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WO1994021272A1 - Procede de traitement d'une infection microbienne chez un animal en lui administrant une composition comprenant lif et une cytokine - Google Patents

Procede de traitement d'une infection microbienne chez un animal en lui administrant une composition comprenant lif et une cytokine Download PDF

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Publication number
WO1994021272A1
WO1994021272A1 PCT/AU1994/000136 AU9400136W WO9421272A1 WO 1994021272 A1 WO1994021272 A1 WO 1994021272A1 AU 9400136 W AU9400136 W AU 9400136W WO 9421272 A1 WO9421272 A1 WO 9421272A1
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WO
WIPO (PCT)
Prior art keywords
animal
lif
cytokine
human
active
Prior art date
Application number
PCT/AU1994/000136
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English (en)
Inventor
Paul Michael Waring
Donald Metcalf
Original Assignee
Amrad Corporation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amrad Corporation Limited filed Critical Amrad Corporation Limited
Priority to AU63698/94A priority Critical patent/AU6369894A/en
Publication of WO1994021272A1 publication Critical patent/WO1994021272A1/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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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]
    • A61K38/2093—Leukaemia inhibitory factor [LIF]

Definitions

  • the present invention relates generally to the use of leukaemia inhibitory factor and functionally active parts, fragments, derivatives and/or analogues thereof and pharmaceutical compositions comprising same for use in the prevention, treatment and/or prophylaxis of microbial infection in animals. More particularly, the present invention contemplates a method of preventing, treating or otherwise ameliorating the adverse effects of microbial induced sepsis and shock in mammals.
  • Leukaemia inhibitory factor (hereinafter referred to as "LIF 1 ) was purified (1,2) and cloned (3) on the basis of its capacity to induce differentiation in, and suppress the proliferation of, the Ml mouse myeloid leukaemic cell line (see International Patent Application No. PCT/AU88/ 00093) .
  • the present invention arose in part from an investigation of the use of LIF in ameliorating the effects of septic shock or sepsis in an animal.
  • Septicaemia results from blood stream invasion by microrganisms, usually, but not exclusively, from Gram-negative bacteria. Septicaemic individuals respond by releasing inflammatory mediators such as the cytokines Tumour Necrosis Factor ⁇ (TNF ⁇ ), Interleukin-l ⁇ (IL-l ⁇ ), Interleukin-6 (IL-6), Interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF) and LIF. Some of these mediators, particularly TNF ⁇ and IL-l ⁇ , appear to be deleterious at high levels and to contribute to the clinico-pathological picture of septic shock. Septic shock is a major problem in intensive care medicine and has a high (40 - 75%) mortality rate despite aggressive treatment with antibiotics and supportive therapy.
  • TNF ⁇ Tumour Necrosis Factor ⁇
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • G-CSF granulocyte colony-stimulating factor
  • LIF gran
  • endotoxin components of bacterial cell walls or microbial cell walls known as endotoxin.
  • injection of high doses of endotoxin can induce a clinico-pathological state, known as endotoxemia, which, although similar to septic shock, does not result in the full disease manifestations concomitant with live microbial infection.
  • live microbial organisms for example E.coli, cause additional untoward effects in a mammal over and above those caused by endotoxin alone; for instance, the later development of acute inflammatory foci and abscesses.
  • endotoxins as part of in-vivo models of septic shock are artificial as they measure only the endotoxin - induced component of septic shock.
  • one aspect of the present invention contemplates a method for treating microbial infection in an animal, said method comprising administering to said animal an effective amount of LIF or an active part, fragment, derivative or analogue thereof for a time and under conditions sufficient to prevent, reduce or otherwise ameliorate the adverse effects of microbial infection.
  • treatment is used in its most broadest sense to include prophylactic (i.e. preventative) treatment as well as treatments designed to ameliorate the effects of microbial infection.
  • the treatment may be aimed at the microbial organism or the effects of microbial infection.
  • Reference herein to a "microorganism" includes a prokaryotic organism, a lower eukaryotic organism and a virus.
