WO2019166649A1 - Veterinary compositions for controlling mosquitoes - Google Patents

Veterinary compositions for controlling mosquitoes Download PDF

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Publication number
WO2019166649A1
WO2019166649A1 PCT/EP2019/055202 EP2019055202W WO2019166649A1 WO 2019166649 A1 WO2019166649 A1 WO 2019166649A1 EP 2019055202 W EP2019055202 W EP 2019055202W WO 2019166649 A1 WO2019166649 A1 WO 2019166649A1
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Prior art keywords
compound
human mammal
weeks
composition
mosquitoes
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PCT/EP2019/055202
Other languages
French (fr)
Inventor
Marie VARLOUD
Romain DELCOMBEL
Hamadi Karembe
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Ceva Sante Animale
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Publication of WO2019166649A1 publication Critical patent/WO2019166649A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N51/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds having the sequences of atoms O—N—S, X—O—S, N—N—S, O—N—N or O-halogen, regardless of the number of bonds each atom has and with no atom of these sequences forming part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

Definitions

  • the present invention relates to the use of compositions in the veterinary field and more particularly in the parasitology field.
  • the invention relates more specifically to the use of veterinary compositions for controlling mosquitoes and/or mosquito-bome diseases in non-human mammals, such as cats and dogs.
  • Aedus spp. (or Stegomyia spp.), especially Aedus Aegypti, is also a vector of the life- threatening mosquito-bome disease in dogs, such as nematodes.
  • the heartworm or Dirofilaria immitis is a nematode transmitted to dog at L3 larvae stage consecutively to mosquitoes biting. After developing and molting, adult male and female worms reach pulmonary arteries and heart where they mate to give birth to microlarvae, referred to as microfilariae. Microfilariae circulate in the dog’s peripheral blood where they can be ingested by mosquitoes during blood meal.
  • aegypti can also be the vector of Dirofilaria repens, the zoonotic agent of the cutaneous dirofilariosis and of Brugyia spp. ( B . malayi, B. timori, B. pahangi, B. beaveri, B. lepori, B. guyanensis), the zoonotic agents of lymphatic filariosis.
  • B repens dogs and other canidae are reservoir.
  • dogs and cats are among the reservoirs.
  • the gold standard for the protection of naive dogs is based on annual or seasonal administration of macrocyclic lactones (MLs).
  • Ivermectin, moxidectin, milbemycin oxime or selamectin are available as oral tablets, topical solution or subcutaneous cutaneous suspension for monthly or every six or twelve months applications.
  • Macrocyclic lactones inhibit the development of L3 stage to adults by killing the Dirofilaria spp. larvae. However, they do not prevent the transmission or dissemination of this nematode larval stage. Therefore, additional preventive measures should be considered to inhibit transmission and to support the preventive activity of macrocyclic lactones.
  • Vector control is a pragmatic approach.
  • Several topical spot-on formulations containing repellent and insecticide molecules have been developed in veterinary medicine.
  • these commercially available products comprise a repellent pyrethroid (permethrin, flumethrin, deltamethrin) and can further comprise an insecticide such as phenylpyrazoles (Fipronil), neonicotinoids (Dinotefuran and imidacloprid), or methoprene.
  • phenylpyrazoles Fupronil
  • neonicotinoids Dinotefuran and imidacloprid
  • methoprene methoprene.
  • Advantix ® product (Bayer) comprising imidacloprid and permethrin
  • Exspot ® product comprising 65% permethrin in propylene glycol mo no methyl ether, allow to obtain an efficient repellency effect against A. aegypti for 2-
  • a veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family allows to obtain a long-term control of mosquitoes compared to the existing treatments.
  • the inventors have demonstrated that such composition provides an efficient control of mosquitoes beyond 4 weeks, particularly for at least 5 weeks and up to 8 weeks, illustrated by an efficient repellency effect, an efficient insecticidal effect, and an efficient knock-down effect.
  • the present invention therefore relates to a veterinary composition
  • a veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks, preferably at least every six weeks, more preferably at least every seven weeks, even more preferably at least every eight weeks.
  • the weight ratio of the compound of the pyrethroid family to the compound of the neonicotinoid family is between 4 and 15, preferably between 6 and 9, and more preferably between 7 and 8.
  • the compound of the neonicotinoid family is dinotefuran.
  • the compound of the pyrethroid family is permethrin.
  • the composition further comprises an insect growth regulator.
  • the weight ratio of the insect growth regulator to the compound of the neonicotinoid family is between 0.05 and 0.12, preferably between 0.06 and 0.1, and more preferably between 0.07 and 0.09.
