WO1994028884A1 - Complexe de monoglycerolate de zinc destine a un traitement anti-rejet du corps humain ou animal - Google Patents

Complexe de monoglycerolate de zinc destine a un traitement anti-rejet du corps humain ou animal Download PDF

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Publication number
WO1994028884A1
WO1994028884A1 PCT/AU1994/000326 AU9400326W WO9428884A1 WO 1994028884 A1 WO1994028884 A1 WO 1994028884A1 AU 9400326 W AU9400326 W AU 9400326W WO 9428884 A1 WO9428884 A1 WO 9428884A1
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WIPO (PCT)
Prior art keywords
rejection
cyclosporine
zinc monoglycerolate
human
dose
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Application number
PCT/AU1994/000326
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English (en)
Inventor
Grant Edwards
Reginald Morton Taylor
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Glyzinc Pharmaceuticals Limited
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Publication date
Application filed by Glyzinc Pharmaceuticals Limited filed Critical Glyzinc Pharmaceuticals Limited
Priority to AU69664/94A priority Critical patent/AU6966494A/en
Publication of WO1994028884A1 publication Critical patent/WO1994028884A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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

  • This invention relates to a Zinc Monoglycerolate complex when used for the anti-rejection treatment of the human or animal body.
  • transplant donors are matched as much as possible with the recipient, but unless an identical twin acts as a donor then the immune system of the recipient will mount a rejection response or a graft versus host reaction may result.
  • the rejection may be almost immediate where the recipient has been sensitized to the donor organ and a hyperacute reaction takes place within a few hours; sometimes the organ does not survive the duration of the transplant operation.
  • an acute rejection reaction takes place where an immune response is mounted, which usually takes the form of an antibody response and might take between 5 and 10 days.
  • a third type of rejection is known as chronic rejection and takes the form of a gradual deterioration of the transplanted organ. Chronic rejection is thought to be associated with a humoral immune response, a different response than that of the acute reactions, and is quite uncommon.
  • immunosuppressive drugs are administered to minimize the effects of the rejection reaction, initially in high dose to establish the transplant, and then in a much smaller maintenance dose whilst the transplant is resident in the recipient. From time to time during maintenance, an acute rejection reaction might occur and larger doses may be needed to overcome the rejection.
  • Several drugs are used for immunosuppressive therapy, but they are relatively nonspecific. Their action is not directed at the cause of the disease, and they can therefore inhibit normal immune and inflammatory responses as well.
  • Agents such as Mercaptopurine, Azathioprine, Cyclophosphamide, and Methotrexate are cytotoxins and they interfere with cell replication and metabolism in various ways causing disruption of normal cell function. Interference with replication or rapidly dividing cells results in several undesirable side effects.
  • Azathioprine was introduced in the early 1960's for maintenance immunosuppression in clinical renal transplantation. Azathioprine interferes with nucleic acid synthesis in all replicating cells. It first affects the most actively dividing cells, which are the lymphocytes, to temporarily prevent rejection of the grant. It also inhibits replication of cells in bone marrow and in the gastrointestinal tract.
  • Adrenocorticosteroids such as Prednisone
  • Prednisone have anti-inflammatory as well as immunosuppressive actions.
  • Prednisone was used in high does therapy shortly after the introduction of Azathioprine.
  • Prednisone which promotes lysis of lymphocytes, was then used in lower doses in combination with Azathioprine, as it was found that the combination provided even greater immune suppression.
  • the use of the combination did not prevent the side effects or the increased incidence of secondary infection which results from the use of these agents.
  • Cyclosporine or Cyclosporin A as it is commonly known, is a unique immunosuppressant. It is a metabolite of a solid fungus which has proved to be superior to Azathioprine as an immunosuppressant in organ transplantation. It is more selective than Azathioprine because it primarily affects lymphoid cells and does not cause bone-marrow suppression. In addition, it is not directly cytotoxic. A major and very serious problem with Cyclosporine is its nephrotoxicity, and this occurs at almost the same dose as that required to achieve adequate immunosuppression. There is therefore a relatively narrow range of doses in which the medication will both prevent rejection and be tolerated by the recipient. A further disadvantage with Cyclosporine is that it is an expensive medicine.
  • Immunosuppressive treatments are sometimes used and these include administration of antibodies against T-cells, the monoclonal antibody version of which is extremely effective. However, it is so effective that it compromises the host to an extent that very minor infections can become life threatening. Radiation therapy of either the transplant, or the lymphatic system to immuno-suppress the individual, or other drugs such as Actinomycin D, (Dactinomycin), and Cyclophosphamide can also be used.
