EP1768659A1 - Use of a fatty acid for preparing a topical composition for allaying inflammatory reactions due to venemous hymenoptera stings - Google Patents

Use of a fatty acid for preparing a topical composition for allaying inflammatory reactions due to venemous hymenoptera stings

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Publication number
EP1768659A1
EP1768659A1 EP05791091A EP05791091A EP1768659A1 EP 1768659 A1 EP1768659 A1 EP 1768659A1 EP 05791091 A EP05791091 A EP 05791091A EP 05791091 A EP05791091 A EP 05791091A EP 1768659 A1 EP1768659 A1 EP 1768659A1
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Prior art keywords
acid
fatty acid
cis
use according
inflammatory reactions
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German (de)
French (fr)
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Thierry Jean
Fabrice Balavoine
Mark Crawford
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Cerep SA
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Cerep SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the use of a fatty acid for the preparation of a topical composition for the amelioration of inflammatory reactions due to the bites of Hymenoptera.
  • Insects secreting substances that are harmful to humans are quite numerous in our regions. Among the wasps, hornets, bumble bees, ants and bees the risk of sting is not negligible. These insects are called hymenoptera. Their bite may cause local or general non-allergic reactions or local or generalized allergic reactions.
  • Stings in the oral cavity and particularly at the back of the throat may cause respiratory problems through local edema.
  • punctures in the eye, on the cornea can cause immediate complications such as ocular abscesses or perforations of the globe. Some complications may appear later: cataracts or glaucoma.
  • Hymenoptera include many species including bees, wasps, hornets, ants. Although the majority of the bites of these hymenoptera cause only moderate pain and limited and temporary reaction, they can be dangerous or even fatal if they are multiple, if they occur in the mouth, throat, or at the level eyes, or if the stung subject triggers an allergic-type reaction.
  • the stung person first feels more or less pain depending on the type of insect and the amount of venom injected. The skin around the sting becomes red and swollen. The subject feels itching more or less intense.
  • insect venom and in particular bee venom is a complex substance comprising a large number of active compounds among which histamine, melittin, hyaluronidase and phospholipidase A.
  • histamine, melittin, hyaluronidase and phospholipidase A histamine, melittin, hyaluronidase and phospholipidase A.
  • the sensitivity to these venom proteins might explain some of the reactions outlined above.
  • the Applicant has thus found, surprisingly, that these fatty acids, in particular those containing C12-C24, considerably reduce the inflammatory reaction which follows a bite of hymenopteran.
  • the present invention relates to the use of a fatty acid for the preparation of a topical or injectable composition for the alleviation of inflammatory reactions due to the bites of Hymenoptera.
  • the fatty acids used in the present invention are preferably natural fatty acids, that is to say that can be obtained from natural products such as oils, but also synthetic fatty acids that are identical or different from natural fatty acids. .
  • the usable fatty acids may be saturated or unsaturated fatty acids. It is also conceivable to use the pharmaceutically acceptable salts or derivatives of these fatty acids which are included in the fatty acid designation.
  • C12 to C24 acids Lauric acid (n-Dodecanoic acid), Myristic acid (n-Tetradecanoic acid), Palmitic acid (n-Hexadecanoic acid), Stearic acid (n - Octadecanoic), Arachidic (n-Eicosanoic), Behenic (n-Docosanoic), Lignoceric (n-Tetracosanoic), Palmitoleic (cis- ⁇ 9 -Hexadecenoic), Oleic (cis- ⁇ 9 -Octadecenoic), Linoleic (cis, cis - ⁇ 9 -, ⁇ 12 - Octadecadienoic), Linolenic (all-cis- ⁇ 9 -, ⁇ 12 -, ⁇ 15 -Octadecatrienoic), Arachidonic (all-cis- ⁇ 5 -
  • Polyunsaturated fatty acids and linoleic and oleic acids are particularly active in the object of the invention.
  • Fatty acids have been tested in vitro for their ability to inhibit the activity of some of the pro-inflammatory components of bee venom, and in vivo in rats in models of edema induced by bee venom. The results of these tests show that the fatty acids can be used for the manufacture of compositions intended for the local treatment of inflammations following the bites of venom hymenopterans.
  • composition whose use is the subject of the invention may further comprise other active ingredients including anesthetic and / or an antibiotic and / or an anti-allergic or anti-inflammatory substance.
  • the fatty acids may be formulated in any form suitable for topical administration, in combination with suitable excipients to allow administration of a dose of 0.01 to 50 mg per venom hymenopteran bite.