  • the insect growth regulator is methoprene or pyriproxyfen, preferably pyriproxyfen.
  • the composition is intended to be applied topically to the skin of the non-human mammal.
  • the composition is intended to be applied to the skin of the non-human mammal against the direction of the coat.
  • the composition is intended to be applied continuously against the direction of the coat from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
  • the non-human mammal is a dog or a cat, preferably a dog.
  • the mosquitoes are of the Aedes genus, preferably are Aedes aegypti, and/or of the Cal ex genus, preferably Cal ex pipiens.
  • Another object of the present invention is a veterinary composition as described in the present application, for use for controlling a mosquito-bome disease in a non-human mammal, preferably in cats and/or dogs, more preferably in a dog.
  • a further object of the invention relates to a kit comprising one or more compartments, said compartments comprising a combination of a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for simultaneous use of said composition at least every five weeks, preferably at least every eight weeks for controlling mosquitoes and/or a mosquito-bome disease in a non human mammal, preferably in a dog.
  • the kit further comprises an instruction sheet or notice regarding the method of administration and the procedure of the combination for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog.
  • Figure 1 Anti-feeding (repellency), knock-down and insecticidal effects against Aedes aegypti mosquitoes in dogs treated with a veterinary composition of the invention.
  • compositions of the invention comprise a compound of the neonicotinoid family and a compound of the pyrethroid family, for controlling in non-human mammals.
  • the compounds of the neonicotinoid family are chemically similar to nicotine. They correspond to a class of insecticides that act on the central nervous system of insects by inhibiting nicotinic acetylcholine receptors, thus causing paralysis and death of the parasitic insect. They were introduced onto the market in the l990s and are particularly active against ectoparasites such as fleas, flies and lice.
  • Compounds of the neonicotinoid family include, without limitation, imidacloprid, thiamethoxam, clothianidin, acetamiprid, thiacloprid, dinotefuran, nitenpyram, imidaclothiz, huanyanglin, guadipyr, paichongding, cycloxaprid and derivatives thereof or pharmaceutically acceptable salts thereof.
  • a preferred compound of the neonicotinoid family of the invention is dinotefuran.
  • the term“dinotefuran” also comprises the derivatives or analogs thereof, the metabolites thereof and the pharmaceutically acceptable salts thereof.
  • Dinotefuran was described by the company Mitsui Toatsu Chemicals, Inc. in patent EP 0 649 845 and was developed for insect-pest control.
  • Dinotefuran also called 2-methyl- l-nitro-3-[(tetrahydro-3-furanyl)methyl]guanidine
  • the dinotefuran metabolites include, without limitation, N-desmethyl dinotefuran (2-nitro-l-(tetrahydro-3- furylmethyl)guanidine), DIN-NNO, DIN-dm-NNO, DIN-NNEE, l-methyl-3-
  • the dinotefuran derivatives or analogs comprise all the compounds described in patent EP 0 649 845. More particularly, the dinotefuran derivatives or analogs comprise, without limitation, l-[ ⁇ (tetrahydro-3-furanyl)methyl ⁇ amino]- l-methylamino- 2-nitroethylene, 1 -[ ⁇ (tetrahydro-3-furanyl)methyl ⁇ amino]- 1 -ethylamino-2- nitroethylene, 1 -[ ⁇ (tetrahydro-3-furanyl)methyl) amino]- 1 -dimethylamino-2- nitroethylene, 1 -[ ⁇ (tetrahydro-3-furanyl)methyl) amino]- 1 -(1 -pyrrolidinyl)-2- nitroethylene, l-[N- ⁇ (tetrahydro-3-furanyl)methyl ⁇ -N-methylamino]- 1 -methylamino-2- nitroethylene, l-[N- ⁇ (tetrahydr
  • the compounds of the pyrethroid family are compounds which act on the insect nervous system and disrupt neuron function by interacting with sodium channels.
  • Compounds of the pyrethroid family include, without limitation, ethofenprox, permethrin, prallethrin, resmethrin, sumithrin, allethrin, alpha-cypermethrin, bifenthrin, beta-cypermethrin, cyfluthrin, cypermethrin, deltamethrin, flumethrin, esfenvalerate, lamda-cyhalothrin, zeta-cypermethrin, and the derivatives thereof or the pharmaceutically acceptable salts thereof
  • a preferred compound of the pyrethroid family is permethrin.
  • compositions of the invention further comprise an insect growth regulator.
  • Insect growth regulators are chemical substances which inhibit the lifecycle of insects.
