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WO1991014424A1 - Procedes de protection contre la chute des cheveux provoquee par la chimiotherapie - Google Patents

Procedes de protection contre la chute des cheveux provoquee par la chimiotherapie Download PDF

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Publication number
WO1991014424A1
WO1991014424A1 PCT/US1991/002189 US9102189W WO9114424A1 WO 1991014424 A1 WO1991014424 A1 WO 1991014424A1 US 9102189 W US9102189 W US 9102189W WO 9114424 A1 WO9114424 A1 WO 9114424A1
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Prior art keywords
response modifier
group
lipid
therapeutically effective
effective amounts
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Adel A. Yunis
Joaquin J. Jimenez
Atif M. Hussein
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • 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
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • 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
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
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    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • This invention relates generally to methods for protecting against chemotherapy-induced hair loss. More particularly, the invention relates methods for protecting against chemotherapy induced hair loss by administering to a mammalian subject therapeutically effective amounts of biologic response modifier, recombinant cytokine interleukin-1 (rIL-1) , endotoxin, Lipid A, monophosphoryl Lipid A, antioxidant(s) , or combinations thereof, either parenterally or topically.
  • the invention relates to use of biologic response modifier, recombinant cytokine IL-1, endotoxin, Lipid A, monophosphoryl Lipid A, and antioxidant(s) in the manufacture of medicament packs for use in the treatment of chemotherapy-induced hair loss.
  • chemotherapeutic agents have been used successfully in treating cancer.
  • a frequent and distressing side effect of many of these agents is partial or complete hair loss, i . e . , alopecia.
  • Alopecia not only can be a source of embarrassment and inconvenience to a patient, but in some cases can result in depression and has even caused patients to refuse potentially curative chemotherapy.
  • Another object of the invention is to provide a method for protecting against chemotherapeutic agent induced alopecia without the administration of potentially harmful chemical agents.
  • Another object of the invention is to provide medicament packs suitable for treating chemotherapeutic agent induced alopecia which will not require administration of potentially harmful chemical agents.
  • the invention discloses methods for protecting against chemotherapeutic agent induced alopecia.
  • the invention discloses a method for protecting against chemotherapeutic agent induced alopecia by administering to a mammalian subject therapeutically effective amounts of biologic response modifier that induces release of cytokine(s) , especially IL-1.
  • the invention discloses a method for protecting against chemotherapeutic agent induced alopecia by administering to a mammalian subject therapeutically effective amounts of recombinant cytokine IL-1, endotoxin, Lipid A, monophosphoryl Lipid A, alone or in combination.
  • the invention discloses a method for protecting against chemotherapeutic agent induced alopecia which comprises administering to a mammalian subject therapeutically effective amounts of biologic response modifier that induces release of cytokine(s) , in combination with therapeutically effect amounts of compound(s) selected from the group consisting of recombinant cytokine IL-1, endotoxin, Lipid A, and monophosphoryl Lipid A.
  • the invention discloses a method for protecting against alopecia caused in whole or in part by non cycle- specific chemotherapeutic agents.
  • non-toxic antioxidant is administered to a mammalian subject in combination with therapeutically effective amounts of agents selected from the group consisting of biologic response modifier that induces release of cytokine(s) , recombinant cytokine IL-l, endotoxin, Lipid A, and monophosphoryl Lipid A.
  • agents selected from the group consisting of biologic response modifier that induces release of cytokine(s) recombinant cytokine IL-l, endotoxin, Lipid A, and monophosphoryl Lipid A.
  • agents selected from the group consisting of biologic response modifier that induces release of cytokine(s) recombinant cytokine IL-l, endotoxin, Lipid A, and monophosphoryl Lipid A.
  • the disclosed combinations of biologic response modifier, recombinant IL-l, endotoxin, Lipid A, monophosphoryl Lipid A, and antioxidant(s) can be administered parenterally or topically.
