WO2001060389A2 - Extraits de gui - Google Patents

Extraits de gui Download PDF

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Publication number
WO2001060389A2
WO2001060389A2 PCT/CA2001/000193 CA0100193W WO0160389A2 WO 2001060389 A2 WO2001060389 A2 WO 2001060389A2 CA 0100193 W CA0100193 W CA 0100193W WO 0160389 A2 WO0160389 A2 WO 0160389A2
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WO
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Prior art keywords
extract
mistletoe
helixor
composition
plant
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Application number
PCT/CA2001/000193
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English (en)
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WO2001060389A3 (fr
Inventor
Terry Delovitch
Guillermo Arreaza
Original Assignee
The John P. Robarts Research Institute
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 The John P. Robarts Research Institute filed Critical The John P. Robarts Research Institute
Priority to AU2001237157A priority Critical patent/AU2001237157A1/en
Publication of WO2001060389A2 publication Critical patent/WO2001060389A2/fr
Publication of WO2001060389A3 publication Critical patent/WO2001060389A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to methods and compositions for preventing the development of autoimmune diseases in susceptible subjects.
  • mistletoe order of plant parasites encompasses numerous different families and species that demonstrate similar properties.
  • the mistletoes comprise a polyphyletic group of nearly 2000 species of predominantly tropical, dicotyledonous semi-parasitic plants within six families in the order Santalales. Mistletoes make up about 50% of all parasitic angiosperms, and represent the largest and most diverse group of aerial parasites.
  • the six families comprising the Santales order are Loranthaceae, Misodendraceae, Olacaceae, Piliaceae, Santalaceane and Viscaceane.
  • Mistletoe species are dependent on their host trees for water and minerals, which are drawn from tree fluids, but are capable of synthesising their own carbohydrates through photosynthesis.
  • Chemical compounds found in extracts of mistletoe plants may have been synthesised either by the host tree or by the mistletoe plant. Extracts of mistletoe plants typically contain compounds such as lectins, viscotoxins, alkaloids, flavonoids, lignins, amines, phenyl carboxyiic acids and polysaccharides (1-4).
  • Such compounds have been demonstrated to activate various different components of the immune system, including B and T cells, granulocytes, NK cells, monocytes, macrophages and other inflammatory white blood cells.
  • Extracts of mistletoe plants have been shown to have a number of biological activities in mammals, and mistletoes such as Viscum album L, the European white-berry mistletoe, have been used in a number of traditional herbal remedies (5).
  • the most active components of these extracts appear to be lectins and viscotoxins (6).
  • V. album can induce apoptosis of cultured tumour cells and of lymphocytes, specifically CD8 + cytotoxic T cells, can stimulate the immune system and can protect DNA against chemotherapy and radiation damage (7-9).
  • Mistletoe extracts have therefore been used to upregulate the human immune system. Furthermore, mistletoe extracts can also mediate release of several pro-inflammatory cytokines within humans, including IL-1 , IL-6, TNF- ⁇ and IFN- ⁇ . These pro-inflammatory effects of mistletoe extract have been utilized in the treatment of a variety of cancerous tumors in humans (3, 10, 11 ).
  • Mistletoe extracts from, for example, African mistletoe, Loranthus bequrensis, and from V. album have also been shown to have antidiabetic effects in mammals, both stimulation of insulin release and possibly insulin- independent lowering of blood glucose (12, 13).
  • Type I diabetes has an autoimmune pathogenesis with a multifactorial etiology.
  • T cell infiltration of the pancreatic islets of Langerhans and the progressive T cell-mediated destruction of insulin-producing beta cells heralds the onset of autoimmune diabetes (14, 15).
  • NOD Nonobese diabetic mice spontaneously develop a form of type 1 diabetes that shares many immunologic and pathologic features of the human disease. Diabetes occurs in these mice as a result of the interaction of genetic factors with the environment (14, 15).
  • Type I or autoimmune diabetes develops gradually in both humans and NOD mice and it is desirable to find ways of intervening during this development process to prevent progression to actual diabetes.
  • mistletoe plants are effective to prevent the development of autoimmune diseases such as autoimmune diabetes.
  • Mistletoe extracts may also be used to suppress rejection and prolong the acceptance of transplanted or engrafted tissue in a mammalian recipient.
  • the invention provides a method for preventing the development of an autoimmune disease in a susceptible mammal comprising administering to the mammal an extract of a mistletoe plant.
  • the invention provides a method for prolonging acceptance of an engrafted tissue in a mammalian recipient of a tissue transplant comprising administering to the mammalian recipient an acceptance-prolonging amount of an extract of a mistletoe plant.
  • the invention provides a pharmaceutical composition for preventing the development of an autoimmune disease in a susceptible mammal comprising an effective amount of an extract of a mistletoe plant.