  • insect growth regulators mention may be made, without limitation, of azadirachtin, hydroprene, methoprene, pyriproxyfen, triflumuron, and the derivatives thereof or the pharmaceutically acceptable salts thereof.
  • a preferred insect growth regulator compound is pyriproxyfen or methoprene, and is preferably pyriproxyfen.
  • pharmaceutically acceptable salts is intended to mean both organic salts and inorganic salts.
  • inorganic salts comprise hydrochlorides, hydrobromides, iodates, sulfonates and phosphates.
  • organic salts comprise formates, acetates, trichloroacetates, propionates, benzoates, cinnamates, fumarates, maleates and methanesulfonates.
  • the composition comprises a compound of the neonicotinoid family, preferably dinotefuran, and a compound of the pyrethroid family, preferably permethrin, in weight amounts such that the weight ratio of the compound of the pyrethroid family to the compound of the neonicotinoid family is between 4 and 15, preferentially between 6 and 9, and even more preferentially between 7 and 8.
  • the composition comprises a compound of the neonicotinoid family, preferably dinotefuran, and a compound of the pyrethroid family, preferably permethrin, and an insect growth regulator, preferably pyriproxyfen, in weight amounts such that the weight ratio of the insect growth regulator to the compound of the neonicotinoid family is between 0.05 and 0.12, preferentially between 0.06 and 0.1, and even more preferentially between 0.07 and 0.09.
  • the composition comprises about 60% to 95% of permethrin, about 6% to 22% of dinotefuran, and optionally about 0.8% to 4% of pyriproxyfen. In a more preferred embodiment of the invention, the composition comprises about 70% to 90% of permethrin, about 8% to 15% of dinotefuran, and optionally about 0.9% to 1.5% of pyriproxyfen. According to these preferred embodiments of the invention, the percentages are expressed by weight relative to the total weight of the compounds which are permethrin, dinotefuran and optionally pyriproxyfen.
  • composition comprises:
  • non-human mammal is intended to mean any non-human mammal capable of being stung or bitten by mosquitoes and thus developing mosquito-bome diseases or being a reservoir for any of these diseases, meaning that already suffering from a vector-borne disease and able to contaminate another non-human mammal via mosquitoes.
  • the non-human mammal may in particular be a member of the canine family, such as a dog, a fox, a coyote or a wolf, or a member of the feline family, such as a cat, a lion or a panther.
  • the non-human mammal belongs to the pets group including for instance a dog, a cat, a rodent, a rabbit, etc. In one more preferred embodiment, the non-human mammal is a dog or a cat, more preferentially a dog.
  • control and“controlling” are intended to mean, without limitation, the action of reducing, repelling (anti-feeding), eradicating, eliminating, killing and preventing mosquitoes in non-human mammals.
  • the notion of “preventing” also comprises decreasing, reducing or preventing a mosquito blood meal in non-human mammals, which results in reducing the risks of infection of surrounding subjects and thus contributes to limiting the spread of the mosquito-bome disease.
  • the invention also relates to a method for controlling mosquitoes in non-human mammals, comprising the administration of an effective amount in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks of a composition as defined herein comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in non human mammals.
  • the expression“effective amount” means the amount of the compound of the neonicotinoid family, of the compound of the pyrethroid family, and optionally of the insect growth regulator that is capable of causing sufficient mosquito control. It is accepted by those skilled in the art that sufficient control is obtained when at least 80% of mosquitoes are controlled.
  • the repellent effect (or anti-feeding efficacy) is evaluated using the Abbott formula (Abbott, W.S.: A method of computing the effectiveness of an insecticide; J. Econ. Entomol; 1925; 18; 265-267) calculating the percentage (%) corresponding to the difference between the number of engorged mosquitoes (or feeding mosquitoes) calculated in a non-treated non-human mammal (control group) and the number of engorged mosquitoes calculated in a treated non-human mammal (treated group) relative to the number of engorged mosquitoes calculated in a non-treated, non-human mammal, i.e.:
  • Anti-feeding efficacy (%) ((Number of engorged mosquitoes of the control group - Number of engorged mosquitoes of the treated group) / Number of engorged mosquitoes of the control group) x 100.
  • An engorged mosquito (or fed with blood) corresponds to a mosquito that has already bitten or stung and fed on blood of the non-human mammal.
  • the arithmetic and geometric means are used.