  • a method for treating microbial infection including ameliorating the effects thereof in an animal, said method comprising administering to said animal an effective amount of LIF or an active part, fragment, derivative or analogue thereof, said method further comprising simultaneously or sequentially administering one or more other active molecules.
  • cytokine co-administered with an active molecule selected from a cytokine, cytokine antagonist (such as a soluble cytokine receptor), cytokine agonist, receptor antagonist or agonist, neutralising antibodies such as anti-endotoxin, anti-TNF ⁇ , anti-IL-1 ⁇ , anti-IL-6 antibodies, including monoclonal and polyclonal forms and/or antibiotic agents.
  • cytokine antagonist such as a soluble cytokine receptor
  • cytokine agonist such as a soluble cytokine receptor
  • receptor antagonist such as a soluble cytokine receptor
  • neutralising antibodies such as anti-endotoxin, anti-TNF ⁇ , anti-IL-1 ⁇ , anti-IL-6 antibodies, including monoclonal and polyclonal forms and/or antibiotic agents.
  • the time difference between LIF administration and non-LEF treatment may be seconds, minutes, hours, days, weeks or months depending on the microbial infection being treated, the mammal being treated and the
  • the present invention is particularly exemplified by the in vivo effect of LIF in mice challenged with live E.coli It has been surprisingly discovered in accordance with the present invention that LIF significantly protects mice against microbial induced sepsis, septic shock and death indicating its potential as an anti-microbial agent or as a prophylactic agent against microbial - induced sepsis and septic shock.
  • the effect of LIF is time and dose-dependent.
  • LIF is being used, therefore, as a prophylactic and /or therapeutic agent.
  • the LIF is recombinant LIF of human, murine, livestock animal, companion animal, laboratory test animal or captive wild animal origin. More preferably, it is of human origin.
  • the present invention extends to functionally active parts, mutants, derivatives and analogues of LIF which exhibit the desired activity herein described.
  • the LIF employed may be "homologous" to the animal being treated meaning that it has the same origin as the species of animal to be treated (e.g. human LIF for treatment of a human, or murine LIF for treatment of a mouse) or may be "heterologous" to the animal being treated meaning that the species of the animal are different (i.e. human LIF for treatment of a mouse or livestock LIF for treatment of a human).
  • compositions for the treatment of microbial infection in a mammal comprising LEF and one or more pharmaceutically acceptable carriers and/or diluents.
  • LIF is in combination with one or more other active molecules as hereinbefore described for simultaneous administration.
  • the pharmaceutical composition may be in compartmental form such that LIF and one or more active molecules are mixed prior to use or are arranged to facilitate sequential administration of LIF and the active molecules.
  • the active ingredients of a pharmaceutical composition comprising LIF and optionally one or more other active ingredients are contemplated to exhibit excellent prophylactic or therapeutic activity, for example, in the amelioration of the effects of microbial infection when administered in an amount which depends on e particular case. For example, from about 0.5 ⁇ g to about 2.0 mg of LIF per kilogram of body weight per day may be administered. Alternatively, this amount may represent the combined amounts of LIF and other active molecules. Dosage regimes may be adjusted to provide the optimum prophylactic or therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the active compound may be administered in a convenient manner such as by the oral, intraveneous (where water soluble), intramuscular, subcutaneous, intranasal, intradermal or suppository routes.
  • the active ingredients which comprise LIF and optionally one or more other active molecules may be required to be coated in a material to protect said ingredients from the action of enzymes, acids and other natural conditions which may inactivate said ingredients.
  • LIF maybe coated by, or administered with, a material to prevent its inactivation.
  • LIF may be administered in an adjuvant, co-administered with enzyme inhibitorys or in liposomes.
  • Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether.
  • Enzyme inhibitors include pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEP) and trasylol.
  • Liposomes include water-in-oil-in-water LIF emulsions as well as conventional liposomes.
  • LIF and optionally the other active molecules may also be administered parenterally or intraperitoneally.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganism.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microrganisms such as bacteria or fungi.
  • the carrier can be a coolant of dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils.