  • the invention provides a pharmaceutical composition for prolonging acceptance of an engrafted tissue in a mammalian recipient of a tissue transplant comprising an effective amount of an extract of a mistletoe plant.
  • the invention provides for the use of an extract of a mistletoe plant for the preparation of a pharmaceutical composition for preventing the development of an autoimmune disease in a mammal.
  • the invention provides for the use of an extract of a mistletoe plant for the preparation of a pharmaceutical composition for prolonging the acceptance of an engrafted tissue in a mammalian recipient of a tissue transplant.
  • Figure 1 shows the effect of administration of a mistletoe extract on the development of diabetes in non-obese diabetic mice treated from age 3 weeks to 18 weeks;
  • Figure 2 shows the effect of administration of a mistletoe extract on the development of diabetes in NOD mice treated from 12 to 27 weeks of age;
  • Figure 3 shows the effect of administration of a mistletoe extract on the development of diabetes in NOD mice treated from 18 to 25 weeks of age;
  • Figure 4 shows the severity of insulitis in treated and control NOD mice.
  • the present invention provides a method for preventing the development of an autoimmune disease in a susceptible mammal comprising administering to the mammal an extract of a mistletoe plant.
  • the inventors have shown that the development of autoimmune diabetes in NOD mice can be prevented by treating the mice, before appearance of diabetes, with a mistletoe extract. This treatment was effective even when begun as late as 18 weeks of age, by which time the autoimmune process leading to diabetes in NOD mice is well under way and diabetes is imminent.
  • mistletoe extract treatment is to modulate the balance between Th1 and Th2 T cells in the treated animal or human, leading to a reduction in the process of destructive insulitis which results in the specific destruction of the insulin-producing pancreatic beta cells.
  • Example 3 shows the reduced insulitis seen after treatment of NOD mice with mistletoe extract.
  • autoimmune diseases are believed to develop by a similar mechanism to that involved in the development of autoimmune diabetes, with autoreactive T cells recognising different autoantigens characteristic of each disease.
  • Mistletoe extracts may therefore be used to prevent the development of autoimmune diseases including, but not limited to psoriasis, rheumatoid arthritis, multiple sclerosis, lupus erythematosis and glomerulonephhtis.
  • the invention also provides a method for prolonging acceptance of an engrafted tissue in a mammalian recipient of a tissue transplant comprising administering to the mammalian recipient an acceptance-prolonging amount of an extract of a mistletoe plant.
  • a tissue or organ is transplanted into a mammalian recipient, the immune system of the recipient mounts an immune response to antigens in the transplanted tissue or organ, leading to rejection of the transplanted tissue or organ. It is therefore necessary to treat the recipient with an immunosuppressive agent prior to transplantation and often continuously thereafter.
  • the invention provides a new immunosuppressive therapy in the form of a mistletoe extract to promote and prolong acceptance of a tissue or organ transplant in a mammal.
  • a “mistletoe plant” as used herein means a plant of any species of mistletoe within the order Santalales.
  • a mistletoe plant of the species V. album is preferred.
  • extract of a mistletoe plant means an aqueous extract of a mistletoe plant, either of the whole plant or of a part of the plant such as leaves or berries.
  • the extract may be made, for example, by macerating the mistletoe plant or plant parts in water or phosphate buffered saline followed by removal of solid plant material from the extract, for example by cent fugation.
  • the extract preferably contains at least one compound selected from the group consisting of a lectin, a viscotoxin, an alkaloid, a flavonoid, a lignin, an amine, a phenyl carboxylic acid or a polysaccharide.
  • Suitable mistletoe extracts for use in the methods of the invention include those previously described for cancer treatment.
  • Such mistletoe extracts may be known by different names in different parts of the world; for example V. album extracts are produced by Helixor Heilmettel GmbH, Rosenfeld, Germany and are supplied in Europe under the names Helixor M, Helixor P and Helixor A, and V. album extracts are supplied by Weleda in North America under the names Iscador or Iscar (11 ).
  • Further examples of mistletoe extracts are Plenesol and Isorel (10).
  • mistletoe extracts may be used in the methods and pharmaceutical compositions of the invention.
  • a mistletoe extract may be administered to a human patient without further formulation or may be mixed, modified or introduced into other compositions to develop pharmaceutically acceptable vehicles for delivery into human patients.
  • Mistletoe extracts may be administered orally or parenterally, either by intravenous, intraperitoneal or subcutaneous injection, or by inhalation, transdermal application or rectal administration.
  • the formulation of pharmaceutically acceptable vehicles for these various modes of administration are known to those of skill in the art and are described in standard texts on pharmaceutical formulation (16).
  • various well known tests for diagnostic markers of susceptibility to autoimmune diseases may be employed. These diagnostic tests are known to those skilled in the art.