  • the insecticidal effect is evaluated by calculating the percentage (%) corresponding to the difference between the number of live mosquitoes observed in a non-treated, non human mammal (control group) and the number of live mosquitoes observed in a treated, non-human mammal (treated group) relative to the number of live mosquitoes observed in a non-treated, non-human mammal, i.e.:
  • Insecticidal efficacy (%) ((Number of live mosquitoes of the control group - Number of live mosquitoes of the treated group) / Number of live mosquitoes of the control group) x 100.
  • the knock-down effect is evaluated by calculating the percentage (%) corresponding to the difference between the number of live and moribund mosquitoes observed in a non- treated, non-human mammal (control group) and the number of live and moribund mosquitoes observed in a treated, non-human mammal (treated group) relative to the number of live and moribund mosquitoes observed in a non-treated, non-human mammal, i.e.:
  • Knock-down efficacy (%) ((Number of live and moribund mosquitoes of the control group - Number of live and moribund mosquitoes of the treated group) / Number of live and moribund mosquitoes of the control group) x 100.
  • a moribund mosquito exhibits uncoordinated movement, including under stimulation and is not able to fly.
  • the arithmetic and geometric means are used.
  • a further object of the invention relates to a method for controlling at least about 80% of mosquitoes in a non-human mammal, comprising the administration of an effective amount in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks of a composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in said non-human mammals.
  • a further object of the invention is a composition as disclosed herein for use for preventing and/or controlling a mosquito-bome disease in a non-human mammal, preferably in cats and/or dogs, more preferably in a dog.
  • a “mosquito-bome disease” refers to any disease transmitted by mosquitoes.
  • a“mosquito-bome disease” is due to the transmission of a pathogen in a non-human mammal by the mosquito.
  • The“pathogen” includes for instance viruses (like West Nile vims), bacteriae, protozoae, endoparasites of mammals, more especially hookworms, flatworms, tapeworms, more especially gastro -intestinal nematodes, cardio-pulmonary nematodes and/or heartworms.
  • a mosquito-bome disease is heartworm disease, a Dirofilaria repens and/or Brugyia spp. infestation.
  • compositions as disclosed herein can thus be used to prevent and/or control an infection by a pathogen transmitted during the blood feeding of mosquitoes such as viruses (like West Nile virus), bacteriae, protozoae, endoparasites of mammals, more especially hookworms, flatworms, tapeworms, more especially gastro -intestinal nematodes, cardio-pulmonary nematodes and/or heartworms.
  • mosquitoes such as viruses (like West Nile virus), bacteriae, protozoae, endoparasites of mammals, more especially hookworms, flatworms, tapeworms, more especially gastro -intestinal nematodes, cardio-pulmonary nematodes and/or heartworms.
  • mosquitoes are acknowledged to be disease vectors such as filariae.
  • filariae generally include nematodes that typically reside within the heart and lungs of a host during the final reproductive stages of its life cycle. Some specific filariae may include Dirofilaria immitis (heartworm) and Dirofilaria repens (the agent of cutaneous dirofilariosis) and any other similar nematode of the same class or subclass.
  • “Heartworm disease” is typically a disease due to an infestation of a heartworm as above defined. In a particular embodiment,“Heartworm disease” is a Dirofilaria immitis infestation.
  • the cat and dog endoparasite transmitted by mosquitoes is a nematode and/or a trematode in circulatory system.
  • cat and dog worms those from the Filarioidae family may be cited such as Dirofilaria spp. ( immitis , repens ) and Brugia spp. (pahangi, malayi).
  • a preferred circulatory system worm is Dirofilaria spp. (heartworm).
  • the cat and dog endoparasite transmitted by mosquitoes is a nematode in subcutaneous tissues, preferably Dirofilaria spp. ⁇ repens).
  • Mosquitoes are also acknowledged to be viruses vector.
  • Arboviruses (means virus transmitted by mosquitoes) families Flaviviridae (genus Flavivirus ) and Togaviridae (genus Alphavirus ) are important in both humans and domestic animals, such as alphaviruses (Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus) and flaviviruses (Japanese encephalitis virus and West Nile virus), Alphaviridae, like chikungunya fever, Bunyaviridae like Rift-Valley fever, Dengue, Yellow fever, Zika virus, Usutu virus, etc.
  • Mosquitoes are further acknowledged to be bacteria and/or protozoa vector.
  • bacteria transmitted by mosquitoes Tularemia and Rickettsia spp. may be cited.
  • protozoa transmitted by mosquitoes malaria (. Plasmodium spp.: Plasmodium falciparum, ect.) may be cited.
  • “mosquitoes” include any mosquito able to bite or stung a non-human mammal such as a dog or a cat.
