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WO2004056388A1 - Methodes propres a renforcer la fonction du systeme immunitaire chez un sujet - Google Patents

Methodes propres a renforcer la fonction du systeme immunitaire chez un sujet Download PDF

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Publication number
WO2004056388A1
WO2004056388A1 PCT/US2003/041204 US0341204W WO2004056388A1 WO 2004056388 A1 WO2004056388 A1 WO 2004056388A1 US 0341204 W US0341204 W US 0341204W WO 2004056388 A1 WO2004056388 A1 WO 2004056388A1
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WO
WIPO (PCT)
Prior art keywords
subject
radiation
analogue
exposed
pal
Prior art date
Application number
PCT/US2003/041204
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English (en)
Inventor
Malcolm L. Gefter
Original Assignee
Praecis Pharmaceuticals, Inc.
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Publication date
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Priority to AU2003300351A priority Critical patent/AU2003300351A1/en
Publication of WO2004056388A1 publication Critical patent/WO2004056388A1/fr

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Classifications

    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
    • A61K35/14—Blood; Artificial blood
    • A61K35/19—Platelets; Megacaryocytes

Definitions

  • the present invention provides methods of enhancing immune system function in a subject who has been exposed to a high dose of radiation (e.g., a subject who has been exposed to about 50-150 Rads, about 150-400 Rads, about 400-600 Rads or about 600-1500 Rads of radiation).
  • a high dose of radiation e.g., a subject who has been exposed to about 50-150 Rads, about 150-400 Rads, about 400-600 Rads or about 600-1500 Rads of radiation.
  • the present invention provides a method of enhancing immune system function in a subject who has been exposed to a high dose of radiation, e.g., a subject who has been exposed to gamma rays, x-rays, beta radiation, alpha radiation, or neutron radiation.
  • the method includes administering to the subject an effective amount of a chemical castrating agent.
  • the chemical castrating agent may be an agonist of the LHRH receptor, e.g., Leuprolide, Buserelin, Cystorelin, Goserelin, Gonadorelin, Triptorelin, Nafarelin, Lutrelin, Leuprorelin, Meterelin, Histrelin, Deslorelin and Decapeptyl, or combinations or sub-combinations thereof, or an antagonist of the LHRH receptor, e.g., abarelix, antide, teverelix and cetrorelix, or combinations or sub-combinations thereof.
  • LHRH receptor e.g., Leuprolide, Buserelin, Cystorelin, Goserelin, Gonadorelin, Triptorelin, Nafarelin, Lutrelin, Leuprorelin, Meterelin, Histrelin, Deslorelin and Decapeptyl, or combinations or sub-combinations thereof.
  • the LHRH receptor antagonist is a peptide compound comprising a structure: A-B-C-D-E-F-G-H-I-J, wherein A is pyro-Glu, Ac-D-Nal , Ac- D-Qal, Ac-Sar, or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Trp, D-Pal, D-Nal, L-Nal-D- Pal(N-O), or D-Trp; D is Ser; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He; F is D-Asn or D-Gln; G is Leu or Tip; H is Lys(iPr), Gin, Met, or Arg; I is Pro; and J is Gly-NH2 or D-Ala-NH2; or a pharmaceutically acceptable salt thereof.
  • the LHRH receptor antagonist is a peptide compound comprising a structure: A-B-C-D-E-F-G-H-I-J, wherein A is pyro-Glu, Ac-D-Nal , Ac- D-Qal, Ac-Sar, or Ac-D-Pal; B is His or 4-Cl-D-Phe; C is Tip, D-Pal, D-Nal, L-Nal-D- Pal(N-O), or D-Trp; D is Ser; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He; F is D-Asn; G is Leu or Trp; H is Lys(iPr), Gin, Met, or Arg; I is Pro; and J is Gly- H2 or D-Ala-NH2; or a pharmaceutically acceptable salt thereof.
  • the LHRH receptor antagonist is a peptide compound comprising the structure Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-N-Me-Tyr-D-Asn-Leu- Lys(iPr)-Pro-D-Ala-NH2 or a pharmaceutically acceptable salt thereof.
  • the LHRH receptor antagonist is a peptide compound comprising the structure Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala- H2 or a pharmaceutically acceptable salt thereof.
  • the chemical castrating agent may be administered in a pharmaceutically acceptable formulation.
  • the pharmaceutically acceptable formulation can be a dispersion system, for example a lipid-based formulation, a liposome formulation, or a multivesicular liposome formulation.
  • the pharmaceutically acceptable formulation can also comprise a polymeric matrix, selected, for example, from synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics or selected from naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides.