  • Zinc Monoglycerolate can also play a role in the inhibition of transplant rejection. This is significant because of the non-toxic nature of Zinc Monoglycerolate.
  • Zinc Monoglycerolate is produced by mixing zinc oxide or zinc hydroxide together with glycerol at elevated temperatures.
  • Zinc monoglycerate is also known as zinc glycerolate, or more correctly zinc(1 ,2,3-propanetriolato(2-)- O1.O2), homopolymer, stereoisomer.
  • Zinc Monoglycerolate is a white lubricous powder, the latter property being imparted but its polymeric two- dimensional structure. The compound has very little taste.
  • the formula for Zinc Monoglycerolate is (C 3 H 6 ⁇ 3 Zn) x .
  • Zinc Monoglycerolate complexes were first described in a paper in the Australian Journal of Chemistry volume 23, 1970, page 1963 and in that paper the method of forming these compounds and some of their physical properties are given.
  • Zinc Monoglycerolate is described for instance in P.C.T. International
  • Zinc Monoglycerolate is mentioned as being effective in the treatment and prevention of ammoniacal dermatitis (nappy rash), in the treatment of pruritis, especially in people confined to bed or immobility, for the alleviation of psoriasis, for the treatment and prevention of fungal or bacteriological decomposition of tissue and the resultant odours arising in such complaints as tinea pedis and for the prevention of industrial dermatitis arising from particular environments.
  • Monoglycerolate as a per oral treatment for gastric bleeding or ulceration or in a topical application as a depot for the slow release of the compound refers to diffusion through the skin for the treatment of arthritis and zinc insufficiency and includes psoriasis, and refers also to tests against various organisms including fungi.
  • Zinc Monoglycerolate has a very definite anti- inflammatory action and that this anti-inflammatory action in the rat footpad model is rather similar to that obtained by Cyclosporine (Rainsford et al, Agents and Action 1990; 31 :47-58).
  • the invention results from the finding that Zinc Monoglycerolate can play a role in the inhibition of transplant rejection.
  • the invention resides in a method of treatment of a human or animal body comprising the step of administering a pharmaceutically acceptable amount of Zinc Monoglycerolate by oral, parenteral, or topical administration for the prevention of organ or tissue rejection.
  • Zinc Monoglycerolate may be used either separately or in combination with other anti-rejection measures.
  • Zinc Monoglycerolate is relatively non-toxic, and it is anticipated that the side effects caused by the anti-rejection drugs can be minimised when Zinc Monoglycerolate is used in combination with them, because the dose of the anti-rejection drug can be decreased and the side effects accordingly minimised. This is certainly applicable with the use of Cyclosporine where the narrow choice of ranges of dose is quite limiting.
  • Zinc Monoglycerolate by itself may not be potent enough to act to regress acute rejections, however it may be sufficiently active by itself to act as a maintenance program.
  • the Zinc Monoglycerolate was made up as a 0.02% suspension in water with Tween 20 using sodium chloride 0.15 mole / Litre as the diluent, and injected within 20 minutes of it being suspended. Cyclosporin A was given by gavage.
  • mice were used, consisting of at least six (6) animals in each group.
  • Donor animals were PVG rats of either sex, approximately 250 gm.
  • Recipients were Wistar rats of either sex weighing 300 gm.
  • Group A after transplantation the recipient rats did not receive any immuno ⁇ suppressive drugs.
  • Group B the recipient rats received 4 mg/kg body weight of Cyclosporin A by gavage daily.
  • Group C - rats received 2 mg/kg of Cyclosporin A daily by gavage.
  • Group D - rats received 1 mg/kg of Cyclosporin A daily by gavage.
  • Group E - rats received Zinc Monoglycerolate 62.5 mg/kg given by subcutaneous injection once daily.
  • Group F - rats received 125 mg/kg Zinc Monoglycerolate given by subcutaneous injection once daily.
  • Group G - rats received Zinc Monoglycerolate 62.5 mg/kg body weight given by subcutaneous injection once daily, plus 2 mg/kg body weight of Cyclosporin A, given by gavage also once daily.
  • Premedication and anaesthesia were carried out as for the donor operation.
  • the anaesthetised animal was placed in the supine position and the abdomen shaved.
  • the midline laparotomy was performed.
  • a retractor was inserted and the viscera deflected to the left and covered with a moist swab.
  • the abdominal aorta and vena cava were dissected from the renal vessels to the bifurcation.
  • Bulldog clips were placed on the proximal and distal ends of the dissected vessels and the ascending aorta of the donor anastomosed end to side to the recipient's abdominal aorta, followed by anastomosis of the donor pulmonary artery, end to side, to the vena cava. 10/0 silk was used. The anastomotic time varied from 20 to 35 minutes. After placing swabs around the anastomosis the bulldog clips were removed and the donor heart began to beat. The abdominal cavity was irrigated with warm saline. This technique required the use of magnifying loops, 1 to 2 ml of saline being given as required into the abdominal vena cava via a 27 gauge needle. The abdomen was sutured with a 5-0 nylon and skin with subcutaneous 4-0 nylon. Injection of 0.5 ml of 0.25% Marcaine into the abdominal incision wound prior to closure was given to ensure excellent post-operative analgesia for up to six hours.