  • the invention relates to use of biologic response modifier, recombinant cytokine IL-l, endotoxin, Lipid A, monophosphoryl Lipid A, and antioxidant(s) in the manufacture of medicament packs for use in protecting against chemotherapy-induced hair loss.
  • hair growth is asynchronous, that is, with constant shedding and re- growth throughout life.
  • a typical human scalp contains approximately 100,000 hairs, each hair comprising a hair bulb, containing the germinative cells, the hair root, and the hair shaft or fiber. As the germinative cells in the hair bulb proliferate, the hair is pushed from the root up through the scalp surface.
  • cytokine release inducing biologic response modifier either alone or in combination with rIL-1, endotoxin, Lipid A, monophosphoryl Lipid A, and/or antioxidant(s) can protect against chemotherapeutic agent induced alopecia.
  • CTI-BRM is capable of activating peripheral blood mononuclear cells in vitro causing the release of a number cytokines including interleukin-1 and tumor necrosis factor. See Example 8.
  • CTI-BRM is a bacterial product and a powerful activator of monocyte/macrophages.
  • CTI-BRM was protecting the hair root from the toxic action of chemotherapy, and suggested that CTI-BRM could offer protection from chemotherapy-induced hair loss in the cancer patient.
  • CTI-BRM could protect against ARA-C induced alopecia
  • studies were designed to determine whether CTI-BRM could protect against alopecia caused by other chemotherapeutic agents.
  • Such agents are broadly divided into two groups: cycle-specific drugs that damage the cell primarily during cell division, and non cycle-specific drugs that can damage resting cells.
  • ARA-C is a cycle- specific drug
  • CX cytoxan
  • an alkylating agent is a non cycle specific drug.
  • CTI-BRM protects against hair loss from cycle-specific drugs ARA-C and doxorubicin (DX) , but unfortunately not against the non cycle-specific drug cytoxan (CTX) . See Example 2.
  • Cytoxan is an alkylatying agent which exerts its cell damage by producing toxic 0 2 radicals. These radicals which cause oxidant damage, and cell death. Therefore experiments were designed to determine if antioxidant(s) would protect against cytoxan-induced hair loss. The results of these experiments are illustrated in Examples 3-5. In Examples 3, subjects were given cytoxan along with the antioxidant N- acetylcysteine (NAC) . As the results in Table 3 illustrate, cytoxan-induced alopecia can be effectively prevented by N-acetylcysteine, whether administered parenterally, or topically in liposomes.
  • NAC N- acetylcysteine
  • Example 7 As the results in Example 7 indicate, IL-l, and to a lesser degree TNF, provide protection from cycle-specific chemotherapeutic agent induced hair loss.
  • endotoxin which is a sub-component of CTI- BRM
  • Lipid A which is a sub-component of endotoxin
  • monophosphloryl Lipid A which is a non toxic form of Lipid A. See Example 9.
  • CTI-BRM is preferred as a cytokine release inducing biologic response modifier.
  • Other biologic response modifiers can be used if they induce cytokine release, which can be determined by the method of Example 8.
  • cytokine release inducing biologic response modifier used alone or in combination with the other compounds of the present invention, is useful for providing protection against chemotherapy-induced alopecia.
  • Recombinant molecules derived from human genes are identified as “Hu”, e .g. , “rHuIL-1”.
  • Recombinant molecules derived from murine genes are identified as "Mu”, e . g. , rMuTNF. Molecules are further identified by Greek letters, alpha ⁇ , beta jS, etc.
  • IL-l means interleukin 1;
  • rHuIl-1 means recombinant human type interleukin 1.
  • TNF tumor necrosis factor
  • rMuTNF ⁇ recombinant murine type tumor necrosis factor alpha
  • IG interferon gamma.
  • GM-CSF Granulocyte/Macrophage Colony Stimulating Factor.