  • the dose may of course vary depending on the amount of venom absorbed, the number of bites or the type of insect.
  • galenic formulations that can be adapted for the implementation of the invention include ointments, creams, gels, patches, powders, sprays or lotions.
  • An application with a stick can be particularly advantageous for single stings on a member for example. If the mucous membranes or the eyes are affected, a formulation in the form of a spray or eye drops is preferred.
  • composition forming the subject of the present invention by local injection.
  • active substances of the pharmaceutical compositions according to the invention may be dissolved or suspended in a pharmaceutically acceptable sterile injectable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids for local administration, to allow administration of a dose of 0.001 to 1 mg per venom hymenopteran bite.
  • a pharmaceutically acceptable sterile injectable liquid such as sterile water, a sterile organic solvent or a mixture of these two liquids for local administration, to allow administration of a dose of 0.001 to 1 mg per venom hymenopteran bite.
  • Fig. 1 illustrates the percentage inhibition of PLA 2 activity of bee venom as a function of the acid concentration which is used for: 1.A - Linoleic acid (Example 1) 1.B - Acid oleic (example 1)
  • Fig. 2 illustrates the effect of oleic and linoleic acid on the increase in the volume of the rat paw in an inflammation model, as a function of the time after injection of the bee venom (example 2 - experiment 1).
  • Fig. 3 illustrates the effect of oleic and linoleic acid the increase in the volume of the rat paw in a model of inflammation, as a function of the time after injection of the bee venom (example 2 - experiment 2)
  • Fig. 4 illustrates the effect of oleic and linoleic acid the increase in the volume of the rat paw in a model of inflammation, as a function of the time after injection of the bee venom (example 2 - experiment 3)
  • Example I In vitro inhibitory effects of linoleic acid and oic acid on the activity of phospholipase A2 of bee venom (PLA2), a major inflammatory component of this venom:
  • PLA2 activity is measured according to the hexane extraction method described by K ⁇ tsum ⁇ t ⁇ , M. Gupt ⁇ , G. and Goldman AS., (1986), Anal. Biochem. 154 (2), 676-681.
  • PLA2 activity is determined using a radioactive substrate, La-dipalmitoyl- [2,9,10 (N) -3H-p-mitoyl] -phosphatidylcholine.
  • the reaction is carried out in 1 ml of glycine / NaOH buffer, pH 9, containing 2.2 mM deoxycholate, 0.11 ⁇ Ci of dipalmitoyl-PC and 32 mU / ml PLA2 of bee venom. After 20 minutes of incubation, the reaction is stopped by adding 0.2 ml of a Triton X-100 / EDTA solution, then the reaction product, the radiolabelled palmityc acid, is extracted with a hexane solution containing 0.1% of acetic acid and 0.7g / ml of Na2SO4. The radioactivity of the extracts is determined using a liquid scintillation counter. The results represent the mean ⁇ SEM of the CPM values obtained in two independent experiments.
  • FIGS. 1A and 1B illustrate the percentage inhibition of PLA2 activity (vertical axis) as a function of the concentration of fatty acid used (horizontal axis). These results demonstrate that linoleic and oleic acid inhibit in a dose-dependent manner the enzymatic activity of PLA2 of bee venom.
  • Bee venom (20 ⁇ g / ml in NaCl 0.9%) is incubated at room temperature, in the presence or absence of linoleic acid (32 ⁇ M). 30 minutes after the start of the incubation, the solutions (25 ⁇ l) are injected subcutaneously to Sprague Dawley rats (110-140 g), at the level of the upper surface of the foot. Edema is measured with a plethysmometer 5 - 10 - 15 - 20 - 30 - 60 and 90 minutes after injection. The results represent the mean ⁇ SEM of 5 animals. Statistical comparisons are made by a t-test, of which the control group consists of animals that received venom alone. * P ⁇ 0.05, *** P ⁇ 0.005. The results are shown in Figure 2. Experience 2:

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The invention relates to the use of a fatty acid for preparing a composition for allaying inflammatory reactions due to hypenoptera stings.

Description

UTILISATION D'UN ACIDE GRAS POUR LA PRÉPARATION D'UNE. COMPOSITION TOPIQUE DESTINÉE A L'APAISEMENT DES REACTIONS INFLAMMATOIRES DUES AUX PIQURES D'HYMENOPTERES A VENIN USE OF A FATTY ACID FOR THE PREPARATION OF A. TOPICAL COMPOSITION FOR TREATING INFLAMMATORY REACTIONS DUE TO VENIN HYMENOPTER PENSIONS
La présente invention a pour objet l'utilisation d'un acide gras pour la préparation d'une composition topique destinée à l'apaisement des réactions inflammatoires dues aux piqûres d'hyménoptères.The present invention relates to the use of a fatty acid for the preparation of a topical composition for the amelioration of inflammatory reactions due to the bites of Hymenoptera.