  • the pharmaceutically acceptable formulation provides sustained delivery, e.g., "slow release" of the chemical castrating agent to a subject for at least one, two or three weeks, more preferably at least one, two or three months, after the pharmaceutically acceptable formulation is administered to the subject.
  • the chemical castrating agent may be administered to the subject in an amount sufficient to rejuvinate the thymus, e.g., at a dosage of about 15-300, 5-250, 15-200, 15- 150, 15-100, 50-100, 50-150, 50-200, 50-250, 50-300, 100-150, 100-200, 100-250, 100- 300, 150-200, 150-250, 150-300, 200-250, 200-300 or 250-300 ⁇ g/kg/day.
  • the methods of the invention further include administering to the subject a second treatment known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation, e.g., administration of an antiemetic (e.g., diphenhydramine or ondansetron), a blood product (e.g., platelets or red blood cells), a hematopoietic growth factor, or an antibiotic.
  • a second treatment known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation e.g., administration of an antiemetic (e.g., diphenhydramine or ondansetron), a blood product (e.g., platelets or red blood cells), a hematopoietic growth factor, or an antibiotic.
  • an antiemetic e.g., diphenhydramine or ondansetron
  • a blood product e.g., platelets or red blood cells
  • the present invention provides methods of enhancing immune system function in a subject who has been exposed to a high dose of radiation.
  • the methods include administering to a subject an effective amount of a chemical castrating agent, thereby enhancing immune system function in a subject who has been exposed to a high dose of radiation.
  • chemical castration induces thymic growth and increase production of T cells, such as lymphocytes in a subject.
  • radiation includes ionizing radiation, such as ultraviolet radiation, x-radiation and radioactivity, for example, beta, alpha or gamma emission or neutron radiation.
  • a "high dose of radiation” is a dose of radiation which is greater than that typically received in a medical procedure and is, typically, a dose that can be lethal in the absence of appropriate medical support.
  • a high dose of radiation is typically a dose greater than or equal to 25 Rads, and can be, for example 50 Rads, 75 Rads, 100 Rads, 150 Rads, 200 Rads, 250 Rads, 300 Rads, 350 Rads, 400 Rads, 450 Rads, 500 Rads, 600 Rads, 700 Rads, 800 Rads, 900 Rads or 1000 Rads. All ranges between any two of the foregoing values are also contemplated herein. Exposure to high dose radiation can occur in a variety of situations, including nuclear power plant accidents and explosion of nuclear weapons.
  • Rad is an art known term and is an acronym standing for “Radiation Absorbed Dose.” An exposure of one Rad results in the absorption of 100 ergs of energy per gram of tissue exposed.
  • immune system function is intended to include any function of the immune system, e.g., functions associated with non-specific (innate) immunity as well as functions associated with specific (adaptive) immunity.
  • the term "chemical castrating agent” is intended to include any pharmaceutical agent which is capable of reducing, e.g., significantly reducing, serum sex hormone levels in a subject, i.e., reducing the serum testosterone level of a male subject and reducing the serum estrogen level of a female subject.
  • Suitable examples of chemical castrating agents are known in the art and include agonists and antagonists of gonadotropin-releasing hormone (GnRH). These GnRH agonists and antagonists include both GnRH analogues and small molecule GnRH agonists and antagonists.
  • the chemical castrating agent is a GnRH analogue which is a GnRH agonist.
  • GnRH agonists include leuprorelin, goserelin, decapeptyl (triptorelin), buserelin, histrelin, deslorelin, meterelin, recirelin, nafarelin and those described in U.S. Patent Nos. 5,744,450; 4,128,638; 4,010,125; 4,003,884; and 4, 100,274, the contents of each of which are incorporated herein by reference.
  • the chemical castrating agent can also be a GnRH analogue which is an antagonist of GnRH.
  • Suitable GnRH antagonists include abarelix, cetrorelix, antide, teverelix and others described in U.S.
  • a preferred GnRH antagonist for use in the methods of the present invention is abarelix.
  • the chemical castrating agent can also be a small-molecule GnRH antagonist, such as those described in U.S. Patent Nos. 6,346,534; 6,288,078; 6,218,426; 6,197,975; and 5,981,550.
  • the term "subject” includes warm-blooded animals, preferably mammals, such as canine, feline, bovine, porcine, ovine or equine animals, or non- human primates.
  • the subject is more preferably a human, such as an adult or adolescent human.
  • administering includes dispensing, delivering or applying a chemical castrating agent, e.g., a chemical castrating agent in a pharmaceutical formulation, to a subject by any suitable route for delivery of the composition to the desired location in the subject, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route.