  • mosquitoes feeding on the blood of cat and dogs are from the family Culicidae:
  • Aedes spp. (or Stegomyia spp.): A. cinereus, A. esoensis, A. rossicus, A. vexans, A. vittatus, A. aegypti, A. albopictus, A. stricticus, A. cantans, A. communis, A. punctor, A. japonicus, A. geniculatus, A. detritus, A. africanus, A. furcifer, A. niveus, A. taylori, A. luteocephalus, A. simpsoni, and A. scapularis;
  • Anopheles spp. A. anopheles, A. cellia, kerteszia, A. gambiae, A. lophodomyia, A. nyssorhynchus, A. stethomyia, A. baimaia, A. messeae, A. maculipennis, A. claviger, A. plumbeus, A. aquasalis, A. belator, A. darlingi, A. funestus, A. arabiensis, A. bwanbae, A; melas, A. merus, A. nili, and A. pauliania;
  • C. pipiens C. anips, C. annulirostris, C. apicalis, C. conservator, C. corniger, C. pilosus, C. reevesi, C. adami, C. rubinotus, C. tar sails, C. tritaeniorhynchus, C. modestus, C. antennatus, C. bahamensis, C. erraticus, C. nigripalpus, C. quinquefasciatus, C. restuans, C. salinarius, C. theileri, C. tritaeniorhynchus, C. univittatus, and C. vishnui
  • Ochlerotatus spp. O. acartomyia, O. culicelsa, O. gilesia, O. protoculex, O. empihals, O. pholeomyia, O. sallumia, O. buvirillia, and O. caspius
  • Uranotaenia spp. abdita, nigerrima, nigerrima, harrisoni, yunnanensis, pifanoi, leucoptera, gerdae, campestris, grasse, mayottensis, mashonaensis, madagascarensis and
  • the mosquitoes are Aedes aegypti, Aedes albopictus and Culex pipiens.
  • the invention thus also relates to a veterinary composition
  • a veterinary composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for use for controlling a mosquito-bome disease in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks.
  • the invention also relates to the use of a veterinary composition
  • a veterinary composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in manufacturing of a drug for controlling a mosquito-bome disease in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks.
  • the invention also relates to a method for controlling a mosquito-bome disease in non human mammal, comprising the administration of an effective amount of a composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family and optionally an insect growth regulator, in a non-human mammal which may or may not be suffering from heartworm disease, said composition being intended to be administered in a single dose, at least every five weeks.
  • the expressions“controlling mosquito-bome diseases”, “mosquito-bome diseases treatment” and “mosquito-bome prevention” denote the protection of the non-human mammal against mosquito-bome diseases, i.e. the protection of the non-human mammal by controlling mosquitoes. According to one particular embodiment, these expressions include the preventive treatment of the non human mammal against mosquito-bome diseases.
  • a preventive treatment denotes a treatment carried out before the non-human mammal has been exposed to or has been in contact with the causative agent of a mosquito-bome disease, i.e. mosquitoes.
  • a preventive treatment therefore reduces the risks of the non-human mammal developing a mosquito-bome disease.
  • a preventive treatment also denotes a treatment carried out in a non-human mammal suffering from a mosquito-bome disease. The treatment carried out in a sick subject makes it possible to control the mosquitoes in its environment and to reduce the risks of infection in the surrounding healthy subjects, contributing thereby to limit the spread of the mosquito-bome disease.
  • the composition is intended to be administered in a single dose, at least every five weeks.
  • the composition is administered to the non-human mammal at a time TO and is then again administered at a time Tl, at least 5 weeks later, such as 5, 6, 7, or 8 weeks later.
  • the composition is administered every 5 to 8 weeks, every 6 to 8 weeks, or every 7 to 8 weeks.
  • the treatment can be repeated every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.
  • the composition is administered to the non-human mammal every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.
  • the duration of the treatment is 5 weeks, 8 weeks, 16 weeks, 32 weeks, 1 year, 64 weeks, 2 years, 5 years, and more preferably until the death of the non-human mammal.
  • the composition is intended to be administered in a single dose to the non-human mammal at a time TO and is not repeated later.
  • the term“every” means a unique treatment in with the composition is efficient up to 5, 6, 7, and preferably up to 8 weeks.
  • the present invention also relates to a 5, 6, 7, or 8 weeks long acting veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes in a non-human mammal.
  • compositions as defined above are intended to be applied topically to the skin of the non-human mammal.
  • the compositions used in the present invention can be in the form of solutions, emulsions or gels.
  • the compositions of“spot-on” or“line-on” type are particularly suitable for a topical application.