  • chemotherapeutic agents can be broadly divided into two groups: (1) cycle-specific drugs that damage the cell primarily during cell division, and (2) non cycle-specific drugs that can damage resting cells that are not undergoing cell division.
  • Cycle-specific chemotherapeutic agents include Cytosine Arabinoside (ARA-C) (also known as Cytarabine) , Doxorubicin (DX) (also know as
  • Non cycle-specific chemotherapeutic agents include alkylating agents such as Nitrogen mustard, Melphalan, Cisplatin, Nitrosourea, DTIC, Procarbazine,
  • Cyclophosphamide also known as Cytoxan or CTX
  • Other chemotherapeutic agents that do not fit into these two broad categories include Bleomycin, Etoposide, Teneposide, Actinomycin D, etc .
  • ARA-C means the cycle- specific chemotherapeutic agent Cytosine Arabinoside.
  • DX means the cycle- specific chemotherapeutic agent Doxorubicin.
  • CX means the non cycle- specific chemotherapeutic agent cyclophosphamide, which is also known by the trade name Cytoxan.
  • NAC means the antioxidant, N-acetylcysteine (a sulfhydryl compound) .
  • non-toxic means within a level of toxicity which is tolerable by the mammalian subject receiving the compound (e . g. , antioxidant) or the biologic response modifier according to the methods of the invention.
  • substantially non-pathogenic in humans means not or rarely associated with disease in humans of normal health. Since most microorganisms are capable of causing opportunistic infections under the right circumstances, such as in persons whose immune system has been compromised, this definition excludes only those organism which typically cause non-opportunistic infections.
  • tolerable level of endotoxin, cell walls, and cell membrane fragments means that any such fractions, if present, have a low enough level of biologic activity to maintain a non-toxic characteristic as defined herein.
  • natural membrane vesicles means membrane vesicles prepared from membranes which are derived from living or dead natural cells.
  • BRM means biologic response modifier.
  • CTI-BRM means the biological response modifier described in United States Patent 4,971,801 and PCT/US87/01397.
  • ImuVert ® is the registered (United States Patent and Trademark Office) trademark of Cell Technology, Inc., Boulder, Colorado, USA, and indicates the source of a biologic response modifier comprised of a natural membrane vesicle - ribosome preparation derived from the bacterium Serratia marcescens by a series of lytic and separation techniques. ImuVert ® is the most preferred of the CTI-BRMs disclosed and claimed in United States Patent 4,971,801 and PCT/US87/01397.
  • cytokine release inducing biologic response modifier means a biologic response modifier that can induce or stimulate release of cytokines from human cells (e .g. , peripheral blood mononuclear cells) in vitro or in vivo .
  • human cells e .g. , peripheral blood mononuclear cells
  • protecting against chemotherapeutic agent induced alopecia in a mammalian subject means no detectable alopecia or less severe alopecia as a result of treatment according to the methods of the present invention.
  • treatment means administration of therapeutically effective amounts of biologic response modifier, recombinant IL-l. endotoxin, Lipid A, monophosphoryl Lipid A, and antioxidant, etc, wherein therapeutically effect amounts are those non-toxic amounts that result in no alopecia or a lessening of chemotherapy agent induced hair loss.
  • Example 1 This example demonstrates that parenteral administration of CTI-BRM provides protection from cytosine arabinoside (ARA-C) (a cycle-specific drug) induced alopecia in leukemic and normal subjects.
  • ARA-C cytosine arabinoside
  • a total of 84 eight day old rats were randomly divided into four groups. Each rat received 10 5 MIA C51 leukemia cells intraperitoneally (IP) . Six hours after cell transfer, the rats received the following once-daily IP injections for 7 days: Group I (21 rats), control group, 0.1 ml buffer; Group II (23 rats) , ARA-C 20 mg/kg; Group III (20 rats) , CTI-BRM 25 ⁇ g; and Group IV (20 rats) , ARA-C 20 mg/kg plus CTI-BRM 25 ⁇ g.