Les insectes sécrétant des substances nocives pour les êtres humains sont assez nombreux dans nos régions. Entre les guêpes, les frelons, les bourdons, les fourmis et les abeilles les risques de piqûre ne sont pas négligeables. Ces insectes sont appelés hyménoptères. Leur piqûre peut provoquer des réactions locales ou générales non allergiques ou encore des réaction allergiques locales ou généralisées.Insects secreting substances that are harmful to humans are quite numerous in our regions. Among the wasps, hornets, bumble bees, ants and bees the risk of sting is not negligible. These insects are called hymenoptera. Their bite may cause local or general non-allergic reactions or local or generalized allergic reactions.
Les réactions locales non allergiques sont dues à une réaction inflammatoire non spécifique. Une réaction habituelle après une piqûre d'hyménoptère est constituée d'une douleur immédiate associée à une rougeur, une démangeaison et un œdème sur plusieurs centimètres. L'évolution de la réaction est variable. Cette dernière peut durer quelques heures (trois en moyenne) et ne dure en général pas plus d'un jour. Il existe dans ce type de réactions des cas particuliers. Des piqûres entraînant des réactions non allergiques sur des sites précis peuvent avoir des conséquences dramatiques.Local non-allergic reactions are due to a nonspecific inflammatory reaction. A typical reaction after a Hymenoptera sting is immediate pain associated with redness, itching and edema of several centimeters. The evolution of the reaction is variable. This last can last a few hours (three on average) and does not generally last more than one day. There are special cases in this type of reaction. Stings resulting in non-allergic reactions at specific sites can have dramatic consequences.
Des piqûres dans la cavité buccale et en particulier au fond de la gorge peuvent entraîner des troubles respiratoires par l'intermédiaire d'un oedème local. Enfin des piqûres au niveau de l'œil, sur la cornée, peuvent engendrer des complications immédiates comme des abcès oculaires ou des perforations du globe. Certaines complications peuvent apparaître plus tard : des cataractes ou des glaucomes.Stings in the oral cavity and particularly at the back of the throat may cause respiratory problems through local edema. Finally, punctures in the eye, on the cornea, can cause immediate complications such as ocular abscesses or perforations of the globe. Some complications may appear later: cataracts or glaucoma.
Les réactions générales non allergiques se rencontrent lors d'envenimation massive en cas de piqûres multiples. Ces réactions se présentent sous forme de troubles digestifs avec diarrhées et vomissements, chute de tension parfois associée à des palpitations, des convulsions non constantes et une atteinte des muscles pouvant entraîner une insuffisance rénale (dans le cadre d'une rabdomyolyse). Ces réactions apparaissent généralement après plus d'une trentaine de piqûres. Les réactions allergiques concernent approximativement 1% de la population. Elles peuvent être locales, régionales, généralisées ou retardées. Elles sont généralement classées en plusieurs stades en fonction du degré de gravité : réaction locale (réaction élargie par rapport à la réaction normale mais limitée à un membre) réaction régionale (réaction atteignant les articulations du membre piqué), réaction générale (cutanées à distance, manifestations respiratoires, œdème de Quincke, asthme, manifestations digestives, palpitations), choc anaphylactique (chute de tension s'ajoutant aux signes décrits spontanément mortels).General non-allergic reactions are encountered during massive envenomation in case of multiple stings. These reactions are in the form of digestive disorders with diarrhea and vomiting, blood pressure sometimes associated with palpitations, non-constant convulsions and muscle damage that may lead to kidney failure (as part of rabdomyolysis). These reactions usually appear after more than thirty bites. Allergic reactions affect approximately 1% of the population. They can be local, regional, generalized or delayed. They are generally classified in several stages according to the degree of gravity: local reaction (reaction enlarged compared to the normal reaction but limited to a limb) regional reaction (reaction reaching the joints of the quilted member), general reaction (cutaneous at a distance, respiratory manifestations, Quincke's edema, asthma, digestive manifestations, palpitations), anaphylactic shock (a drop in blood pressure in addition to the spontaneously described signs).