  • the compositions are applied to the skin of the non-human mammal, against the direction of the coat.
  • the expression “an application against the direction of the coat” is intended to mean an application to the skin of the non-human mammal, in the opposite direction to the implantation of the hairs.
  • the application against the direction of the coat is generally carried out in the direction starting from the base of the tail toward the shoulder blades of the non-human mammal.
  • the veterinary compositions used in the invention are and continuously applied against the direction of the coat.
  • the continuous application of the composition is carried out by keeping the composition in contact with the animals’ skin, this being until all of the desired dose of the composition is administered externally to the skin of the non-human mammal.
  • the notion“continuously” can also be defined as an infinite succession of spots.
  • the continuous application of the composition can be carried out along a rectilinear path.
  • the compositions used are continuously applied against the direction of the coat, starting from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
  • the user holds the animal against himself with one of his hands and continuously applies the composition against the direction of the coat using his other hand starting from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
  • compositions used in the invention are preferentially formulated in unit dose form adjusted to the weight and/or to the size of the non-human mammal, all of the dose being applied to the non-human mammal.
  • the doses of composition range from 0.1 to 100 mL, preferentially from 0.5 to 20 mL, and even more preferentially from 0.5 to 10 mL.
  • the doses of composition typically range from 0.5 to 10 mL.
  • the compositions are applied at a dose between 0.05 and 0.6 mL/kg of body weight of the non-human mammal, preferably 0.12 mL/kg BW.
  • the compound of the neonicotinoid family, the compound of the pyrethroid family and optionally the insect growth regulator, as defined previously and including the preferred embodiments are in compositions distinct from one another.
  • Another subject of the invention therefore relates to the use of a combination intended to be administered in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks, and comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for controlling mosquitoes in a non- human mammal.
  • a further object of the invention relates to such a combination for use for controlling a mosquito-bome disease in a non human mammal.
  • the present invention also provides a kit comprising one or more compartments, said compartments comprising a combination of a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for simultaneous use of said composition at least every five weeks, preferably at least every eight weeks, for controlling mosquitoes and/or a mosquito-bome disease in a non human mammal, preferably in a dog.
  • the kit also comprises an instruction sheet or notice and the procedure of the combination for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog.
  • a product for implementing the use of the compositions of the invention for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal can in particular be the product comprising the dinotefuran-permethrin-pyriproxyfen combination such as the product sold under the name Vectra ® 3D by Ceva Sante Animale.
  • Vectra ® 3D by Ceva Sante Animale.
  • Repellency of DPP was >92% from day 7 to 28. It was maintained >85% until day 56. Knock-down effect was >82% from day 7 to 28. It was maintained >59% until day 56. Insecticidal was >99% from day 7 to 28. It was maintained >93% until day 56.
  • the study confirms the rapid onset of activity and demonstrates the long-lasting efficacy of Vectra 3D for at least 8 weeks against mosquitoes that may carry various pathogens such as heartworm. In real-life situations, compliance is a recurrent issue and pet owners may not follow the monthly administration schedule. This dataset provides the evidence of the high efficacy standard of the product and additional piece of mind for the prescribing veterinarian.

Abstract

The present invention relates to a veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes and/or a mosquito-borne disease in a non-human mammal.

Description

VETERINARY COMPOSITIONS FOR CONTROLLING MOSQUITOES
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the use of compositions in the veterinary field and more particularly in the parasitology field. The invention relates more specifically to the use of veterinary compositions for controlling mosquitoes and/or mosquito-bome diseases in non-human mammals, such as cats and dogs.
TECHNICAL BACKGROUND OF THE INVENTION
Adult female mosquitoes are worldwide blood-feeding parasites and vectors of numerous pathogens. Culex pipiens is widely distributed and the vector of West Nile virus. Aedes aegypti, the yellow fever mosquito, is largely prevalent in south-west of United States of America, South America, Africa, India, Southwest Asia and Northern Australia. It is considered as an invasive species in Europe. This flying insect species has been demonstrated to be a vector of Human viral diseases such as chikungunya, Zika virus or Dengue (Brady et al, 2014).