  • IP intraperitoneally
  • Hair loss was graded as described in Hussein, et al .. Science 249:1564-1566 (1990). 0, No detectable alopecia; 1+, Mild alopecia defined as less than 50% hair loss; 2+, Moderately severe alopecia with more than 50% hair loss; 3+, Total or virtually total absence of hair.
  • Example 2 This example demonstrates that parenteral administration of CTI-BRM provides protection from alopecia induced by doxorubicin (DX) (a cycle-specific drug) , but not cytoxan (CTX) (a non cycle-specific drug) .
  • DX doxorubicin
  • CX cytoxan
  • doxorubicin (a cycle- specific chemotherapeutic agent) and cytoxan (CTX) (a non cycle-specific chemotherapeutic agent) were also examined.
  • DX doxorubicin
  • CX cytoxan
  • Group I control buffer; Group II, DX 2 mg/kg; Group III, CTI-BRM 25 ⁇ g; Group IV, DX 2 mg/kg + CTI-BRM 25 ⁇ g. All rats receiving DX alone (Group II) had complete alopecia over the head and proximal part of the neck. None of the animals given CTI-BRM (Group IV) had alopecia.
  • mice were treated with a single dose of CTX (25 ⁇ g/kg IP) without or with CTI-BRM (25 ⁇ g/day IP for 7 days) .
  • Group I control, buffer;
  • Group II CTX 25 ⁇ g/kg;
  • Group III CTI-BRM 25 ⁇ g;
  • Group IV CTX 25 ⁇ g/kg + CTI-BRM 25 ⁇ g.
  • cytoxan-induced alopecia can be effectively prevented by N- acetylcysteine, administered parenterally or applied topically in liposomes.
  • alkylating agents such as cytoxan (CTX) exert their cell damage by producing toxic 0 2 radicals which attack the cell's vital structure leading to its death (oxidant damage) . Therefore, experiments were run to see whether an antioxidant (N-acetylcysteine, also known as NAC) would protect against cytoxan-induced hair loss.
  • NAC N-acetylcysteine
  • a third experiment was performed as follows: 12 8-day old rats received each CTX 30 mg/kg IP as a single injection and randomized into two groups of 6 rats each. Immediately after CTX injection, rats in Group I were each placed erect tail first in a tube containing 1 ml of 30 mg/kg NAC- liposome suspension and kept in for 12 hours. They were then taken out for 12 hours, then resubmerged for another 12-hr-period. The suspension was changed every 4 hrs. Control rats were similarly treated using liposome suspension without NAC. All 6 rats in the control group had total body alopecia. In contrast, all rats in the NAC-treated group were virtually completely protected over the caudal half of their body (Table 3, Exp.3).
  • Hair loss was graded as described in Hussein, et al . , Science 249:1564-1566 (1990). 0, No detectable alopecia; 1+, Mild alopecia defined as less than 50% hair loss; 2+, Moderately severe alopecia with more than 50% hair loss; 3+, Total or virtually total absence of hair.
  • Example 4 This example demonstrates parenteral administration of BRM-NAC provides protection from alopecia caused by the combination of cytoxan (CTX) (a non cycle-specific drug) and cytosine arabinoside (ARA-C) (a cycle-specific drug) .
  • CX cytoxan
  • ARA-C cytosine arabinoside
  • Twenty 8-day old rats were randomized into two groups of 10 rats each and were each given CTX 50 mg/kg in a single injection IP plus ARA-C 50 mg/kg IP daily for 5 days.
  • Group I received beginning on the first day and continuing for 5 days CTI-BRM 10 ⁇ g plus NAC 4 mg SC.
  • Group II received PBS injections. The degree of alopecia was scored on day 10 of experiment. All rats in Group II developed total body alopecia. In contrast, 3 rats in Group I developed 2+ alopecia, and 7 of 10 rats had only 1+ alopecia. See Table 4.