Les hyménoptères regroupent de nombreuses espèces dont les abeilles, les guêpes, les frelons, les fourmis. Bien que la majorité des piqûres de ces hyménoptères ne provoquent qu'une douleur modérée et une réaction limitée et temporaire, elles peuvent se révéler dangereuses voire mortelles si elles sont multiples, si elles se produisent dans la bouche, dans la gorge, ou au niveau des yeux, ou encore si le sujet piqué déclenche une réaction de type allergique. Le sujet piqué ressent tout d'abord une douleur plus ou moins vive en fonction du type d'insecte et de la quantité de venin injectée. La peau autour de la piqûre devient rouge et enflée. Le sujet ressent des démangeaisons plus ou moins intenses.Hymenoptera include many species including bees, wasps, hornets, ants. Although the majority of the bites of these hymenoptera cause only moderate pain and limited and temporary reaction, they can be dangerous or even fatal if they are multiple, if they occur in the mouth, throat, or at the level eyes, or if the stung subject triggers an allergic-type reaction. The stung person first feels more or less pain depending on the type of insect and the amount of venom injected. The skin around the sting becomes red and swollen. The subject feels itching more or less intense.
Des travaux récents ont montré que le venin d'insecte et notamment le venin d'abeille est une substance complexe comprenant un grand nombre de composés actifs parmi lesquels l'histamine, la melittine, l'hyaluronidase et la phospholipidase A. La sensibilité à ces protéines du venin pourrait expliquer certaines des réactions exposées ci-dessus. La demanderesse a ainsi trouvé de façon surprenante que ces acides gras en particulier en C12-C24 diminuent considérablement la réaction inflammatoire qui fait suite à une piqûre d'hyménoptère.Recent work has shown that insect venom and in particular bee venom is a complex substance comprising a large number of active compounds among which histamine, melittin, hyaluronidase and phospholipidase A. The sensitivity to these venom proteins might explain some of the reactions outlined above. The Applicant has thus found, surprisingly, that these fatty acids, in particular those containing C12-C24, considerably reduce the inflammatory reaction which follows a bite of hymenopteran.
C'est pourquoi la présente invention concerne l'utilisation d'un acide gras pour la préparation d'une composition topique ou injectable destinée à l'apaisement des réactions inflammatoires dues aux piqûres d'hyménoptères.Therefore, the present invention relates to the use of a fatty acid for the preparation of a topical or injectable composition for the alleviation of inflammatory reactions due to the bites of Hymenoptera.
Les acides gras utilisés dans la présente invention sont de préférence les acides gras naturels, c'est-à-dire pouvant être obtenus à partir de produit naturels tels que les huiles, mais également des acides gras de synthèse identiques ou non aux acides gras naturels.The fatty acids used in the present invention are preferably natural fatty acids, that is to say that can be obtained from natural products such as oils, but also synthetic fatty acids that are identical or different from natural fatty acids. .
En outre, les acides gras utilisables peuvent être des acides gras saturés ou insaturés. On peut également envisager d'utiliser les sels ou dérivés pharmaceutiquement acceptables de ces acides gras qui sont compris dans la dénomination acide gras.In addition, the usable fatty acids may be saturated or unsaturated fatty acids. It is also conceivable to use the pharmaceutically acceptable salts or derivatives of these fatty acids which are included in the fatty acid designation.
Parmi les acides gras utilisés dans le cadre de la présente invention on peut notamment citer les acides en C12 à C24, l'acide Laurique (n-Dodecanoïque), Myristique (n-Tetradecanoïque), Palmitique (n-Hexadecanoïque), Stearique (n- Octadecanoïque), Arachidique (n-Eicosanoïque), Behenique (n-Docosanoïque), Lignocerique (n-Tetracosanoïque), Palmitoleique (cis-Δ9-Hexadecenoïque), Oleique (cis- Δ9-Octadecenoïque), Linoleique (cis, cis- Δ9-, Δ12- Octadecadienoïque), Linolenique (all-cis- Δ9-, Δ12-, Δ15-Octadecatrienoïque), Arachidonique (all-cis- Δ5-, Δ8-, Δ11-, Δ14-Eicosatetraenoïque)Among the fatty acids used in the context of the present invention, mention may especially be made of C12 to C24 acids, Lauric acid (n-Dodecanoic acid), Myristic acid (n-Tetradecanoic acid), Palmitic acid (n-Hexadecanoic acid), Stearic acid (n - Octadecanoic), Arachidic (n-Eicosanoic), Behenic (n-Docosanoic), Lignoceric (n-Tetracosanoic), Palmitoleic (cis-Δ 9 -Hexadecenoic), Oleic (cis- Δ 9 -Octadecenoic), Linoleic (cis, cis - Δ 9 -, Δ 12 - Octadecadienoic), Linolenic (all-cis- Δ 9 -, Δ 12 -, Δ 15 -Octadecatrienoic), Arachidonic (all-cis- Δ 5 -, Δ 8 -, Δ 11 -, Δ 14 -Eicosatetraenoic)
On préfère les acides gras polyinsaturés et l'acide linoleique et oléique sont particulièrement actifs dans l'utilisation objet de l'invention.Polyunsaturated fatty acids and linoleic and oleic acids are particularly active in the object of the invention.
