on the back of the mice, one point on the midline of the shoulder, and the other two points on both sides of the midline of the lower back. Inject 1/3 of each site.
  • 200ng/pertussis toxin was injected intraperitoneally.
  • mice with an animal neurological function score of about 2 were screened and randomly divided into model control group, prednisone acetate group, "Li Zaishi” low (10U/Kg), medium (20U/Kg) ), high dose group (40U/Kg), 16 animals/group.
  • mice were selected from each group for testing:
  • the general clinical manifestations of the animals were observed daily, and the body weights of the animals were measured once a week.
  • the neurological function score was performed once a week, and the degree of improvement was calculated.
  • the mean scores of neurological function in LZS low (10U/Kg), medium (20U/Kg), high-dose (40U/Kg) and prednisone acetate groups at 7-28 days of administration have a downward trend.
  • the functional scores of LZS middle-dose group and high-dose group were significantly decreased (P ⁇ 0.05), and the improvement degrees were 35.3% and 55.6%, respectively.
  • the functional scores of LZS middle-dose group and high-dose group were significantly decreased (P ⁇ 0.05), and the improvement degrees were 41.2% and 55.6%, respectively.
  • the functional scores of the LZS low-dose group, middle-dose group and high-dose group were significantly decreased (P ⁇ 0.05), and the improvement degrees were 38.9%, 52.9%, and 55.6%, respectively, which were better than 27.8% of the prednisone acetate group.
  • T cell subsets Th1, Th17, Treg, CD4+IL-10+T cells
  • IL-6 level The IL-6 level of mice in the model group was lower than that of the blank control group on the 23rd day of administration, and was higher than that of the blank control group on the 30th day of administration, with no statistical difference (P>0.05). After 30 days of administration, the levels of IL-6 in the positive control group and LZS low and medium dose groups were significantly decreased (P ⁇ 0.05).
  • TNF- ⁇ level The TNF- ⁇ level of the model group mice was significantly lower than that of the blank control group on the 23rd day of administration (P ⁇ 0.04), and the TNF- ⁇ level on the 30th day of administration was higher than that of the blank control group But there was no statistical difference (P>0.05). After 30 days of administration, the level of TNF- ⁇ in the LZS medium-dose group was significantly decreased (P ⁇ 0.05).

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Abstract

L'invention concerne l'utilisation d'un extrait de peau de lapin enflammée par le virus de la vaccine dans la préparation d'un médicament, plus spécifiquement, une utilisation dans la préparation d'un médicament pour le traitement d'une maladie démyélinisante d'un système nerveux. De plus, l'invention concerne une utilisation de l'extrait de peau de lapin enflammée par le virus de la vaccine pour préparer un médicament pour récupérer la fonction neurale chez des patients atteints de la maladie démyélinisante du système nerveux. La maladie démyélinisante du système nerveux peut être la sclérose en plaques, l'encéphalomyélite aiguë disséminée ou la neuromyélite optique. De plus, l'extrait de peau de lapin enflammée par le virus de la vaccine peut être le lépalvir.
PCT/CN2022/075464 2021-02-19 2022-02-08 Utilisation d'extrait de peau de lapin enflammée par le virus de la vaccine dans le traitement d'une maladie démyélinisante du système nerveux WO2022174743A1 (fr)

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CN202280015598.4A CN117355317A (zh) 2021-02-19 2022-02-08 痘苗病毒致炎兔皮提取物治疗神经系统脱髓鞘疾病的用途

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CNPCT/CN2021/076788 2021-02-19
PCT/CN2021/076788 WO2022174378A1 (fr) 2021-02-19 2021-02-19 Utilisation d'extrait de peau de lapin enflammée par le virus de la vaccine dans le traitement d'une maladie démyélinisante du système nerveux

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PCT/CN2022/075464 WO2022174743A1 (fr) 2021-02-19 2022-02-08 Utilisation d'extrait de peau de lapin enflammée par le virus de la vaccine dans le traitement d'une maladie démyélinisante du système nerveux

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