  • Example 5 This example demonstrates that topical administration of BRM-NAC (in liposomes) provides protection from cytoxan (CTX) induced alopecia. Fifty eight-day old rats were randomized into 5 groups of 10 rats each. All rats received CTX 50 mg/kg IP as a single injection and ARA-C 50 mg/kg IP daily for 4 days. Group I received no additional treatment and served as control.
  • CTX cytoxan
  • drug-in- liposome suspensions are prepared according to Huang, C.H, Biochem. 8:344-351 (1969), and for use herein were prepared as follows: soybean L- ⁇ -lecithins were suspended in phosphate buffered saline (PBS) at a concentration of 0.6 gm/ml with NAC, 100 mg/ l and CTI-BRM 1 mg/ml. The mixture was sonicated at 0° - 4° for 30 min, or two 15 min periods, separated by a 10 min cooling interval, with the standard tip of the sonic dismembrator (Fischer Scientific, Pittsburg, PA) at a setting of 60 W. When necessary, suspensions were filtered with 0.45 ⁇ m filter.
  • PBS phosphate buffered saline
  • Example 7 This example demonstrates that recombinant cytokine IL-l, provides protection from cytosine arabinoside (ARA-C) induced alopecia.
  • ARA-C cytosine arabinoside
  • CTI-BRM is a powerful immunomodulator: it is rapidly phagocytosed by monocytes/macrophages which then show increased phagocytic, bactericidal and tumoricidal activity. Patients injected subcutaneously with CTI-BRM show significant rises in granulocyte counts 24 hours later. Co-culture of CTI BRM with human peripheral blood mononuclear cells results in elevation of NK activity, increased T-cell mediated cytotoxicity, and augmented lymphocyte and monocyte antibody mediated cytotoxicity (ADCC) . The enhancement of these cellular effector functions is believed to be the result of a cascade of cytokine release which occurs after CTI-BRM stimulation.
  • Example 8 This example discloses a method for determining the ability of a biologic response modifier to induce cytokine release.
  • the biologic response modifier is evaluated for the ability to induce the expression of the cytokines interleukin 1 beta (IL-l/3) , tumor necrosis factor alpha (TNF ⁇ ) , interleukin 6 (IL-6) , granulocyte macrophage-colony stimulating factor (GM- CSF) , and the inflammation mediator prostaglandin E 2 (PGE 2 ) following the exposure of the human peripheral blood mononuclear cells (PBMCs) to the BRM (i . e . , the BRM being evaluated, hereinafter referred to as the "BRM sample”) in vitro.
  • PBMCs peripheral blood mononuclear cells
  • PBMCs are isolated by the application of heparinized human blood to leukoprep gradients (Becton-Dickinson, Lincoln Park, NJ) and centrifuging for 20 minutes at 1,800 x g.
  • Mononuclear cells are removed from the gradient by aspiration and washed twice by resuspension in phosphate buffered saline (PBS) followed by centrifugation at 200 x g for 10 minutes.
  • PBS phosphate buffered saline
  • X-Vivo 10 medium Woodtaker Biologicals
  • 2 mM gluta ine Sigma
  • 1.3 x 10 6 cells are added to each well of a 24 well plate (Costar, Cambridge, MA) .
  • BRM sample is diluted in X-vivo medium and added to the wells to make a final concentration of 2 micrograms per milliliter.
  • BRM sample containing cell suspensions are incubated for 24 hr. at 37°C in 5% C0 2 .
  • Enzyme-linked immunosorbent assay is used to measure TNF ⁇ , IL-ljS (Cistron) , IL-6, and GM- CSF (Genzyme) .
  • PGE 2 is quantified by radioimmunoassay (Advanced Magnetics) .
  • Human IL-lj8, TNF ⁇ , IL-6, GM- CSF, and PGE 2 serve as standards in each of the respective assays. The results of each assay are reported as picograms of component per milliliter of cell supernatant.