  • the animal was returned to a single cage and covered with a swab.
  • Results are shown in Table I. Student's t-test was used to make statistical comparisons, and the level of significance is given below the table. It is clear that the control experiments indicate that when transplantation is performed between these two well defined strains of rat, without immunosuppression, the heart arrest occurred at a mean of 6.4 days, with the standard deviation of 0.9. The same narrow deviation is also seen in the groups receiving 1 mg of Cyclosporin A per kg/body weight or 2 mg of Cyclosporin A per kg body weight, or 62.5 mg of Zinc Monoglycerolate per kg body weight, or 125 mg of Zinc Monoglycerolate per kg body weight. Thus these substances given in that dosage have no effect on the rejection rate of this model.
  • Zinc Monoglycerolate is acting by means of its known anti-inflammatory properties.
  • the mode of action derives from the concomitant inflammatory results of an acute rejection episode being diminished by Zinc Monoglycerolate and hence the heart is able to continue beating longer than the control period.
  • a non-specific anti-inflammatory action is used in the treatment of acute rejection episodes, when Methyl Prednisolone is given in high dose by injection.
  • Zinc Monoglycerolate could be altering the kinetics of Cyclosporine absorption, disposition and elimination.
  • the method of administering treatments for humans will be varied to suit acceptable standards and dose levels, and as is presently the case these doses will be tailored to suit the recipient.
  • the present example is a postulated procedure for use in humans where an admixture of Cyclosporine and Zinc Monoglycerolate is used, as part of an anti-rejection therapy.
  • the dose to be used will vary and will depend upon the individual concerned. A clinical appraisal of the patient may change the anti-rejection drug being administered where adverse effects become apparent.
  • Cyclosporine is dissolved in olive oil based solution, and for intravenous use in a polyoxyethylated castor oil and alcohol solution.
  • Cyclosporine may be given by intravenous infusion over 4 to 12 hours, at approximately one third the oral dose, for example 5mg/kg body weight daily, initially or this may be administered during surgery as a single dose injection.
  • Cyclosporine that is to be used may be reduced pehaps by as much as half of the values used above where it is used in conjunction with Zinc Monoglycerolate.
  • Zinc Monoglycerolate to be administered will need to be determined empirically, however an oral dose in the range of 50 to 500mg/kg body weight daily is suggested as an appropriate starting point for dose-ranging studies, where Zinc monoglycerolate is used in conjunction with Cyclosporine for immediate post operative treatment. This dose is understood to decrease where Zinc Monoglycerolate is used as a maintenance dose.
  • This dose is likely to be dependant on the mode by which it is delivered and it is anticipated where intravenous administration is used then a decrease in the dose given will be possible. Where perhaps better means of solubilizing Zinc monoglycerolate is achieved, lower doses may also be achieved.
  • pulses of any usually used anti-rejection drug may be administered, which pulse may be an effective dose of Methyl Prednisolone
  • Zinc Monoglycerolate has a synergistic effect in combination with Cyclosporine in the rat models described above, however, it is also to be understood that Zinc Monoglycerolate may have a synergistic effect when used together with other immunosuppressive steroid drugs such as Prednisone, Azathioprine and Methyl Prednisolone.
  • Zinc Monoglycerolate may show an immunosuppressive effect on its own in acute reaction, or perhaps might simply act to reduce the chance of a rejection action occurring.
  • the activity may be ideally suited to use for the maintenance of a transplant.
  • Zinc Monoglycerolate may supplement the activity of other anti-rejection treatments such as treatment with anti-immune anti-sera such as the OT3 or Orthoclone anti-sera which is a monoclonal antibody sometimes used during acute rejection.
  • Zinc Monoglycerolate may also be used in combination with other drugs such as Cyclophosphamide or Actinomycin D as a maintenance treatment in the first instance or as a treatment against chronic rejection in the latter case.
  • drugs such as Cyclophosphamide or Actinomycin D as a maintenance treatment in the first instance or as a treatment against chronic rejection in the latter case.
  • Zinc Monoglycerolate may also be used as an immunosuppressant for purposes other than as an anti- rejection role, for example for experimental purposes.
  • Zinc Monoglycerolate can be topical and can be applied as a dry powder or as a suspension in a suitable liquid medium and can be applied topically by an applicator (e.g. by transdermal delivery patch) where internal mobilisation in the blood is required for transport to other internal remote areas.
  • an applicator e.g. by transdermal delivery patch
  • parenteral means such as by injection in a suitable suspension or solution.
  • Oral intake in the form of a tablet, capsule or lozenge may also be suitable for some applications of the invention.

