WO2001089529A1 - Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation - Google Patents

Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation Download PDF

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Publication number
WO2001089529A1
WO2001089529A1 PCT/US2000/014064 US0014064W WO0189529A1 WO 2001089529 A1 WO2001089529 A1 WO 2001089529A1 US 0014064 W US0014064 W US 0014064W WO 0189529 A1 WO0189529 A1 WO 0189529A1
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Prior art keywords
topically active
active corticosteroid
versus
patient
intestinal
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PCT/US2000/014064
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English (en)
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George B. Mcdonald
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Enteron Pharmaceuticals, Inc.
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Application filed by Enteron Pharmaceuticals, Inc. filed Critical Enteron Pharmaceuticals, Inc.
Priority to CA002413883A priority Critical patent/CA2413883C/fr
Priority to PCT/US2000/014064 priority patent/WO2001089529A1/fr
Priority to AU2000250389A priority patent/AU2000250389A1/en
Publication of WO2001089529A1 publication Critical patent/WO2001089529A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention is directed to the prevention of tissue damage, such as damage to the intestine or liver caused by graft-versus-host disease following hematopoietic cell transplantation, or caused by host-versus-graft disease following intestinal or liver transplantation, by oral administration of a prophylactically effective amount of a topically active cortico steroid, such as beclomethasone dipropionate (BDP).
  • tissue damage such as damage to the intestine or liver caused by graft-versus-host disease following hematopoietic cell transplantation, or caused by host-versus-graft disease following intestinal or liver transplantation
  • a prophylactically effective amount of a topically active cortico steroid such as beclomethasone dipropionate (BDP).
  • GVHD Acute graft-versus-host disease
  • HLA human leukocyte antigen
  • Standard initial treatment for acute GVHD includes systemic immunosuppressive agents, usually high-dose prednisone at 2 mg per kg per day added to prophylactic medications such as methotrexate, cyclosporine and tacrolimus.
  • Prednisone achieves a complete and sustained remission of gastrointestinal symptoms in 50-70% of patients with GVHD.
  • Patients who fail to respond receive therapy with additional immunosuppressive regimens, such as higher-dose prednisone, anti-thymocyte globulin, and investigational anti-T-cell monoclonal antibodies or immunotoxins.
  • additional immunosuppressive regimens such as higher-dose prednisone, anti-thymocyte globulin, and investigational anti-T-cell monoclonal antibodies or immunotoxins.
  • the risks of prolonged immunosuppressive therapy are significant, especially among patients with immature marrow grafts.
  • BDP beclomethasone dipropionate
  • a drawback with the above regimen is that treatment is initiated with BDP only after presentation of symptoms of intestinal GVHD, with typical patient enrollment at a mean of 58 days post-transplant (i.e., ranging from day 21-231 after transplant).
  • the difficulty with treatment after presentation of intestinal GVHD symptoms is that significant inflammation and/or damage to the intestine has already occurred prior to initiation of therapy. Severe damage to the lining of the intestine is often fatal, as malnutrition, protein loss, and blood stream infections preclude regeneration of lining cells.
  • This study did, however, provide evidence that oral BDP therapy was safe and effective in the treatment of mild-to-moderate intestinal GVHD, taken alone or when added to prednisone.
  • HVGD host-versus-graft disease
  • organ allograft rejection A related condition to GVHD is host-versus-graft disease (HVGD), also referred to as organ allograft rejection.
  • HVGD disease may occur, for example, when a donor intestine is transplanted into a patient with a diseased intestine. In this case, cells of the patient's immune system (the host) may attack the -foreign intestinal tissue (the graft). While intestinal transplantation is not routine at the present time, such techniques will likely become more common. Thus, prophylactic medications are needed to prevent HVGD for many of the reasons noted above with regard to GVHD.
  • this invention discloses a method for preventing tissue damage, particularly of the intestinal and/or liver, caused by graft-versus-host disease (GVHD) that commonly follows hematopoietic cell transplantation, or caused by host-versus-graft disease (HVGD) or organ allograft rejection.
  • GVHD graft-versus-host disease
  • HVGD host-versus-graft disease
  • Hematopoietic cell transplantation is the generic term that encompasses bone marrow transplantation, peripheral blood stem cell transplantation, umbilical vein blood transplantation, or any other source of pleuripotent hematopoietic stem cells.
  • the method includes the oral administration of a prophylactically effective amount of a topically active corticosteroid (abbreviated herein as "TAC”) to a patient having undergone hematopoietic cell transplantation.
  • a representative TAC of this invention is beclomethasone dipropionate (BDP).
  • BDP beclomethasone dipropionate
  • the tissue damage is caused by intestinal inflammation associated with intestinal graft-versus-host disease in a patient having undergone hematopoietic cell transplantation.
  • a prophylactically effective amount of a TAC is orally administered to a patient in need thereof for a period of time following hematopoietic cell transplantation and prior to the presentation of symptoms of intestinal GVHD.
  • the tissue damage is caused by HVGD or organ allograft rejection, including (but not limited to) intestinal or liver transplantation.