  • Example 9 This example demonstrates that endotoxin, Lipid A, and MPL (monophosphloryl Lipid A) provide protection from cycle-specific (ARA-C) induced alopecia.
  • ARA-C cycle-specific
  • the preferred biologic response modifier of the present invention contains endotoxin, which in turn contains Lipid A.
  • MPLA is a non-toxic analogue of Lipid A. See United States Patent 4,971,801.
  • Lipid A was given as follows: Day one, 2.5 ⁇ g; day two, 5 ⁇ g; day three through seven, 10 ⁇ g. Experimental results are shown in Table 5.
  • Hair loss was graded as described in Hussein, et al . , Science 249:1564-1566 (1990). 0, No detectable alopecia; 1+, Mild alopecia defined as less than 50% hair loss; 2+, Moderately severe alopecia with more than 50% hair loss; 3+, Total or virtually total absence of hair.
  • Lipid A and endotoxin lipopolysaccharide, LPS
  • Lipid A and LPS were given as follows: Day one, 2.5 ⁇ g; day two 5 ⁇ g; day three through seven, 10 ⁇ g.
  • Lipopolysaccharide (LPS) from Sigma. Experimental results are shown in Table 6. Table 6
  • MPLA Monophosphoryl Lipid A from S. typni- ⁇ .uriu-72
  • MPLA I.P was given as follows: Day one, 2.5 ⁇ g; day two 5 ⁇ g; day three through seven, 10 ⁇ g.
  • MPLA S.C. given as follows: Day one through seven, 5 ⁇ g. Experimental results are shown in Table 7. Table 7
  • MPL Monophosphoryl Lipid A from S. typhimurium .
  • RIBI. ** 4 rats, complete hair protection at site of injection, approximately 2 cm square. Hair loss was graded as described in Hussein, et al . , Science 249:1564-1566 (1990). 0, No detectable alopecia; 1+ Mild alopecia defined as less than 50 percent hair loss; 2+ Moderately severe alopecia with more than 50% hair loss; 3+ Total absence of hair.

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Abstract

Procédés de protection contre la chute des cheveux provoquée par la chimiothérapie, c'est-à-dire l'alopécie. On décrit un procédé de protection contre l'alopécie provoquée par les agents chimiothérapeutiques par l'administration à un sujet mammifère de quantités à efficacité thérapeutique d'un modificateur de la réponse biologique provoquant une libération de cytokines, de quantités à efficacité thérapeutique d'un ou plusieurs composés sélectionnés dans le groupe constitué de cytokine recombinante IL-1, d'endotoxine, de lipide A, et de lipide A monophosphorylique, ainsi que d'anti-oxydants. Selon le procédé, ledit modificateur, lesdits composés et l'anti-oxydant non toxique peuvent s'administrer de manière parentérale ou s'appliquer de façon locale. En outre, on décrit l'utilisation dudit modificateur, desdits composés et de l'anti-oxydant pour la fabrication d'ensembles de médicaments servant à la protection contre l'alopécie provoquée par les agents chimiothérapeutiques.
PCT/US1991/002189 1990-03-28 1991-03-28 Procedes de protection contre la chute des cheveux provoquee par la chimiotherapie Ceased WO1991014424A1 (fr)

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Cited By (9)

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US5430045A (en) * 1992-04-23 1995-07-04 Free Radical Sciences, Inc. Method of reducing or preventing bone marrow hypoplasia
US5447712A (en) * 1993-12-09 1995-09-05 Free Radical Sciences Method of reducing cyclophosphamide induced hemorrhagic cystitis
US5747459A (en) * 1991-02-04 1998-05-05 Nestec, Ltd. Method for insuring adequate intracellular glutathione in tissue
US5824693A (en) * 1991-01-10 1998-10-20 Transcend Therapeutics, Inc. Method for treatment for pulmonary disease
FR2826261A1 (fr) * 2001-06-26 2002-12-27 Lmd Composition a usage topique comprenant un produit cytotoxique et son utilisation dans le traitement de l'alopeche
EP1401791A4 (fr) * 2001-05-21 2006-06-28 Guilford Pharm Inc Composes de liaison de cyclophiline non peptidique et leurs utilisations
WO2006117405A1 (fr) * 2005-05-04 2006-11-09 Coty Prestige Lancaster Group Gmbh Utilisation de piegeurs de radicaux libres dans la protection de la peau et des cheveux et le traitement des dommages causes a la peau et aux cheveux par la chimiotherapie
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.