  • 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 superfactants.
  • the prevention of the action of microrganisms can be brought about by various antibacterial and anti fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared incorporating the various sterilised active ingredient(s) into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile filtered solution thereof.
  • the composition may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatine capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspension, syrups, waffers, and the like.
  • Such compositions and preparations should contain at least 1% on weight of active compound.
  • the percentage of the compositions and preparations may of course be varied and may conventionally be between about 5 to about 80% of the weight of the unit.
  • the amount of active compound(s) in the pharmaceutical compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared, so that an oral dosage unit form contains between about 0.5 ng and 320 mg or active compound.
  • the tablets, troches, pills capsules and the like may also contain the following: a binder such as gum gragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum gragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup of elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound maybe incorporated into sustained release preparations and formulations.
  • pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substance is well known in the art. Except insofar an any convential media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the present invention further relates to the use of LIF or an active part, fragment, derivative or analogue thereof alone or together with one or more other active molecules such as a cytokine in the manufacture of a medicament for the treatment or prophylaxis of patients having, or likely to be exposed to, bacterial infection.
  • a livestock animal includes cows, pigs, sheep, horses, donkeys and goats.
  • a companion animal incudes cats and dogs.
  • a laboratory test animal includes mice, rabbits, guinea pigs, hamsters and poultry birds such as chickens.
  • a captive wild animal incudes emus, foxes, kangaroos and wild birds.
  • the LIF employed is preferably in recombinant form as described in International Patent Application No. PCT/AU88/00093.
  • the LIF comprises an amino acid sequence set forth in one or more of the Figures in PCT/AU88/00093 or is substantially similar thereto.
  • the LIF has the amino acid sequence set forth in Figures 15, 26 or 29 of PCT/AU88/00093 or has an amino acid sequence with at least 40%, more preferably at least 50%, even more preferably at least 60%, still more preferably at least 70-80% and yet even more preferably at least 90-95%, similarity or identity to one or more regions of the amino acid sequence set forth in Figures 15, 26 or 29 of PCT/AU88/00093.
  • the LIF may also contain single or multiple amino acid insertions, deletions and/or additions to the naturally occurring sequence and may be derivatised or fragmented to a part carrying the active site of LIF. All such derivatives or fragmented LIF molecules are encompassed by the present invention and are included in the expression "LIP 1 , provided all such molecules have the effect of protecting from or ameliorating against the effects of microbial infection.
  • Administration may be by any suitable route such as intravenous, intranasal, subcutaneous, intraperitoneal, intramuscular, intradermal, infusion, suppository, implant and oral including slow release capsules.
  • the injected preparation may need to be modified to reduce serum degradation and/or alternative routes of administration employed.
  • Administration may also be by gene therapy including expression of the LIF gene in vectors which are introduced to the mammal to be treated.
  • the LIF gene can be expressed in bacteria which are then incorporated into the normal flora of the host.
  • LIF significantly increases the survival rate of mice treated with extreme doses of live E.colias compared to untreated controls.
  • LIF is acting to inhibit the adverse effects of TNF- ⁇ released in vivo in response to microbial infection or to reduce the capacity of the animal to mount a systemic inflammatory response upon subsequent microbial challenge.
  • LIF may directly stimulate host macrophages or other cells to more effectively eliminate the microorganisms. Regardless of the mode of action, LIF protects in vivo against the toxicity of microbial infection.
  • the effective amount of LIF will depend on the animal and the condition to be treated. For example, amounts ranging from about 0.1 ng/kg/body weight/day to about lOOOug/kg/body weight/day are contemplated to be useful in destroying, suppressing or ameliorating bacterial infection. More preferably, the effective amount is lng/ leg body weight/day to lOOug/kg body weight/day. Even more preferably, the effective amount is lOng/kg body weight/day to lOug/kg body weight/day. Such effective amounts may reflect actual administration protocols or may reflect an average of an alternate administration protocol. The protocol may be varied to administer LIF pier hour, week or month or in conjunction with antibiotic therapy.