  • a chemical castrating agent e.g., a chemical castrating agent in a pharmaceutical formulation
  • the term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to enhance immune system function in a subject who has been exposed to a high dose of radiation.
  • An effective amount of a chemical castrating agent, as defined herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the chemical castrating agent to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the chemical castrating agent are outweighed by the therapeutically beneficial effects.
  • any pharmaceutical agent which is capable of reducing, e.g., significantly reducing, serum sex hormone (e.g., testosterone levels or estrogen levels) in a subject may be used in the methods of the present invention.
  • Suitable examples of chemical castrating agents are known in the art and include agonists and antagonists of gonadotropin-releasing hormone (GnRH). These GnRH agonists and antagonists include both GnRH analogues and small molecule GnRH agonists and antagonists.
  • the chemical castrating agent is a GnRH analogue which is a GnRH agonist.
  • GnRH agonists include leuprorelin, goserelin, decapeptyl (triptorelin), buserelin, histrelin, deslorelin, meterelin, recirelin, nafarelin and those described in U.S. Patent Nos. 5,744,450; 4,128,638; 4,010,125; 4,003,884; and 4, 100,274, the contents of each of which are incorporated herein by reference.
  • the chemical castrating agent can also be a GnRH analogue which is an antagonist of GnRH.
  • Suitable GnRH antagonists include abarelix, cetrorelix, antide, teverelix and others described in U.S.
  • a preferred GnRH antagonist for use in the methods of the present invention is abarelix.
  • the chemical castrating agent can also be a small-molecule GnRH antagonist, such as those described in U.S. Patent Nos. 6,346,534; 6,288,078; 6,218,426; 6,197,975; and 5,981,550.
  • GnRH antagonists for use in the methods of the invention include those described in U.S. Patent 5,843,901, the contents of which are incorporated herein by reference.
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure:
  • A-B-C-D-E-F-G-H-I-J wherein A is D-Glu, L-Glu, or an analogue thereof; B is D-His, L-His, or an analogue thereof; C is D-Trp, L-Trp, or an analogue thereof; D is D-Ser, L-Ser, or an analogue thereof; E is D-Tyr, L-Tyr, or an analogue thereof; F is D- asparagine, L-asparagine, D- glutamine, or L-glutamine; G is D-Leu, L-Leu or an analogue thereof; H is D-Arg, L- Arg, or an analogue thereof; I is D-Pro, L-Pro, or an analogue thereof; and J is D-Gly, L- Gly, or an analogue thereof; or a pharmaceutically acceptable salt thereof.
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure:
  • A-B-C-D-E-F-G-H-I wherein A is D-Glu, L-Glu, or an analogue thereof; B is D-His, L-His, or an analogue thereof; C is D-Trp, L-Trp, or an analogue thereof; D is D-Ser, L-Ser, or an analogue thereof; E is D-Tyr, L-Tyr, or an analogue thereof; F is D- asparagine, L-asparagine, D- glutamine, or L-glutamine; G is D-Leu, L-Leu or an analogue thereof; H is D-Arg, L- Arg, or an analogue thereof; and I is D-Pro, L-Pro, or an analogue thereof; or a pharmaceutically acceptable salt thereof.
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure:
  • A-B-C-D-E-F-G-H-I-J wherein A is pyro-Glu, Ac-Nal , Ac-Qal, Ac-Sar, or Ac-Pal, or an analogue thereof; B is His or 4-Cl-Phe, or an analogue thereof; C is Tip, Pal, Nal, Nal-Pal(N-O), or Tip, or an analogue thereof; D is Ser, or an analogue thereof; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is Asn or Gin; G is Leu or Trp, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; I is Pro, or an analogue thereof; and J is Gly-NH2 or Ala-NH2, or an analogue thereof
  • A-B-C-D-E-F-G-H-I-J wherein A is pyro-Glu, Ac-Nal , Ac-Qal, Ac-Sar, or Ac-Pal, or an analogue thereof; B is His or 4-Cl-Phe, or an analogue thereof; C is Tip, Pal, Nal, L-Nal-Pal(N-O), or Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is Asn; G is Leu or Tip, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; I is Pro, or an analogue thereof; and J is Gly-NH2 or Ala- H2, or an analogue thereof
  • A-B-C-D-E-F-G-H-I wherein A is pyro-Glu, Ac-Nal , Ac-Qal, Ac-Sar, or Ac-Pal, or an analogue thereof; B is His or 4-Cl-Phe, or an analogue thereof; C is Trp, Pal, Nal, Nal-Pal(N-O), or Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is Asn or Gin; G is Leu or Trp, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; and I is Pro, or an analogue thereof; or a pharmaceutically acceptable salt thereof.