CN114302729A (zh) * 2019-08-29 2022-04-08 生物医学研究集团有限公司 癌化学疗法支持剂、食品及药品

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JPS5849311A (ja) * 1981-09-18 1983-03-23 Eisai Co Ltd 安全なるリポソ−ムの製造法
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US3993754A (en) * 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
JPS5849311A (ja) * 1981-09-18 1983-03-23 Eisai Co Ltd 安全なるリポソ−ムの製造法
US4670185A (en) * 1982-07-19 1987-06-02 Lion Corporation Aqueous vesicle dispersion having surface charge
US4761288A (en) * 1984-09-24 1988-08-02 Mezei Associates Limited Multiphase liposomal drug delivery system
US4971801A (en) * 1986-06-09 1990-11-20 Cell Technology, Inc. Biologic response modifier
US4985241A (en) * 1986-11-21 1991-01-15 Cetus Corporation Therapeutic combination of free-radical scavenger and tumor necrosis factor
US4828837A (en) * 1987-03-30 1989-05-09 Liposome Technology, Inc. Non-crystalline minoxidil composition, its production and application

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824693A (en) * 1991-01-10 1998-10-20 Transcend Therapeutics, Inc. Method for treatment for pulmonary disease
US5747459A (en) * 1991-02-04 1998-05-05 Nestec, Ltd. Method for insuring adequate intracellular glutathione in tissue
US5430045A (en) * 1992-04-23 1995-07-04 Free Radical Sciences, Inc. Method of reducing or preventing bone marrow hypoplasia
US5447712A (en) * 1993-12-09 1995-09-05 Free Radical Sciences Method of reducing cyclophosphamide induced hemorrhagic cystitis
EP1401791A4 (fr) * 2001-05-21 2006-06-28 Guilford Pharm Inc Composes de liaison de cyclophiline non peptidique et leurs utilisations
WO2003000208A1 (fr) * 2001-06-26 2003-01-03 Lmd Composition a usage topique comprenant un produit cytotoxique
FR2826261A1 (fr) * 2001-06-26 2002-12-27 Lmd Composition a usage topique comprenant un produit cytotoxique et son utilisation dans le traitement de l'alopeche
WO2006117405A1 (fr) * 2005-05-04 2006-11-09 Coty Prestige Lancaster Group Gmbh Utilisation de piegeurs de radicaux libres dans la protection de la peau et des cheveux et le traitement des dommages causes a la peau et aux cheveux par la chimiotherapie
EA010927B1 (ru) * 2005-05-04 2008-12-30 Коти Престиж Ланкастер Груп Гмбх Использование поглотителей свободных радикалов для защиты и обработки кожи и волос, повреждённых вследствие химиотерапии
WO2017220998A1 (fr) * 2016-06-22 2017-12-28 Paxman Coolers Ltd Traitement de l'alopécie secondaire à la chimiothérapie.
CN114302729A (zh) * 2019-08-29 2022-04-08 生物医学研究集团有限公司 癌化学疗法支持剂、食品及药品
EP4019024A4 (fr) * 2019-08-29 2022-10-05 Biomedical Research Group Inc. Agent assistant une chimiothérapie anticancéreuse, aliment et médicament
CN114302729B (zh) * 2019-08-29 2024-09-24 生物医学研究集团有限公司 癌化学疗法支持剂及药品

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