Les acides gras ont été testés in vitro pour leur capacité à inhiber l'activité de certains des composants pro-inflammatoires du venin d'abeille, et in vivo chez le rat dans des modèles d'oedèmes induits par du venin d'abeille. Les résultats de ces essais montrent que les acides gras peuvent être utilisés pour la fabrication de compositions destinées au traitement local des inflammations faisant suite aux piqûres d'hyménoptères à venin.Fatty acids have been tested in vitro for their ability to inhibit the activity of some of the pro-inflammatory components of bee venom, and in vivo in rats in models of edema induced by bee venom. The results of these tests show that the fatty acids can be used for the manufacture of compositions intended for the local treatment of inflammations following the bites of venom hymenopterans.
Dans le cas présent, la composition dont l'utilisation est l'objet de l'invention peut en outre comprendre d'autres principes actifs notamment un anesthésiant et/ou un antibiotique et/ou une substance anti-allergique ou anti¬ inflammatoire.In this case, the composition whose use is the subject of the invention may further comprise other active ingredients including anesthetic and / or an antibiotic and / or an anti-allergic or anti-inflammatory substance.
Les acides gras peuvent être formulés sous toutes les formes adaptées à l'administration topique, en association avec des excipients appropriés pour permettre une administration d'une dose de 0,01 à 50 mg par piqûre d'hyménoptère à venin. La dose pourra bien entendu varier en fonction de la quantité de venin absorbée, du nombre de piqûres ou encore du type d'insecte. Parmi les formulations galéniques qui peuvent être adaptées pour la mise en œuvre de l'invention on peut citer les pommades, les crèmes, les gels, les patchs, les poudres, les sprays ou encore les lotions. Une application grâce à un stick peut s'avérer particulièrement avantageuse pour les piqûres uniques sur un membre par exemple. Si les muqueuses ou encore les yeux sont atteints on préfère respectivement une formulation sous forme d'un spray ou d'un collyre.The fatty acids may be formulated in any form suitable for topical administration, in combination with suitable excipients to allow administration of a dose of 0.01 to 50 mg per venom hymenopteran bite. The dose may of course vary depending on the amount of venom absorbed, the number of bites or the type of insect. Among the galenic formulations that can be adapted for the implementation of the invention include ointments, creams, gels, patches, powders, sprays or lotions. An application with a stick can be particularly advantageous for single stings on a member for example. If the mucous membranes or the eyes are affected, a formulation in the form of a spray or eye drops is preferred.
Dans certains cas on préférera administrer la composition faisant l'objet de la présente invention par voie d'injection locale. Les substances actives des compositions pharmaceutiques selon l'invention peuvent être dissoutes ou mises en suspension dans un liquide injectable stérile pharmaceutiquement acceptable, tel que l'eau stérile, un solvant organique stérile ou un mélange de ces deux liquides pour une administration par voie locale, pour permettre une administration d'une dose de 0,001 à 1 mg par piqûre d'hyménoptère à venin. L'invention sera mieux comprise à la lecture des exemples qui suivent et qui se réfèrent aux figures ci-après :In some cases it will be preferred to administer the composition forming the subject of the present invention by local injection. The active substances of the pharmaceutical compositions according to the invention may be dissolved or suspended in a pharmaceutically acceptable sterile injectable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids for local administration, to allow administration of a dose of 0.001 to 1 mg per venom hymenopteran bite. The invention will be better understood on reading the examples which follow and which refer to the figures below:
Fig. 1 : illustre le pourcentage d'inhibition de l'activité PLA 2 du venin d'abeille en fonction de la concentration en acide qui est utilisé pour : 1.A - L'acide linoléique (exemple 1) 1.B - L'acide oléique (exemple 1)Fig. 1: illustrates the percentage inhibition of PLA 2 activity of bee venom as a function of the acid concentration which is used for: 1.A - Linoleic acid (Example 1) 1.B - Acid oleic (example 1)
Fig. 2 : illustre l'effet de l'acide oléique et linoléique sur l'augmentation du volume de la patte de rat dans un modèle d'inflammation, en fonction du temps après injection du venin d'abeille (exemple 2 - expérience 1).Fig. 2: illustrates the effect of oleic and linoleic acid on the increase in the volume of the rat paw in an inflammation model, as a function of the time after injection of the bee venom (example 2 - experiment 1).