  • A-B-C-D-E-F-G-H-I wherein A is pyro-Glu, Ac-Nal , Ac-Qal, Ac-Sar, or Ac-Pal, or an analogue thereof; B is His or 4-Cl-Phe, or an analogue thereof; C is Trp, Pal, Nal, L-Nal-Pal(N-O), or Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is Asn; G is Leu or Trp, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; and I is Pro, or an analogue thereof; or a pharmaceutically acceptable salt thereof.
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure: A-B-C-D-E-F-G-H-I-J wherein A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof; B is His or 4-Cl-D-Phe, or an analogue thereof; C is Trp, D-Pal, D-Nal, L-Nal- D-Pal(N-O), or D-Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N- Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is D-Asn or D-Gln; G is Leu or Tip, or an analogue thereof;
  • A-B-C-D-E-F-G-H-I-J wherein A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof; B is His or 4-Cl-D-Phe, or an analogue thereof; C is Trp, D-Pal, D-Nal, L-Nal- D-Pal(N-O), or D-Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N- Me- Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is D-Asn; G is Leu or Trp, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; I is Pro, or an analogue thereof;
  • A-B-C-D-E-F-G-H-I wherein A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof; B is His or 4-Cl-D-Phe, or an analogue thereof; C is Trp, D-Pal, D-Nal, L-Nal- D-Pal(N-O), or D-Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N- Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is D-Asn or D-Gln; G is Leu or Trp, or an analogue thereof; H is Lys(iPr), Gin, Met, or Arg, or an analogue thereof; and I is Pro, or an
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure: A-B-C-D-E-F-G-H-I wherein A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof; B is His or 4-Cl-D-Phe, or an analogue thereof; C is Trp, D-Pal, D-Nal, L-Nal- D-Pal(N-O), or D-Trp, or an analogue thereof; D is Ser, or an analogue thereof; E is N- Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or He, or an analogue thereof; F is D-Asn; G is Leu or Trp, or an analogue thereof; H is Lys(i
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure: B-C-D-E-F-G-H-I-J,
  • GnRH antagonists suitable for use in the methods of the invention include peptides comprising a structure in which the amino acid corresponding to position 6 of the naturally occurring GnRH is D-asparagine or D- glutamine
  • GnRH antagonists suitable for use in the methods of the invention include GnRH antagonists which inhibit ovulation in at least 50% of treated rats in a standard rat antiovulatory assay at a dose of 5 ⁇ g/rat and which have a low histamine-releasing activity.
  • the term "histamine-releasing activity", as used herein, refers to the tendency of a compound to release histamine when administered to a subject.
  • the histamine-releasing activity of a compound can be measured with an in vitro assay (described in more detail, infra).
  • Preferred GnRH antagonist peptides have high activity in the rat antiovulatory activity assay, but low histamine releasing activity.
  • Preferred GnRH antagonist peptides have an ED50 in the histamine release assay of at least 3 ⁇ g/ml, more preferably at least 5 ⁇ g/ml, and still more preferably at least 10 ⁇ g/ml.
  • Chemical castrating agents suitable for use in the methods of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject, such as those described in U.S. Patent Nos. 5,968,895 and 6,180,608, the contents of which are incorporated herein by reference, which allow for sustained delivery of the chemical castrating agents for a period of at least several weeks to a month or more.
  • a chemical castrating agent is/are the only active ingredient(s) formulated into the pharmaceutical composition, although in certain embodiments the chemical castrating agent may be combined with one or more other active ingredients such as a hematopoietic growth factor or an effective amount of platelets.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for parenteral administration or for administration via inhalation.
  • the carrier can be suitable for intravenous, intraperitoneal or intramuscular administration.
  • the carrier is suitable for oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • compositions of the invention typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants, hi many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • the compounds of the invention can be administered in a time release formulation, for example in a composition which includes a slow release polymer. Time release formulations are described in U.S. Patent No.
  • the chemical castrating agents can be prepared with carriers that will protect the chemical castrating agents against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
  • Sterile injectable solutions can be prepared by incorporating the chemical castrating agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and fieeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the chemical castrating agent can be formulated with one or more additional compounds that enhance the solubility of the chemical castrating agent.
  • Preferred compounds to be added to formulations to enhance the solubility of the chemical castrating agent are cyclodextrin derivatives, preferably hydroxypropyl- ⁇ -cyclodextrin.
  • cyclodextrin derivatives preferably hydroxypropyl- ⁇ -cyclodextrin.
  • inclusion in the formulation of hydroxypropyl- ⁇ -cyclodextrin at a concentration 50-200 mM may increase the aqueous solubility of the chemical castrating agent.