  • the method of the present invention further contemplates the administration of LIF as a prophylactic agent prior to, for example, surgery, transplantation, childbirth, immunosuppression, chemotherapy and irradiation.
  • the doses to be used will be similar to the effective amounts described above and may be given up to 72 hours prior to surgery, more preferably 24-48 hours prior to surgery, transplantation, childbirth, immunosuppression, chemotherapy or irradiation and even more preferably 6-24 hours prior to surgery, transplantation, childbirth, immunosuppression, chemotherapy or irradiation.
  • the method of the present invention further contemplates the administration of LIF alone or in combination with other cytokine antagonists, anti-endotoxin antibodies etc and /or antibiotic agents.
  • cytokines include, but are not limited to BL-1, IL-6, IL-10, TNF- ⁇ , G-CSF, and /or granulocyte-macrophage colony-stimulating factor (GM-CSF).
  • Antibiotic agents contemplated by the present invention include, but are not limited to Penicillins, Penicillin analogues and derivatives, Cephalosporins up to and including "fourth" and "fifth" generation Cephalosporins, Sulpha drugs and other antibacterial agents which are clinically used. Amounts of other cytokines will be similar to the effective amounts of LIF. The effective amounts of antibiotic agents will vary depending on the agent.
  • the present invention also extends to the use of derivatives of other cytokines and/or antibiotic agents.
  • derivatives is meant recombinant, chemical or other synthetic forms of LIF or other cytokines or chemotherapeutic agent and/or any alteration such as addition, substitution and/or deletion to the amino acid sequence component of the molecule or to the carbohydrate or other associated molecule moiety of LIF or other cytokine provided the derivative possesses the ability to destroy, ameliorate or protect against microbial infection.
  • reference herein to LIF or to a cytokine or antibiotic agent includes reference to its derivatives.
  • the most preferred form of LIF is human or murine recombinant LIF.
  • compositions described in accordance with the present invention will be useful in the treatment or prophylaxis inter alia of microbial (e.g. bacterial) induced toxaemias including but not limited to septicaemia, septic shock, sepsis, Gram-negative bacteraemia and other disease states resulting from acute microbial infection.
  • microbial e.g. bacterial
  • toxaemias including but not limited to septicaemia, septic shock, sepsis, Gram-negative bacteraemia and other disease states resulting from acute microbial infection.
  • Figure 1 is a graphical representation showing the percentage of DBA-2 mice surviving over time after challenge with a lethal intravenous does (0.5 ⁇ 0.1 x 10 9 organisms/mouse) of live E.coli after receiving rmLIF (lO ⁇ g i.p), 0.2ml in 5% v/v Fetal Calf Serum (FCS) / normal saline (FCS/NS) or 0.2ml 5% v/v FCS/ saline (i.p) 24, 16, 8 or 0 hours prior to challenge.
  • FCS Fetal Calf Serum
  • FCS/NS normal saline
  • FCS/NS normal saline
  • i.p 0.2ml 5% v/v FCS/ saline
  • mice DBA-2 mice weighing approximately 25g were housed 8 per cage and kept in a controlled environment.
  • Escherichia coli produced recombinant mouse LIF (Lot no. 122) was supplied by AMRAD Corporation Limited, Kew, Victoria, Australia and had endotoxin content of 0.25 En/ml as measured by the Limulus Amoebocyte Lysate (LAL) assay.
  • the stock solution was diluted 50 fold prior to administration to animals.
  • Control mice received inert protein carrier Solution (5% v/v FCS/NS). Live Escherichia coZ/organisms were grown and reconstituted in saline. Cultures of E.c ⁇ li were administered to mice in volumes of 0.2ml.
  • mice (8 per group) were injected with lO ⁇ g rmLIF intraperitoneally 24, 16, 8 or 0 hours prior to E.coli challenge. At each time point a control group of 8 mice were injected intraperitoneally with equal volumes of 5% v/v FCS saline.
  • the live E.coli organisms (0.5 ⁇ 0.1 x 10 9 organisms /mouse) were injected directly into mouse tail vein.