Fig. 3 : illustre l'effet de l'acide oléique et linoléique l'augmentation du volume de la patte de rat dans un modèle d'inflammation, en fonction du temps après injection du venin d'abeille (exemple 2 - expérience 2)Fig. 3: illustrates the effect of oleic and linoleic acid the increase in the volume of the rat paw in a model of inflammation, as a function of the time after injection of the bee venom (example 2 - experiment 2)
Fig. 4 : illustre l'effet de l'acide oléique et linoléique l'augmentation du volume de la patte de rat dans un modèle d'inflammation, en fonction du temps après injection du venin d'abeille (exemple 2 - expérience 3)Fig. 4: illustrates the effect of oleic and linoleic acid the increase in the volume of the rat paw in a model of inflammation, as a function of the time after injection of the bee venom (example 2 - experiment 3)
Exemple I : Effets inhibiteurs in vitro de l'acide linoléique et de l'acide oiéique sur l'activité phospholipase A2 de venin d'abeille (PLA2), composante inflammatoire majeure de ce venin :Example I: In vitro inhibitory effects of linoleic acid and oic acid on the activity of phospholipase A2 of bee venom (PLA2), a major inflammatory component of this venom:
L'effet de l'acide linoléique et oléique sur l'activité PLA2 est mesuré selon la méthode d'extraction à l'hexane décrite par Kαtsumαtα, M. Guptα, G. and Goldman AS., (1986), Anal. Biochem. 154 (2), 676-681. L'activité PLA2 est déterminée en utilisant un substrat radioactif, le L-a-dipalmitoyl-[2,9,10 (N)-3H- pa!mitoyl]-phosphatidylcholine. La réaction est réalisée dans 1 ml de tampon glycine/NaOH, pH 9, contenant 2.2 mM de désoxycholate, 0.11 μCi de dipalmitoyl-PC et 32 mU/ml de PLA2 de venin d'abeille. Après 20 minutes d'incubation, la réaction est arrêtée en ajoutant 0.2 ml d'une solution Triton X- 100/EDTA, puis le produit de la réaction, l'acide palmityque radiomarqué, est extrait par une solution d'hexane contenant 0.1 % d'acide acétique et 0.7g/ml de Na2SO4. La radioactivité des extraits est déterminée à l'aide d'un compteur à scintillation liquide. Les résultats représentent la moyenne ± SEM des valeurs en CPM obtenues dans deux expériences indépendantes. Les figures 1A et 1 B illustrent le pourcentage d'inhibition de l'activité PLA2 (axe vertical) en fonction de la concentration d'acide gras utilisé (axe horizontal). Ces résultats démontrent que l'acide linoléique et oléique inhibent de manière dose dépendante l'activité enzymatique de la PLA2 de venin d'abeille.The effect of linoleic and oleic acid on PLA2 activity is measured according to the hexane extraction method described by Kαtsumαtα, M. Guptα, G. and Goldman AS., (1986), Anal. Biochem. 154 (2), 676-681. PLA2 activity is determined using a radioactive substrate, La-dipalmitoyl- [2,9,10 (N) -3H-p-mitoyl] -phosphatidylcholine. The reaction is carried out in 1 ml of glycine / NaOH buffer, pH 9, containing 2.2 mM deoxycholate, 0.11 μCi of dipalmitoyl-PC and 32 mU / ml PLA2 of bee venom. After 20 minutes of incubation, the reaction is stopped by adding 0.2 ml of a Triton X-100 / EDTA solution, then the reaction product, the radiolabelled palmityc acid, is extracted with a hexane solution containing 0.1% of acetic acid and 0.7g / ml of Na2SO4. The radioactivity of the extracts is determined using a liquid scintillation counter. The results represent the mean ± SEM of the CPM values obtained in two independent experiments. FIGS. 1A and 1B illustrate the percentage inhibition of PLA2 activity (vertical axis) as a function of the concentration of fatty acid used (horizontal axis). These results demonstrate that linoleic and oleic acid inhibit in a dose-dependent manner the enzymatic activity of PLA2 of bee venom.