  • Another formulation for a chemical castrating agent comprises the detergent
  • Tween-80 polyethylene glycol (PEG) and ethanol in a saline solution.
  • PEG polyethylene glycol
  • a non-limiting example of such a preferred formulation is 0.16% Tween-80, 1.3% PEG-3000 and 2% ethanol in saline.
  • the chemical castrating agent is administered to the subject as a sustained-release formulation using a pharmaceutical composition comprising a solid ionic complex of a chemical castrating agent and a carrier macromolecule, wherein the carrier and chemical castrating agent used to form the complex are combined at a weight ratio of carrierxhemical castrating agent of for example, 0.5:1 to 0.1:1.
  • the carrier and chemical castrating agent used to form the complex are combined at a weight ratio of carrier:chemical castrating agent of 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.25:1, 0.2:1, 0.15:1, or 0.1:1.
  • the complex is not a microcapsule.
  • Ranges intermediate to the above recited values e.g., 0.8:1 to 0.4:1, 0.6:1 to 0.2:1, or 0.5:1 to 0.1:1 are also intended to be part of this invention.
  • ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • the chemical castrating agent is administered to the subject using a pharmaceutical composition comprising a solid ionic complex of a chemical castrating agent and a carrier macromolecule, wherein the chemical castrating agent content of said complex is at least 40% by weight, preferably at least 45%, 50%, 55%, 57%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% by weight.
  • Ranges intermediate to the above recited values e.g., at least about 50% to about 80%, at least about 60% to about 90%, or at least about 57% to about 80%, are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • carrier macromolecule is intended to refer to a macromolecule that can complex with a peptide to form a water-insoluble complex.
  • the macromolecule has a molecular weight of at least 5 kDa, more preferably at least 10 kDa.
  • anionic carrier macromolecule is intended to include negatively charged high molecular weight molecules, such as anionic polymers.
  • cationic carrier macromolecule is intended to include positively charged high molecular weight molecules, such as cationic polymers.
  • water-insoluble complex is intended to refer to a physically and chemically stable complex that forms upon appropriate combining of a chemical castrating agent and carrier macromolecule according to procedures described herein. This complex typically takes the form of a precipitate that is produced upon combining aqueous preparations of the chemical castrating agent and carrier macromolecule.
  • the formation of preferred water-insoluble complexes used in the methods of the invention is thought to involve (e.g., be mediated at least in part by) ionic interactions in situations where the chemical castrating agent is cationic and the carrier molecule is anionic or vice versa.
  • a water-insoluble complex of the invention may involve (e.g., be mediated at least in part by) hydrophobic interactions. Still further, formation of a water-insoluble complex of the invention may involve (e.g., be mediated at least in part by) covalent interactions. Description of the complex as being "water-insoluble” is intended to indicate that the complex does not substantially or readily dissolve in water, as indicated by its precipitation from aqueous solution. However, it should be understood that a "water-insoluble" complex of the invention may exhibit limited solubility in water either in vitro or in the aqueous physiological environment in vivo.
  • sustained delivery or “sustained release” is intended to refer to continual delivery of a chemical castrating agent in vivo over a period of time following administration, preferably at least several days, a week or several weeks and up to a month or more.
  • a formulation of the invention achieves sustained delivery for at least about 28 days, at which point the sustained release formulation can be re-administered to achieve sustained delivery for another 28 day period (which re-administration can be repeated every 28 days to achieve sustained delivery for several months to years).
  • Sustained delivery of the chemical castrating agent can be demonstrated by, for example, the continued therapeutic effect of the chemical castrating agent over time.
  • sustained delivery of the chemical castrating agent may be demonstrated by detecting the presence of the chemical castrating agent in vivo over time.
  • a complex used in the methods of the invention is prepared by combining the chemical castrating agent and the carrier macromolecule under conditions such that a water-insoluble complex of the chemical castrating agent and the carrier macromolecule forms.
  • a solution of the chemical castrating agent and a solution of the carrier macromolecule are combined until a water-insoluble complex of the chemical castrating agent and the carrier macromolecule precipitates out of solution.
  • the solutions of the chemical castrating agent and the carrier macromolecule are aqueous solutions.
  • the chemical castrating agent or the carrier molecule or both
  • the chemical castrating agent and/or carrier macromolecule can be dissolved in a water-miscible solvent, such as an alcohol (e.g., ethanol) prior to combining the two components of the complex.
  • the solution of the chemical castrating agent and the solution of the carrier macromolecule are combined and heated until a water-insoluble complex of the chemical castrating agent and the carrier macromolecule precipitates out of solution.