  • a prophylactically effective amount of a TAC is orally administered to a patient in need thereof for a period of time following transplantation and prior to presentation of symptoms of HVGD.
  • administration is prior to symptoms of intestinal HVGD, and in the case of liver transplantation prior to signs of liver HVGD (rejection).
  • the TAC is administered orally at a dosage of 4 mg/day to 12 mg/day in a form suitable for oral administration, such as capsules, pills, coated microspheres with specific dissolution qualities, or emulsions.
  • Other agents may optionally also be included in such oral formulations.
  • this invention is directed to a method for preventing tissue damage caused by graft-versus-host disease (GVHD) which commonly follows hematopoietic cell transplantation, as well as by host-versus-graft disease (HVGD) or allograft rejection which commonly follows organ transplantation.
  • GVHD graft-versus-host disease
  • HVGD host-versus-graft disease
  • allograft rejection which commonly follows organ transplantation.
  • the term “prevent” or “prevention” means preventing, delaying and/or reducing the severity of the symptoms associated with GVHD following hematopoietic cell transplantation or HVGD following organ allograft transplantation.
  • Prevention in the context of this invention is to be distinguished from “treatment,” which occurs following the onset of the first symptom(s) of GVHD or HVGD.
  • tissue means intestinal mucosa or the small bile ducts in the liver.
  • Intestinal mucosa includes mucosa of the esophagus, stomach, small intestine and colon.
  • "Damage” to such tissue may range from mild inflammation to destruction of the mucosa of the intestine to fatal exfoliation of intestinal epithelial calls. Inflammation typically presents as fever, abdominal pain, nausea, vomiting, diarrhea, intestinal bleeding, and jaundice.
  • the method of the present invention employs oral administration of a propylactically effective amount of a topically active corticosteroid (TAC) to a patient having undergone hematopoietic cell or organ allograft transplantation.
  • TACs include, but are not limited to, beclomethasone dipropionate, alclometasone dipropionate, busedonide, 22S busesonide, 22R budesonide, beclomethasone- 17- monopropionate, clobetasol propionate, diflorasone diacetate, flunisolide, flurandrenolide, fluticasone propionate, halobetasol propionate, halcinocide, mometasone fiiroate, and triamcinalone acetonide.
  • TACs are well known to those skilled in the field of, for example, intestinal disorders, and are commercially available from any number of sources. Suitable TACs of this invention have rapid first-pass metabolism in the intestine and liver, low systemic bioavailability, high topical activity, and rapid excretion (see, e.g., Thiesen et al., Alimentary Pharmacology & Therapeutics 70:487-496, 1996) (incorporated herein by reference). In one embodiment of this invention, the TAC is beclomethasone dipropionate (BDP).
  • BDP beclomethasone dipropionate
  • BDP is a compound which is available from a number of commercial sources, such as Schering-Plough Corporation (Kenilworth, N.J.) in bulk crystalline form, and has the following structure (i.e., beclomethasone 17,21- dipropionate):
  • Patients having undergone hematopoietic cell or organ allograft transplantation are allogenic hematopoietic cell recipients who have typically received marrow-ablative chemotherapy and/or total body irradiation followed by donor hematopoietic cell infusion, or patients having undergone intestinal or liver transplantation. Such procedures have been widely disclosed, and are well known to those skilled in this field. Such patients receive a prophylactically acceptable amount of a TAC by oral administration.
  • the TAC may be formulated for oral administration by techniques well known in the formulation field, including formulation as a capsule, pill, coated microsphere with specific dissolution qualities, or emulsion.
  • Suitable capsules or pills generally contain from 1 mg to 2 mg TAC, and typically about 1 mg TAC, plus optional fillers, such as lactose, and may be coated with a variety of materials, such as cellulose acetate phthalate.
  • materials such as cellulose acetate phthalate.
  • enteric- coated capsules prepared with a coating of cellulose acetate phthalate are known to dissolve in the alkaline environment of the small bowel, thus delivering its content to the small bowl and colon.
  • Emulsions containing a TAC may also be employed for oral delivery, including optional emulsifying agents.
  • prophylactically acceptable carriers and/or diluents may be employed and are familiar to those skilled in the art.
  • Formulations in the form of pills, capsules, microspheres, granules or tablets may contain, in addition to one or more TACs, diluents, dispersing and surface active agents, binders and lubricants.
  • One skilled in the art may further formulate the TAC in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Phartnaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1990 (incorporated herein by reference).
  • a prophylactically effective amount of a TAC is administered to a patient in need thereof.
  • a prophylactically effective amount of a TAC is an amount which, when delivered orally, prevents, delays and/or reduces the severity of the symptoms associated with GVHD following hematopoietic cell transplantation, or associated with HVGD following organ allograft transplantation.
  • Such an amount may be readily determined by one skilled in the art by well known dose-response investigations, and will generally range from 4 mg day to 12 mg/day, and more typically range from 6 mg/day to 8 mg/day.
  • other active prophylactic agents may be administered in combination with the TAC, including (but not limited to) cyclosporine, methotrexate, tacrolimus and biological agents that affect T-lymphocytes.