Exemple 11 :Example 11
Activité de l'acide oléique et linoléique dans un modèle d'œdème inflammatoire provoqué par le venin d'abeille chez le rat (Rabinovich, GA.Sotomayor CE., Riera, CM., Bianco I. and Correa SG. (2000), Eur. J. Immunol. 30, 1331-1339; Chen, J., Luo C, Li, HL. And Chen HS, (1999), Pain, 83, 67-76) Expérience 1 :Activity of oleic and linoleic acid in a model of inflammatory edema caused by bee venom in rats (Rabinovich, GA.Sotomayor CE, Riera, CM, Bianco I. and Correa SG (2000), Eur J. Immunol 30, 1331-1339, Chen, J., Luo C, Li, HL And Chen HS, (1999), Pain, 83, 67-76) Experiment 1:
Le venin d'abeille (20μg/ml dans NaCI 0.9%) est incubé, à température ambiante, en présence ou non d'acide linoléique (32 μM). 30 minutes après le début de l'incubation, les solutions (25μl) sont injectées par voie sous cutanée à des rats Sprague Dawley (110-140g), au niveau de la face supérieure du pied. L'oedème est mesuré à l'aide d'un pléthysmomètre 5 - 10 - 15 - 20 - 30 - 60 et 90 minutes après l'injection. Les résultats représentent la moyenne ± SEM de 5 animaux. Les comparaisons statistiques sont réalisées par un test de t, dont le groupe témoin est constitué par les animaux ayant reçut le venin seul. * P< 0.05, *** P< 0.005. Les résultats sont représentés en figure 2. Expérience 2 :Bee venom (20 μg / ml in NaCl 0.9%) is incubated at room temperature, in the presence or absence of linoleic acid (32 μM). 30 minutes after the start of the incubation, the solutions (25 μl) are injected subcutaneously to Sprague Dawley rats (110-140 g), at the level of the upper surface of the foot. Edema is measured with a plethysmometer 5 - 10 - 15 - 20 - 30 - 60 and 90 minutes after injection. The results represent the mean ± SEM of 5 animals. Statistical comparisons are made by a t-test, of which the control group consists of animals that received venom alone. * P <0.05, *** P <0.005. The results are shown in Figure 2. Experience 2:
120 et 30 minutes avant l'injection du venin d'abeille (20μg/ml dans NaCI 0.9%) des rats Sprague Dawley (110-14Og) sont traités ou non, sur le dessus du pied, par application topique d'acide linoléique. L'oedème est mesuré à l'aide d'un pléthysmomètre 5 - 10 - 15 - 20 et 30 minutes après l'injection sous cutané du venin d'abeille au niveau de la face supérieure du pied de l'animal. Les résultats (figure 3) représentent la moyenne ± SEM de 20 animaux. Les comparaisons statistiques sont réalisées par un test de t, dont le groupe témoin est constitué par les animaux traités par le véhicule (acétone). * P< 0.05, ** P< 0.01 , *** P< 0.005120 and 30 minutes before the injection of the bee venom (20 μg / ml in NaCl 0.9%) Sprague Dawley rats (110-14Og) are treated or not, on the top of the foot, by topical application of linoleic acid. The edema is measured with a plethysmometer 5 - 10 - 15 - 20 and 30 minutes after the subcutaneous injection of the bee venom at the level of the upper surface of the foot of the animal. The results (Figure 3) represent the mean ± SEM of 20 animals. The statistical comparisons are made by a t test, the control group of which consists of the animals treated with the vehicle (acetone). * P <0.05, ** P <0.01, *** P <0.005
Expérience 3 :Experience 3:
120 et 30 minutes avant l'injection du venin d'abeille (20μg/ml dans NaCI 0.9%) des rats Sprague Dawley (110-14Og) sont traités ou non, sur le dessus du pied, par application topique d'acide oléique. L'oedème est mesuré à l'aide d'un pléthysmomètre 5 - 10 - 15 et 20 minutes après l'injection sous cutané du venin d'abeille au niveau de la face supérieure du pied de l'animal. Les résultats (figure 4) représentent la moyenne ± SEM de 5 animaux. Les comparaisons statistiques sont réalisées par un test de t, dont le groupe témoin est constitué par les animaux traités par le véhicule (acétone). * P< 0.05. 120 and 30 minutes before the injection of the bee venom (20 μg / ml in NaCl 0.9%) Sprague Dawley rats (110-14Og) are treated or not, on the top of the foot, by topical application of oleic acid. The edema is measured with a plethysmometer 5 - 10 - 15 and 20 minutes after the subcutaneous injection of bee venom at the level of the upper surface of the foot of the animal. The results (Figure 4) represent the mean ± SEM of 5 animals. The statistical comparisons are made by a t test, the control group of which consists of the animals treated with the vehicle (acetone). * P <0.05.