  • the amounts of chemical castrating agent and carrier macromolecule necessary to achieve the water-insoluble complex may vary depending upon the particular chemical castrating agent and carrier macromolecule used, the particular solvent(s) used and/or the procedure used to achieve the complex.
  • the chemical castrating agent will be in excess relative to the anionic molecule on a molar basis.
  • the chemical castrating agent also will be in excess on a weight/weight basis, as indicated above.
  • the carrier macromolecule is preferably carboxymethylcellulose
  • the chemical castrating agent is preferably abarelix.
  • the precipitate can be removed from the solution by means known in the art, such as filtration (e.g., through a 0.45 micron nylon membrane), centrifugation and the like.
  • the recovered paste then can be dried (e.g., in vacuum or in a 70 °C oven) and the solid can be milled or pulverized to a powder by means known in the art (e.g. , hammer or gore milling, or grinding in mortar and pestle).
  • the paste can be frozen and lyophilized to dryness.
  • a pharmaceutical formulation of the invention is a lyophilized solid, a liquid suspension or a semi-solid dispersion.
  • the pharmaceutical formulation used in the methods of the invention is a sterile formulation.
  • the complex can be sterilized, preferably by gamma irradiation or electron beam sterilization.
  • the water-insoluble complex can be isolated using conventional sterile techniques (e.g., using sterile starting materials and carrying out the production process aseptically).
  • the pharmaceutical formulation can be administered to the subject by any route suitable for achieving the desired therapeutic result(s), although preferred routes of administration are parenteral routes, in particular intramuscular (i.m.) injection and subcutaneous/intradermal (s.c./i.d.) injection. Alternatively, the formulation can be administered to the subject orally. Other suitable parental routes include intravenous injection, buccal administration, transdermal delivery and administration by the rectal, vaginal, intranasal or respiratory tract route. It should be noted that when a formulation that provides sustained delivery for weeks to months by the i.m or s.c./i.d.
  • the route is administered by an alternative route, there may not be sustained delivery of the agent for an equivalent length of time due to clearance of the agent by other physiological mechanisms (i.e., the dosage form may be cleared from the site of delivery such that prolonged therapeutic effects are not observed for time periods as long as those observed with i.m or s.c./i.d. injection).
  • the pharmaceutical formulation contains a therapeutically effective amount of the chemical castrating agent.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired result (as described herein).
  • a therapeutically effective amount of a chemical castrating agent may vary according to factors such as the disease state, age, and weight of the individual, and the ability of the chemical castrating agent (alone or in combination with one or more other drugs) to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the chemical castrating agent are outweighed by the therapeutically beneficial effects.
  • the dosage of the chemical castrating agent is about 10-500 mg/month, about 20-300 mg/month, or about 30-200 mg/month. In a preferred embodiment, the dosage of the chemical castrating agent is about 30-120 mg/month. Ranges intermediate to the above recited values, e.g., about 10-200 mg/month, about 30- 250 mg/month, or about 100-200 mg/month, are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. The above recited dosages may also be calculated and expressed in mg/kg/day.
  • the dosage of chemical castrating agent is about 5-500 ⁇ g/kg/day, about 10-400 ⁇ g/kg/day, or about 20-200 ⁇ g/kg/day. In a preferred embodiment, the dosage of the chemical castrating agent is about 100 ⁇ g/kg/day. It is to be noted that dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • Radioactive materials may be transported during the shipment of radioactive materials and waste.
  • the victims or patients are usually vehicle operators, pedestrians, or occupants of other vehicles who are likely to come in contact with the radioactive material involved.
  • Commercial and private aircraft accidents also may involve radioactive materials, primarily radiopharmaceuticals, carried as cargo, or radioactive instrument components.
  • Accidents involving military aircraft that carry radioactive weapons elements may also result in subjects in need of the treatments of the invention.
  • Radioactive material Another potential source of contamination and/or exposure involves the deliberate dispersal of radioactive material by, for example, terrorists. Radiation exposure may result from several different sources. X-ray exposure, similar to that obtained from a medical x-ray unit, but in larger quantity, can result from exposure to radionuclides as well as to x-ray generating equipment. The only difference between gamma rays and x-rays is their origins. X-rays originate in the electron shells of atoms, while gamma rays originate in the nucleus. Once generated, they are virtually indistinguishable and have similar biological effects. Radiation exerts a deleterious effect by the generation of free radicals in cells as well as by direct interaction and deposition of energy in cellular organelles.
  • x-ray or gamma ray energy from a source Only a portion of the x-ray or gamma ray energy from a source is deposited in a subject. The majority of x-rays or gamma rays, unless they are of unusually low energy, pass through the subject and exit without significant interaction. Because of their energy and penetrating ability, gamma or x-rays can cause damage both at the surface and within the body.