  • first degree relatives of patients with autoimmune diabetes are already screened for susceptibility to the disease by tests which look for, for example, antibodies to insulin or to glutamic acid dehydroxylase (17, 18).
  • Subjects found to be potential victims of autoimmune diabetes by such tests may be treated by the method described herein.
  • Similar diagnostic tests are available to detect susceptibility to other autoimmune diseases, looking for diagnostic markers characteristic of those diseases, for example anti-myelin antibodies in multiple sclerosis and anti- collagen antibodies in rheumatoid arthritis. These tests may be employed to identify candidates for the treatment of the invention.
  • Subjects about to undergo a tissue or organ transplant may be treated by the method of the invention either alone or in combination with other immunosuppressive therapies.
  • the appropriate dosage of mistletoe extract administered in accordance with the methods of the invention may vary depending, for example, on the age, sex and weight of the patient.
  • the dosage and dosing regimen may have to be adjusted, depending on the response of the patient, to provide the optimum therapeutic response. Determination of an appropriate effective dosage is within the skill of the ordinary physician.
  • a mistletoe extract is administered to human subjects to prevent or decrease the recruitment of immune cells into human tissues.
  • Administration of mistletoe extract may therefore be used to prevent or treat conditions associated with abnormal or deregulated immune cell recruitment into tissue sites of human disease.
  • a mistletoe extract is administered to human subjects to prevent or decrease effects mediated by the release of cytokines within the human body.
  • cytokine refers to all human cytokines that bind extracellular receptors upon the cell surface and thereby modulate cell function, including but not limited to IL-1 , IL-4, IL-6, TNF- ⁇ and IFN- ⁇ . It is envisioned that mistletoe extracts interfere with the in vivo role of mammalian cytokines. Therefore, administration of mistletoe extract may be used to prevent or treat conditions mediated through abnormal production or release of one or more cytokines within the human body.
  • HELIXOR is available in three different types, derived from three different subspecies of Viscum album which grow on different host trees:
  • HELIXOR A from a mistletoe which grows on fir trees (abietis); HELIXOR M which grows on apple trees (genus malus) and HELIXOR P which grows on pine trees (genus pinus).
  • HELIXOR preparation is a sterile-filtered, unfermented extract of fresh Viscum album plants. It is provided as a 5% isotonic solution (50 mg of fresh plant per ml extract). Toxicological studies of HELIXOR in animals and humans have demonstrated minimal toxicity with a LD 50 in mice >500 mg/kg equivalent to about 700 times the clinical dose (Investigator brochure, HELIXOR Heilsch
  • mice Female NOD mice were treated with HELIXOR M extract at different times during the development of the inflammatory process (insulitis) that leads to islet beta cell damage and diabetes.
  • treatment was begun at 3 weeks of age, before the onset of insulitis, and was continued for 15 weeks until the mice were 18 weeks of age.
  • mice received an amount of Helixor M extract corresponding to 0.5 mg plant tissue extracted, intraperitoneally (ip) twice a week.
  • Controls received PBS.
  • Mice were screened as described in Example 1. This treatment resulted in a lower amount of protection, as 40% of the mice treated with extract were diabetic at 30 weeks of age, compared to an incidence of 80% diabetes in the vehicle- treated control group of mice (Fig. 2).
  • the experiment was repeated on a new group of mice with administration of twice the dose of extract (corresponding to 1 mg plant tissue) ip twice weekly per mouse, from age 18 weeks to 25 weeks. Mice were screened for diabetes as described in Example 1.
  • mice as old as 18 weeks of age or older at the start of treatment were protected from diabetes (Fig. 3).
  • 90% of the mice treated with the extract were non-diabetic at 44 weeks of age whereas 100% of the control group were diabetic by that time.
  • Example 3 As shown in Figure 4, the effect of the mistletoe extract in female NOD mice was to significantly lower the proportion of islets affected by invasive and destructive insulitis (from ?% to ?%). All of the mice appeared healthy at the time of euthanasia and no toxicity or abnormal histology was observed in the organs of mice treated with mistletoe extract.
  • insulitis means lymphocytic infiltrate penetrating islet capsules with reduction of insulin staining.
  • Non- invasive insulitis means peri-vascular or peri-islet lymphocytic infiltration with normal insulin staining.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Organic Chemistry (AREA)
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  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une méthode de prévention du développement d'une maladie auto-immune chez un mammifère à risque. Cette méthode consiste à administrer un extrait de gui au mammifère. L'invention concerne également une méthode permettant de prolonger l'acceptation d'un tissu greffé par l'administration d'un extrait de gui au receveur du tissu greffé.
PCT/CA2001/000193 2000-02-18 2001-02-19 Extraits de gui WO2001060389A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001237157A AU2001237157A1 (en) 2000-02-18 2001-02-19 Mistletoe extracts