  • E.coli ATCC strain 25922
  • PBS phosphate buffered saline
  • the suspension was diluted so that an OD of 0.31 - 0.35 was acheived. Subsequent to culture, 8-10 fold dilutions of the organisms yielded bacterial counts of 2 - 3 x 10 9 colonies / ml). A 0.2ml injection volume, therefore, contained 0.5 ⁇ 0.1 x 10 9 organisms. The suspension was kept on ice prior to injection.
  • Escherichia coli killing Cultures of E.coZ were killed by suspension in a 70/30 v/v alcohol/water and kept at -20 degrees C for 8 hours. Alcohol was removed by three washed in PBS and the suspension reconstituted to the original optical density of 0.31 to 0.35.
  • Table 1 shows the effect of LIF administration in DBA/2 mice at various time points prior to or following E.coli challenge as the number of surviving mice in each group of 8. It was found that LIF administered at least 6 hours prior to E.ccli challenge was able to significantly reduce mortality as compared with saline treated animals. Accordingly, the phenomenon is time and dose dependent (Table 1) with significant protective effect being observed with doses of 5 and lO ⁇ g of rmLIF being given 8- hourly for 24 hours prior to challenge.
  • Table 2 shows the effect of LIF administration prior to challenge with live and killed Exoli, as number of surviving mice in each group. All mice received either (mLIF (lO ⁇ g) or 5% v/v FCS/NS as 0.2ml intraperitoneal injections at 24, 16, 8 and 0 hrs prior to E.coli challenge. Cultures of E.coli were killed by suspension in 70% v/v alcohol at -20° for 8 hrs and alcohol removed by three washes in PBS. It was found that only live E.coli had lethal effects at the dose administered.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention se rapporte généralement à l'utilisation du facteur d'inhibition de leucémie et de parties, fragments, dérivés et/ou analogues à activité fonctionnelle de ce facteur, ainsi qu'à des compositions pharmaceutiques les comprenant, utilisées pour la prévention, le traitement et/ou la prophylaxie d'infections microbiennes chez les animaux. La présente invention se rapporte plus particulièrement à un procédé de prévention, de traitement ou de soulagement des effets adverses produits par la scepticémie et le choc septique induits par des microbes chez des mammifères.
PCT/AU1994/000136 1993-03-17 1994-03-17 Procede de traitement d'une infection microbienne chez un animal en lui administrant une composition comprenant lif et une cytokine WO1994021272A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63698/94A AU6369894A (en) 1993-03-17 1994-03-17 A method for treating microbial infection in an animal by administering a composition comprising lif and a cytokine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL786693 1993-03-17
AUPL7866 1993-03-17

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WO1994021272A1 true WO1994021272A1 (fr) 1994-09-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990010454A1 (fr) * 1989-03-07 1990-09-20 Amrad Corporation Limited Effets metaboliques du facteur inhibiteur de leucemie sur les os
WO1991007992A1 (fr) * 1989-11-24 1991-06-13 Monash University Action proliferatrice d'un facteur inhibiteur de la leucemie sur des cellules satellites
WO1991014443A1 (fr) * 1990-03-20 1991-10-03 Amrad Corporation Limited Procede de regulation du developpement et du maintien des neurones
WO1993012806A1 (fr) * 1991-12-24 1993-07-08 Amrad Corporation Limited Procede de traitement de tumeurs et de sarcomes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990010454A1 (fr) * 1989-03-07 1990-09-20 Amrad Corporation Limited Effets metaboliques du facteur inhibiteur de leucemie sur les os
WO1991007992A1 (fr) * 1989-11-24 1991-06-13 Monash University Action proliferatrice d'un facteur inhibiteur de la leucemie sur des cellules satellites
WO1991014443A1 (fr) * 1990-03-20 1991-10-03 Amrad Corporation Limited Procede de regulation du developpement et du maintien des neurones
WO1993012806A1 (fr) * 1991-12-24 1993-07-08 Amrad Corporation Limited Procede de traitement de tumeurs et de sarcomes

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