  • Beta radiation a particulate form of radiation where the energy is carried by a charged particle (an electron) may also cause damage. Because of the mass of the electron, the range of penetration is relatively small. In general, if damage is caused, it is at the surface of the body or internally from inhalation or ingestion. Typically, beta particle radiation damage is encountered when there is contamination or a particle accelerator beam was the source of exposure. Since all of the particle energy is deposited over a small area, significant local injury may occur, both externally and internally. Depending on the size of the particle itself, or more correctly, the size of the particulate matter upon which the beta particle has been adsorbed, damage may be caused to interior parts of the lungs via normal inhalation processes. In some cases, inhaled material may be released from the lungs into the upper respiratory tract where it can be either exhaled to the atmosphere or subsequently ingested.
  • inhaled material may be released from the lungs into the upper respiratory tract where it can be either exhaled to the atmosphere or subsequently ingested.
  • Alpha radiation consists of the nucleus of the helium atom. The electrons have been stripped away, and the resulting nucleus is highly charged. While it has the potential to cause significant damage, its range is very short. Whenever damage results from alpha particles, it is usually to the skin or another surface. Ingestion of radioactive materials containing alpha particles can result in significant internal organ doses. Alpha particles as well as beta particles are used in therapeutic radiology applications because of the large doses they can deliver over short ranges. For this reason, it is imperative to determine whether ingestion of, or contamination by, radioactive material has occurred. The proper development of a treatment plan is dependent upon whether or not there is ingested material.
  • Neutron radiation is a form of radiation commonly found in nuclear reactors, but it can also be found when neutron beams are improperly used or shielded in research laboratories. These heavy particles, when interacting with tissue, may create radioactive atoms in the tissue much as they form radioactive atoms within a reactor. In essence, some of the reactions that occur in a nuclear reactor could occur within the body when it is exposed to neutron irradiation. Isotopes of sodium or phosphorus may be produced in the exposed area. These isotopes may then circulate to other areas of the body where they could irradiate the entire subject.
  • the present invention provides methods of enhancing immune system function in a subject who has been exposed to a high dose of radiation, for example, as a result of any of the foregoing accidents.
  • the methods include administering to a subject an effective amount of a chemical castrating agent, thereby enhancing immune system function in a subject who has been exposed to a high dose of radiation.
  • administering includes dispensing, delivering or applying a chemical castrating agent, e.g., a chemical castrating agent in a pharmaceutical formulation (as described herein), to a subject by any suitable route for delivery of the compound to the desired location in the subject, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route.
  • a chemical castrating agent e.g., a chemical castrating agent in a pharmaceutical formulation (as described herein)
  • a therapeutically effective amount of a chemical castrating agent may range from about 0.001 to 80 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • an effective dosage may range from about 0.001 to 80 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of a chemical castrating agent can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a chemical castrating agent in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks.
  • the effective dosage of a chemical castrating agent used for treatment may increase or decrease over the course of a particular treatment.
  • the methods of the invention further include administering to a subject a therapeutically effective amount of a chemical castrating agent in combination with a second treatment, e.g., another pharmaceutically active compound, known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation.
  • a second treatment e.g., another pharmaceutically active compound, known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation.
  • a second treatment e.g., another pharmaceutically active compound, known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation.
  • a second treatment e.g., another pharmaceutically active compound, known to enhance immune system function in a subject and/or known to assist in treating a subject who has been exposed to a high dose of radiation.
  • Other pharmaceutically active compounds that may be used can be found in Harrison's Principles of
  • the chemical castrating agent and the additional pharmaceutically active compound may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • a chemical castrating agent may be administered to a subject in combination with an antiemetic (e.g., diphenhydramine or ondansetron); a blood product (e.g., platelets or red blood cells); a hematopoietic growth factor; or an antibiotic.
  • an antiemetic e.g., diphenhydramine or ondansetron
  • a blood product e.g., platelets or red blood cells
  • hematopoietic growth factor e.g., hematopoietic growth factor

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Abstract

La présente invention concerne des méthodes propres à renforcer la fonction du système immunitaire chez un sujet qui a été exposé à des fortes doses de radiations. Ces méthodes consistent à administrer audit sujet une dose efficace d'un agent chimique castrateur.