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18334600P 2000-02-18 2000-02-18
US60/183,346 2000-02-18

Publications (2)

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WO2001060389A2 true WO2001060389A2 (fr) 2001-08-23
WO2001060389A3 WO2001060389A3 (fr) 2002-03-28

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6792715B2 (en) 2001-07-09 2004-09-21 University Of Copenhagen Methods and cuttings for mass propagation of plant parasites
WO2011061725A1 (fr) * 2009-11-23 2011-05-26 Aliou Mamadou Balde Composition antidiabetique contenant un extrait vegetal d'englerina lecardii
CN115025207A (zh) * 2022-06-23 2022-09-09 黑龙江中医药大学 一种用于治疗类风湿性关节炎的药物及其制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1990 MUELLER E A ET AL: "A VISCUM-ALBUM OLIGOSACCHARIDE ACTIVATING HUMAN NATURAL CYTOTOXICITY IS AN INTERFERON GAMMA INDUCER" Database accession no. PREV199191063963 XP002185844 & CANCER IMMUNOLOGY IMMUNOTHERAPY, vol. 32, no. 4, 1990, pages 221-227, ISSN: 0340-7004 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1997 JURIN M ET AL: "Viscum album L. preparation Isorel modifies the immune response in normal and in tumour-bearing mice." Database accession no. PREV199799597866 XP002185842 & ANTI-CANCER DRUGS, vol. 8, no. SUPPL. 1, 1997, pages S27-S31, ISSN: 0959-4973 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1998 WERNER M ET AL: "Stimulation of T-cell locomotion in an in vitro assay by various Viscum album L. preparations (IscadorX)." Database accession no. PREV199900125556 XP002185843 & INTERNATIONAL JOURNAL OF IMMUNOTHERAPY, vol. 14, no. 3, 1998, pages 135-142, ISSN: 0255-9625 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6792715B2 (en) 2001-07-09 2004-09-21 University Of Copenhagen Methods and cuttings for mass propagation of plant parasites
WO2011061725A1 (fr) * 2009-11-23 2011-05-26 Aliou Mamadou Balde Composition antidiabetique contenant un extrait vegetal d'englerina lecardii
FR2952824A1 (fr) * 2009-11-23 2011-05-27 Aliou Mamadou Balde Composition antidiabetique contenant un extrait vegetal d'englerina lecardii
US8703213B2 (en) 2009-11-23 2014-04-22 Aliou Mamadou Balde Anti-diabetic composition containing a plant extract of Englerina lecardii
CN115025207A (zh) * 2022-06-23 2022-09-09 黑龙江中医药大学 一种用于治疗类风湿性关节炎的药物及其制备方法

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AU2001237157A1 (en) 2001-08-27

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