  • TAC active prophylactic agents
  • preventative administration of a TAC begins after infusion of hematopoietic cells, but before engraftment of these cells, and continues for a period of time prior to the presentation of symptoms associated with GVHD. Once symptoms are presented by a patient, prophylactic use of a TAC would no longer be warranted, and use in the context of a treatment regimen would begin (optionally in combination with other active agents). Use of a TAC within a treatment regimen is not encompassed within the scope of this invention.
  • preventative administration of a TAC begins after organ allograft transplantation, and continues for a period of time prior to the presentation of symptoms associated with HVGD. Once symptoms are presented by a patient, prophylactic use of a TAC would no longer be warranted, and use in the context of a treatment regimen would begin (optionally in combination with other active agents).
  • TAC is orally administered such that it is topically administered to the intestinal and/or liver tissue.
  • oral administration is not intended to encompass systemic administration, such as by intravenous injection. Rather, the TAC has little (if any) systemic availability, but high topical activity on intestinal and/or liver tissue. Such limited distribution results in fewer side effects, which is a significant advantage of this invention.
  • prophylactic administration and treatment there is also a biological basis between prophylactic administration and treatment. In prophylaxis, the objective is to achieve tolerance for hematopoietic precursor cells and their progeny, or an organ allograft.
  • tolerance means a phenomenon whereby the immune system is modified to accept “foreign” cells and proteins without rejecting them.
  • Another objective in prophylaxis is to prevent the initiation of a cascade of biological events that result in tissue destruction.
  • the objectives are to suppress a wide variety of biological events that have already resulted in tissue destruction, for example, the generation of inflammatory cytokines, the recruitment of additional inflammatory cells to the site of injury, the destruction of the barrier function of the intestinal mucosa (the lining), the passage of bacteria and toxins through the damaged intestinal mucosa, the up-regulation of biologic responses to bacteria and endotoxin, and the widespread organ responses to these events (such as leaky blood vessels, increased cardiac output, decreased systemic vascular resistance, diffuse lung injury, and renal insufficiency).
  • TAC oral administration of a TAC is effective as prophylaxis because the initiating event in GVHD is the recognition of host epithelial cells that line the intestine by allogeneic donor lymphocytes, while the initiating event in HVGD is recognition of epithelial cells in the transplanted intestine by host lymphocytes.
  • TAC enterically coated capsules
  • the TAC can be delivered to all of the mucosal surface of the intestine in high doses.
  • the TAC can achieve high concentrations in the intestinal mucosa where this initiating alloimmune recognition event is taking place. It is believed that blunting the initiating event prevents the large cascade of biologic events that make up the syndromes of GVHD and HVGD.
  • the orally administered TAC is either metabolized by the epithelial cells lining the intestinal tract, or is delivered intact directly to the liver.
  • the intestine is unique in that its draining venous blood supply does not go directly back to the heart, but rather is routed through the liver via the portal circulation.
  • One important organ affected by acute GVHD and HVGD is the liver, where epithelial cells that form bile ducts are targets of donor lymphocytes.
  • oral TAC (and/or its active metabolites) will be delivered directly to the liver in sufficiently high concentration to have the same effect on donor lymphocytes within the liver as discussed above in the context of in intestinal mucosa, thereby preventing destruction of bile duct cells and thus the onset of liver GVHD post-hematopoietic cell transplantation and HVGD post-liver transplantation.
  • Example 1 A patient with an underlying disease is treated for that disease with a form of therapy that includes the intravenous infusion of hematopoietic cells from an allogeneic donor.
  • a form of therapy that includes the intravenous infusion of hematopoietic cells from an allogeneic donor.
  • the patient takes by mouth medication in the form of eight capsules of BDP per day, 1 mg per capsule, half of which are plain gelatin capsules that dissolve in acidic stomach fluid, the other half being gelatin capsules coated with a material that dissolves in the alkaline fluid of the small intestine and/or colon.
  • the BDP capsules are taken on a daily basis (eight per day) for 80 days following the infusion of the hematopoietic cells.
  • the daily dose of BDP capsules is decreased by 50% for the ensuing 7 days (i.e., four capsules per day), then by an additional 50% for the next 7 days (i.e., two capsules per day), and then discontinued.
  • Example 2 A patient with a serious intestinal disease (infarction of the intestine following disruption of blood flow) is treated for that disease with a form of therapy that includes the transplantation of intestine from another person who is not related to the patient.
  • the patient takes (by mouth) medication in the form of eight capsules of BDP per day, 1 mg per capsule, where each capsule is coated with a material that dissolves in the alkaline fluid of the transplanted intestine.
  • the BDP capsules are taken on a daily basis (8 per day) for 90 days, and then decreased by 50%, to a dose of 4 capsules per day which would be taken indefinitely to prevent host-versus-graft-disease, or rejection of the transplanted intestine.