PCT/US2003/041204 2002-12-19 2003-12-19 Methodes propres a renforcer la fonction du systeme immunitaire chez un sujet WO2004056388A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022239A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Formulations pharmaceutiques utiles pour l'apport continu d'un medicament
WO2007022254A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Preparations pharmaceutiques pour la liberation prolongee de medicaments
WO2007021970A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Formes pharmaceutiques stables et methodes d'utilisation de celles-ci
WO2009033799A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US20110183021A1 (en) * 2007-08-16 2011-07-28 Daly Michael J Compositions Containing Purine Nucleosides and Manganese and Their Uses
US9234168B2 (en) 2010-04-29 2016-01-12 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Compositions containing amino acids, phosphate and manganese and their uses
US20160263196A1 (en) * 2013-11-04 2016-09-15 Sloan-Kettering Institute For Cancer Research Hematopoietic recovery from radiation injury

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843902A (en) * 1995-12-15 1998-12-01 Praecis Pharmaceuticals Incorporated Methods for treating prostate cancer with LHRH antagonists
US20030045475A1 (en) * 2001-01-26 2003-03-06 Jacobson Jill D. Prevention of diabetes and prolongation of the honeymoon phase of diabetes by administration of GnRH antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843902A (en) * 1995-12-15 1998-12-01 Praecis Pharmaceuticals Incorporated Methods for treating prostate cancer with LHRH antagonists
US20030045475A1 (en) * 2001-01-26 2003-03-06 Jacobson Jill D. Prevention of diabetes and prolongation of the honeymoon phase of diabetes by administration of GnRH antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JARRELL ET AL: "Effects of ionizing radiation and pretreatment with [D-Leu6,des-Gly10] luteinizing hormone-releasing hormone ethylamide on developing rat ovarian follicles", CANCER RESEARCH, vol. 47, 1 October 1987 (1987-10-01), pages 5005 - 5008, XP002977719 *
KAMISCHKE A. ET AL: "Gonadal protection from radiation by GnRH antagonist or recombinant human FSH: a controlled trial in a male nonhuman primate (Macaca fascicularis)", J. OF ENDOCRINOLOGY, vol. 179, 2003, pages 183 - 194, XP002977720 *
SCHALLY A.V. ET AL: "Protective effects of analogs of luteinizing hormone-releasing hormone against x-radiation-induced testicular damage in rats", PNAS, vol. 84, February 1987 (1987-02-01), pages 851 - 855, XP001157014 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022239A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Formulations pharmaceutiques utiles pour l'apport continu d'un medicament
WO2007022254A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Preparations pharmaceutiques pour la liberation prolongee de medicaments
WO2007021970A2 (fr) * 2005-08-15 2007-02-22 Praecis Pharmaceuticals, Inc. Formes pharmaceutiques stables et methodes d'utilisation de celles-ci
WO2007021970A3 (fr) * 2005-08-15 2008-10-09 Praecis Pharm Inc Formes pharmaceutiques stables et methodes d'utilisation de celles-ci
WO2007022239A3 (fr) * 2005-08-15 2008-10-16 Praecis Pharm Inc Formulations pharmaceutiques utiles pour l'apport continu d'un medicament
WO2007022254A3 (fr) * 2005-08-15 2008-10-23 Praecis Pharm Inc Preparations pharmaceutiques pour la liberation prolongee de medicaments
US20110183021A1 (en) * 2007-08-16 2011-07-28 Daly Michael J Compositions Containing Purine Nucleosides and Manganese and Their Uses
US9186406B2 (en) * 2007-08-16 2015-11-17 The Henry M. Jackson Foundation for Advancement of Military Medicine, Inc. Compositions containing nucleosides and manganese and their uses
US10342871B2 (en) 2007-08-16 2019-07-09 The Henry Jackson Foundation For The Advancement Of Military Medicine, Inc. Compositions containing nucleosides and manganese and their uses
WO2009033799A3 (fr) * 2007-09-11 2009-05-14 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009033799A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US9234168B2 (en) 2010-04-29 2016-01-12 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Compositions containing amino acids, phosphate and manganese and their uses
US9758760B2 (en) 2010-04-29 2017-09-12 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Compositions containing amino acids, phosphate and manganese and their uses
US20160263196A1 (en) * 2013-11-04 2016-09-15 Sloan-Kettering Institute For Cancer Research Hematopoietic recovery from radiation injury
EP3065827A4 (fr) * 2013-11-04 2017-05-24 Sloan-Kettering Institute for Cancer Research Récupération hématopoïétique d'une radiolésion
AU2014341910B2 (en) * 2013-11-04 2020-02-27 Sloan-Kettering Institute For Cancer Research Hematopoietic recovery from radiation injury
AU2020202828B2 (en) * 2013-11-04 2022-02-03 Sloan-Kettering Institute For Cancer Research Hematopoietic recovery from radiation injury

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