Aedus spp. (or Stegomyia spp.), especially Aedus Aegypti, is also a vector of the life- threatening mosquito-bome disease in dogs, such as nematodes. The heartworm or Dirofilaria immitis is a nematode transmitted to dog at L3 larvae stage consecutively to mosquitoes biting. After developing and molting, adult male and female worms reach pulmonary arteries and heart where they mate to give birth to microlarvae, referred to as microfilariae. Microfilariae circulate in the dog’s peripheral blood where they can be ingested by mosquitoes during blood meal. A. aegypti can also be the vector of Dirofilaria repens, the zoonotic agent of the cutaneous dirofilariosis and of Brugyia spp. ( B . malayi, B. timori, B. pahangi, B. beaveri, B. lepori, B. guyanensis), the zoonotic agents of lymphatic filariosis. For D. repens, dogs and other canidae are reservoir. For Brugyia, dogs and cats are among the reservoirs.
Eradication of mosquito-bome diseases needs then to achieve two goals, first preventing novel infestations of naive uninfected dogs by mosquito vector and second hindering the dissemination of disease from infected dogs to naive mosquitoes with vector competency.
The gold standard for the protection of naive dogs is based on annual or seasonal administration of macrocyclic lactones (MLs). Ivermectin, moxidectin, milbemycin oxime or selamectin are available as oral tablets, topical solution or subcutaneous cutaneous suspension for monthly or every six or twelve months applications. Macrocyclic lactones inhibit the development of L3 stage to adults by killing the Dirofilaria spp. larvae. However, they do not prevent the transmission or dissemination of this nematode larval stage. Therefore, additional preventive measures should be considered to inhibit transmission and to support the preventive activity of macrocyclic lactones.
Vector control is a pragmatic approach. Several topical spot-on formulations containing repellent and insecticide molecules have been developed in veterinary medicine. Generally, these commercially available products comprise a repellent pyrethroid (permethrin, flumethrin, deltamethrin) and can further comprise an insecticide such as phenylpyrazoles (Fipronil), neonicotinoids (Dinotefuran and imidacloprid), or methoprene. For instance, Advantix® product (Bayer) comprising imidacloprid and permethrin, and Exspot® product comprising 65% permethrin in propylene glycol mo no methyl ether, allow to obtain an efficient repellency effect against A. aegypti for 2-
3 weeks (Tiawsirisup et ah, Parasitol Res, 2007, 101 :527-531; Meyer et ah, Veterinary Therapeutics, Vol. 4, No. 2, Summer 2003). Effitix® product (Virbac) comprising fipronil and 44.88% permethrin, and Frontline Tri-Act® product comprising fipronil and permethrin allow to obtain an efficient repellency effect against A. aegypti prolonged to
4 weeks (Franc et ah, Parasitol Res, 2015, 114, 2093-2097; Fankhauser et ah, Parasites & Vectors, 2015, 8:64). Also, some permethrin-based products such as Activyl Tick Plus® (MSD) comprising 42.5% permethrin and indoxacarb have failed to produce a durable protection (anti- feeding) against mosquitoes.
However, no treatment developed to date using topical formulations allow to obtain a repellent and/or insecticidal efficacy against mosquitoes for a period of more than 4 weeks. Thus, there remains today, in the context of mosquitoes control and/or mosquito-bome diseases control, a need to develop new long-term efficient formulations having a repellent and/or insecticidal effect against mosquitoes.
SUMMARY OF THE INVENTION
In this context, the inventors have surprisingly demonstrated that a veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family allows to obtain a long-term control of mosquitoes compared to the existing treatments. In particular, the inventors have demonstrated that such composition provides an efficient control of mosquitoes beyond 4 weeks, particularly for at least 5 weeks and up to 8 weeks, illustrated by an efficient repellency effect, an efficient insecticidal effect, and an efficient knock-down effect.
The present invention therefore relates to a veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks, preferably at least every six weeks, more preferably at least every seven weeks, even more preferably at least every eight weeks.
In one particular embodiment according to the invention, the weight ratio of the compound of the pyrethroid family to the compound of the neonicotinoid family is between 4 and 15, preferably between 6 and 9, and more preferably between 7 and 8.
Preferably, the compound of the neonicotinoid family is dinotefuran.
Preferably, the compound of the pyrethroid family is permethrin.
In another particular embodiment according to the invention, the composition further comprises an insect growth regulator.
In one preferred embodiment, the weight ratio of the insect growth regulator to the compound of the neonicotinoid family is between 0.05 and 0.12, preferably between 0.06 and 0.1, and more preferably between 0.07 and 0.09. In another preferred embodiment, the insect growth regulator is methoprene or pyriproxyfen, preferably pyriproxyfen.
In one particular embodiment of the invention, the composition is intended to be applied topically to the skin of the non-human mammal.
In one preferred embodiment, the composition is intended to be applied to the skin of the non-human mammal against the direction of the coat.