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Abstract

La présente invention concerne un procédé de prévention de dommages tissulaires associés à une réaction du greffon contre l'hôte chez un patient ayant subi une transplantation de cellules hématopoïétiques et associés à une réaction de l'hôte contre le greffon chez un patient ayant subi une allogreffe d'organe. Ce procédé consiste à administrer à un patient, par voie orale, une quantité à efficacité prophylactique d'un corticostéroïde à action topique, tel que le dipropionate de béclométhasone, pendant une certaine période suivant la transplantation de cellules hématopoïétiques ou l'allogreffe d'organe, et avant l'apparition de symptômes associés à une réaction du greffon contre l'hôte ou à une réaction de l'hôte contre le greffon. Des tissus représentatifs de l'invention comprennent le tissu de l'intestin et du foie et des dommages tissulaires représentatifs de l'invention comprennent l'inflammation desdits tissus.
PCT/US2000/014064 2000-05-22 2000-05-22 Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation WO2001089529A1 (fr)

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Application Number Priority Date Filing Date Title
CA002413883A CA2413883C (fr) 2000-05-22 2000-05-22 Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation
PCT/US2000/014064 WO2001089529A1 (fr) 2000-05-22 2000-05-22 Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation
AU2000250389A AU2000250389A1 (en) 2000-05-22 2000-05-22 Method for preventing tissue damage associated with graft-versus-host or host-versus-graft disease following transplantation

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PCT/US2000/014064 WO2001089529A1 (fr) 2000-05-22 2000-05-22 Procede de prevention de dommages tissulaires associes a une reaction du greffon contre l'hote ou une reaction de l'hote contre le greffon qui suit une transplantation

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA ON STN, CHEMICAL ABSTRACTS SERVICE (COLUMBUS, OHIO, USA),; BAEHR ET AL.: "Oral beclomethasone diproprionate for treatment of human intestinal graft-versus-host disease" *
DATABASE CA ON STN, CHEMICAL ABSTRACTS SERVICE (COLUMBUS, OHIO, USA),; MCDONALD ET AL.: "Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial" *
GASTROENTEROLOGY,, vol. 115, no. 1, January 1998 (1998-01-01), pages 28 - 35 *
TRANSPLANTATION,, vol. 60, no. 11, November 1995 (1995-11-01), pages 1231 - 1238 *

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CA2413883C (fr) 2009-07-28
CA2413883A1 (fr) 2001-11-29
AU2000250389A1 (en) 2001-12-03

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