Claims

Revendications claims
1. Utilisation d'un acide gras pour la préparation d'une composition topique ou injectable destinée à l'apaisement des réactions inflammatoires dues aux piqûres d'hyménoptères.1. Use of a fatty acid for the preparation of a topical or injectable composition for the alleviation of inflammatory reactions due to bites of hymenoptera.
2. Utilisation selon la revendication 1 , caractérisée en ce que l'acide gras est un acide en C12 à C24.2. Use according to claim 1, characterized in that the fatty acid is a C12 to C24 acid.
3. Utilisation selon l'une des revendications 1 et 2, caractérisée en ce que l'acide gras est choisi parmi : l'acide Laurique (n-Dodecanoïque), Myristique (n- Tetradecanoïque), Palmitique (n-Hexadecanoïque), Stearique (n- Octadecanoïque), Arachidique (n-Eicosanoïque), Behenique (n-Docosanoïque), Lignocerique (n-Tetracosanoïque), Palmitoleique (cis-Δ9-Hexadecenoïque), Oleique (cis- Δ9-Octadecenoïque), Linoleique (cis, cis- Δ9-, Δ12- Octadecadienoïque), Linolenique (all-cis- Δ9-, Δ12-, Δ15-Octadecatrienoïque), Arachidonique (all-cis- Δ5-, Δ8-, Δ11-, Δ14-Eicosatetraenoïque)3. Use according to one of claims 1 and 2, characterized in that the fatty acid is selected from: Lauric acid (n-Dodecanoic), Myristic (n-Tetradecanoic), Palmitic (n-Hexadecanoic), Stearic (n-Octadecanoic), Arachidic (n-Eicosanoic), Behenic (n-Docosanoic), Lignoceric (n-Tetracosanoic), Palmitolic (cis-Δ 9 -Hexadecenoic), Oleic (cis- Δ 9 -Octadecenoic), Linoleic (cis , cis- Δ 9 -, Δ 12 - Octadecadienoic), Linolenic (all-cis- Δ 9 -, Δ 12 -, Δ 15 -Octadecatrienoic), Arachidonic (all-cis- Δ 5 -, Δ 8 -, Δ 11 - , Δ 14 -Eicosatetraenoic)
4. Utilisation selon l'une des revendications 1 et 2, caractérisée en ce que l'acide gras est choisi parmi l'acide linoleique et l'acide oléique.4. Use according to one of claims 1 and 2, characterized in that the fatty acid is selected from linoleic acid and oleic acid.
5. Utilisation selon l'une quelconque des revendications 1 à 4, caractérisée en ce que l'acide gras peut être appliqué sous différentes formes galéniques choisie parmi les pommades, les crèmes, les gels, les patchs, les poudres, les sprays, les lotions ou les sticks.5. Use according to any one of claims 1 to 4, characterized in that the fatty acid may be applied in different dosage forms selected from ointments, creams, gels, patches, powders, sprays, lotions or sticks.
6. Utilisation selon l'une des revendications 1 à 4, caractérisée en ce que la composition est sous forme injectable. 6. Use according to one of claims 1 to 4, characterized in that the composition is in injectable form.
EP05791091A 2004-07-21 2005-07-18 Use of a fatty acid for preparing a topical composition for allaying inflammatory reactions due to venemous hymenoptera stings Withdrawn EP1768659A1 (en)

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FR0408070A FR2873293B1 (en) 2004-07-21 2004-07-21 USE OF A FATTY ACID FOR THE PREPARATION OF A TOPIC COMPOSITION FOR THE SATURATION OF INFLAMMATORY REACTIONS DUE TO VENOUS HYMENOPTER PENSIONS
PCT/FR2005/001826 WO2006021647A1 (en) 2004-07-21 2005-07-18 Use of a fatty acid for preparing a topical composition for allaying inflammatory reactions due to venemous hymenoptera stings

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JP6628946B2 (en) 2017-12-26 2020-01-15 大太朗 福岡 Pharmaceutical composition for use in hair growth, scalp or skin modification, wound healing, bone formation promotion, or hair modification

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