WO1998016219A1 - Medicament contenant du triptolide pour prevenir et/ou traiter les rejets de greffes aigus - Google Patents

Medicament contenant du triptolide pour prevenir et/ou traiter les rejets de greffes aigus Download PDF

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Publication number
WO1998016219A1
WO1998016219A1 PCT/CN1997/000100 CN9700100W WO9816219A1 WO 1998016219 A1 WO1998016219 A1 WO 1998016219A1 CN 9700100 W CN9700100 W CN 9700100W WO 9816219 A1 WO9816219 A1 WO 9816219A1
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WO
WIPO (PCT)
Prior art keywords
triptolide
day
rejection
group
cyclosporine
Prior art date
Application number
PCT/CN1997/000100
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English (en)
Chinese (zh)
Inventor
Leishi Li
Original Assignee
Nanjing General Hospital Of Nanjing Command Pla
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing General Hospital Of Nanjing Command Pla filed Critical Nanjing General Hospital Of Nanjing Command Pla
Publication of WO1998016219A1 publication Critical patent/WO1998016219A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins

Definitions

  • the invention relates to a medicament for treating acute graft rejection of an epoxy diterpene hydrazone compound.
  • BACKGROUND-Tripterygium wilfordii has been widely used in folk medicine for a long time, and has also been used to treat arthritis and skin diseases.
  • a large number of clinical and experimental studies since the 1970s have shown that Tripterygium wilfordii has anti-inflammatory, immunosuppressive and anti-fertility pharmacological effects.
  • triple anti-rejection drugs based on cyclosporine A, azathioprine, and corticosteroids are currently used. Ming Ming's public
  • triptolide is also known as triptolide. It is a colorless needle-like crystal with a melting point of 227 -228 ° C. It has the following structure:
  • triptolide has a significant effect on prolonging the survival time of allografts, and can be used as a drug for preventing and treating acute rejection of grafts.
  • Balb / c (H-2b) mice were used as donors, C57BL / 6 (H-2d) mice were used as recipients, and allograft skin transplantation was performed under sterile conditions.
  • Triptolide at 200 ⁇ m / kg / day has obvious anti-rejection effect, and the survival time of skin grafts is similar to that of cyclosporine A at 20 mg / kg / day (see Example 1).
  • mice Balb / c (H-2b) mice were used as donors, C57BL (H-2d) mice were used as recipients, and allogeneic mouse heterotopic heart transplantation was performed under aseptic conditions. The experiment proved that the dose was 200 m / kg / day Glaunolactone also has significant anti-rejection effects. (See Example 2).
  • Triptolide can be treated synergistically with cyclosporine A. Small doses of triptolide plus J and cyclosporine A have significant therapeutic effects. The survival time of skin and plants has been more than doubled compared to the control group (see Embodiments 1, 3).
  • triptolide can significantly reduce allogeneic
  • the medication on the day of the operation had almost no preventive effect, and the survival time of the graft prolonged accordingly with the advance of the medication time.
  • the preventive and preventive effect of the drug administration on the 14th day before the operation was significantly greater than that on the 3rd and 7th days before the operation.
  • triptolide-containing enzymes as a drug for acute rejection of grafts has obvious curative effects.
  • the anti-rejection effect of triptolide is completely different from that of cyclosporine A, because when the two drug doses When there is no obvious anti-rejection effect, the combined use can produce significant effects through the mutual synergy between the two.
  • the triptolide dosage was 200, 100, 50 ⁇ g / kg / day, CsA is 20, 10, 5 mg / kg / day.
  • the experimental results are shown in Table 1.
  • the average skin graft survival time of Balb / c mice in the control group was 9.8 ⁇ 0.4.
  • the mean survival time of the grafted skin grafts in the triptolide group was 10.6 ⁇ 0.5, 13.8 ⁇ 0.4, and 17.2 ⁇ 0.4 days from low to high.
  • the mean survival time for the CsA treatment group was 11.7 ⁇ 0.53, 13.7 ⁇ 0.5, and 20.5 ⁇ 0.5 days.
  • triptolide has an anti-acute rejection effect on grafts.
  • the dose of the drug is closely related.
  • Triptolide at 200 ⁇ g / kg / day has obvious anti-rejection effect, and the survival time of skin grafts is similar to that of CsA at 20 mg / kg / day.
  • Example 2 The effect of triptolide on the prevention and treatment of acute rejection of allogeneic heart transplantation.
  • Animals The donors were Balb / c (H-2b) mice and the recipients were C57BL / 6H-2d) mice. Allogeneic mouse heterotopic heart transplantation was performed under sterile conditions.
  • mice were divided into triptolide treatment group, cyclomycin A treatment and experimental control.
  • Table 4 Triptolide to prolong survival time of allograft heart. Group number of survival time mean survival time Day triptolide
  • Example 3 The effect of triptolide on the prevention and treatment of acute rejection of allogeneic transplantation was experimentally determined. Animals: Inbred Lou rats were used as donors, and Wistar-Fister rats were used as recipients. Allogeneic rat heterotopic kidney transplantation was performed under aseptic conditions.
  • the experimental results are shown in Tables 5, 6, and 7. Table 5. Survival rates of transplanted kidneys in rats in the triptolide treatment group. Rats in the treatment group. Time (days) Pingyu Yujian (days).
  • Pathological examination results A large number of inflammatory cell infiltration, interstitial edema, and tubular inflammation in the control group can be seen on the 7th day after kidney transplantation. Pathological changes of acute cellular differentiation reactions such as interstitial edema and tubulitis; 7 and 14 days after surgery
  • the transplanted kidney tissue had only mild inflammatory cell infiltration and no tubulitis disease
  • the transplanted kidney tissue Moderate inflammatory cell infiltration and tubulitis
  • 50 g / kg / day triptolide treatment Pathological changes in transplanted kidney tissue in the treatment group were similar to those in the control group.
  • Graft function is normal 13 59.1 56 91.8 Graft super rejection 1 4.6 0 0 Critical changes in the graft kidney 2 9.1 5 8.2 Acute graft rejection 6 27.3 0 0
  • graft function is normal 15 75 37 91.2 Critical graft change 2 10 4 9.8 Acute renal transplant rejection 3 15 0 0
  • this drug has a significant effect on prolonging the survival time of the graft. It can be used in conjunction with sporin A, or in combination with cyclosporine A, azathioprine, and corticosteroids for better efficacy.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Ce médicament prolonge notablement la survie de la greffe à une dose comprise entre 120 et 180 νg/kg/jour. Pour obtenir un meilleur effet, on peut administrer le triptolide avec de la cyclosporine A ou avec de la cyclosporine A, de l'azathioprine et un ou plusieurs corticoïdes.
PCT/CN1997/000100 1996-10-15 1997-10-10 Medicament contenant du triptolide pour prevenir et/ou traiter les rejets de greffes aigus WO1998016219A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN96117128.6 1996-10-15
CN 96117128 CN1179306A (zh) 1996-10-15 1996-10-15 含雷公藤内酯醇的防治移植物急性排异反应的药物