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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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On a découvert que le monoglycérolate de zinc utilisé en combinaison avec la cyclosporine améliore la capacité de doses inférieures de cyclosporine à réduire les réactions de rejet aiguës dans le modèle de c÷ur hétérotrope du rat. L'invention propose l'utilisation du monoglycérolate de zinc seul ou en combinaison avec d'autres médicaments ou mesures anti-rejet, dans la prévention d'un rejet initial et dans l'entretien d'organes et de tissus transplantés chez l'homme et chez l'animal.
PCT/AU1994/000326 1993-06-15 1994-06-15 Complexe de monoglycerolate de zinc destine a un traitement anti-rejet du corps humain ou animal WO1994028884A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69664/94A AU6966494A (en) 1993-06-15 1994-06-15 Zinc monoglycerolate complex for anti-rejection treatment of the human or animal body

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL938693 1993-06-15
AUPL9386 1993-06-15

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WO1994028884A1 true WO1994028884A1 (fr) 1994-12-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7972856B2 (en) 1997-04-24 2011-07-05 The University Of Washington Targeted gene modification by parvoviral vectors
RU2623153C2 (ru) * 2015-11-24 2017-06-22 Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук (ИОС УрО РАН) Кремнийцинкборсодержащий глицерогидрогель для местного применения, обладающий ранозаживляющей, регенерирующей, бактерицидной и противогрибковой активностью

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001867A1 (fr) * 1980-11-24 1982-06-10 Alan J Brock Compose pharmaceutique et procede
WO1987001281A1 (fr) * 1985-08-27 1987-03-12 Glyzinc Pharmaceuticals Limited Complexe de glycerolate de zinc et produits d'addition pour applications pharmaceutiques
WO1994002133A1 (fr) * 1992-07-17 1994-02-03 Glyzinc Pharmaceuticals Limited Traitement de brulures
WO1994002131A1 (fr) * 1992-07-17 1994-02-03 Glyzinc Pharmaceuticals Limited Traitement de maladies herpetiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001867A1 (fr) * 1980-11-24 1982-06-10 Alan J Brock Compose pharmaceutique et procede
WO1987001281A1 (fr) * 1985-08-27 1987-03-12 Glyzinc Pharmaceuticals Limited Complexe de glycerolate de zinc et produits d'addition pour applications pharmaceutiques
WO1994002133A1 (fr) * 1992-07-17 1994-02-03 Glyzinc Pharmaceuticals Limited Traitement de brulures
WO1994002132A1 (fr) * 1992-07-17 1994-02-03 Glyzinc Pharmaceuticals Limited Traitement de maladies de la peau
WO1994002131A1 (fr) * 1992-07-17 1994-02-03 Glyzinc Pharmaceuticals Limited Traitement de maladies herpetiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7972856B2 (en) 1997-04-24 2011-07-05 The University Of Washington Targeted gene modification by parvoviral vectors
RU2623153C2 (ru) * 2015-11-24 2017-06-22 Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук (ИОС УрО РАН) Кремнийцинкборсодержащий глицерогидрогель для местного применения, обладающий ранозаживляющей, регенерирующей, бактерицидной и противогрибковой активностью

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