Publications (1)

Publication Number Publication Date
WO1998016219A1 true WO1998016219A1 (fr) 1998-04-23

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Application Number Title Priority Date Filing Date
PCT/CN1997/000100 WO1998016219A1 (fr) 1996-10-15 1997-10-10 Medicament contenant du triptolide pour prevenir et/ou traiter les rejets de greffes aigus

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CN (1) CN1179306A (fr)
WO (1) WO1998016219A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100398544C (zh) * 2002-09-18 2008-07-02 成都达远药物有限公司 高免疫抑制活性的水溶性雷公藤内酯醇衍生物及其应用
CN106890187A (zh) * 2017-02-22 2017-06-27 中山大学附属第三医院 雷公藤甲素及其修饰物在抑制b细胞产生抗体中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996008262A1 (fr) * 1994-09-15 1996-03-21 Pharmagenesis, Inc. Composition et procede d'immunotherapie

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996008262A1 (fr) * 1994-09-15 1996-03-21 Pharmagenesis, Inc. Composition et procede d'immunotherapie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
INT. J. IMMUNOPHARMAC., Vol. 14, No. 6, 1992, SI-XUN YANG et al., "Immunosuppression of Triptolide and its Effect on Skin Allograft Survival", pages 963-969. *

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CN1179306A (zh) 1998-04-22

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