In one even more preferred embodiment, the composition is intended to be applied continuously against the direction of the coat from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
In a particular embodiment, the non-human mammal is a dog or a cat, preferably a dog. In a further particular embodiment, the mosquitoes are of the Aedes genus, preferably are Aedes aegypti, and/or of the Cal ex genus, preferably Cal ex pipiens.
Another object of the present invention is a veterinary composition as described in the present application, for use for controlling a mosquito-bome disease in a non-human mammal, preferably in cats and/or dogs, more preferably in a dog.
A further object of the invention relates to a kit comprising one or more compartments, said compartments comprising a combination of a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for simultaneous use of said composition at least every five weeks, preferably at least every eight weeks for controlling mosquitoes and/or a mosquito-bome disease in a non human mammal, preferably in a dog.
In one particular embodiment, the kit further comprises an instruction sheet or notice regarding the method of administration and the procedure of the combination for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog. LEGEND OF THE FIGURES
Figure 1: Anti-feeding (repellency), knock-down and insecticidal effects against Aedes aegypti mosquitoes in dogs treated with a veterinary composition of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Composition The veterinary compositions of the invention comprise a compound of the neonicotinoid family and a compound of the pyrethroid family, for controlling in non-human mammals.
The compounds of the neonicotinoid family are chemically similar to nicotine. They correspond to a class of insecticides that act on the central nervous system of insects by inhibiting nicotinic acetylcholine receptors, thus causing paralysis and death of the parasitic insect. They were introduced onto the market in the l990s and are particularly active against ectoparasites such as fleas, flies and lice. Compounds of the neonicotinoid family include, without limitation, imidacloprid, thiamethoxam, clothianidin, acetamiprid, thiacloprid, dinotefuran, nitenpyram, imidaclothiz, huanyanglin, guadipyr, paichongding, cycloxaprid and derivatives thereof or pharmaceutically acceptable salts thereof.
A preferred compound of the neonicotinoid family of the invention is dinotefuran. In the context of the present invention, the term“dinotefuran” also comprises the derivatives or analogs thereof, the metabolites thereof and the pharmaceutically acceptable salts thereof.
Dinotefuran was described by the company Mitsui Toatsu Chemicals, Inc. in patent EP 0 649 845 and was developed for insect-pest control. Dinotefuran (also called 2-methyl- l-nitro-3-[(tetrahydro-3-furanyl)methyl]guanidine) corresponds to the following formula:
Figure imgf000007_0001
Neonicotinoids and in particular dinotefuran metabolize in the body of non-human mammals and thus prolong their duration of action. The main metabolic pathways of dinotefuran involve N-demethylation, nitroreduction, N-methylene hydroxylation and amine cleavage reactions. The dinotefuran metabolites comprise the compounds described by Simon-Delso et al. (Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites, Environ. Sci. Pollut. Res., 2015, 22:5-34) and by Ford KA and Casida JE (Unique and common metabolites of thiamethoxam, clothianidin, and dinotefuran in mice, Chem. Res. Toxicol., 2006, 19:1549-1556; Neonicotinoid metabolism: compounds, substituents, pathways, enzymes, organisms, and relevance, J. Agric. Food Chem., 2011, 59:2923-2931) and FAO dinotefuran (http://www.fao.org/fileadmin/templates/agphome/documents/ PestsPesticides /JMPR/ Evaluation 12/Dinote furan.pdf). In particular, the dinotefuran metabolites include, without limitation, N-desmethyl dinotefuran (2-nitro-l-(tetrahydro-3- furylmethyl)guanidine), DIN-NNO, DIN-dm-NNO, DIN-NNEE, l-methyl-3-
(tetrahydro-3-furylmethyl)guanidine, 3-(tetrahydro-3-furylmethyl)guanidine, 1 -methyl- 3-(tetrahydro-3-furylmethyl)urea, 3-(tetrahydro-3-furylmethyl)urea, 2-hydroxy- dinotefuran, 4-hydroxydinotefuran, l,3-diazinane aminocarbinol, DIN-b (derivative of DIN-dm), DIN-e (guanidine derivative of DIN-a), DIN-f (guanidine derivative of DIN- b), DIN-g (derivative of DIN-5-OH), DIN-h (desmethyl-g), DIN-I (nitroso derivative of
DIN-g), DIN-j (nitroso derivative of DIN-h), DIN-k (guanidine derivative of DIN-h), tetrahydrofuran carboxaldehyde (3-furfural), tetrahydrofuran alcohol (3-furfuryl alcohol), 3-tetrahydrofurancarboxylic acid, 4-hydroxy-3-tetrahydrofuranzcarboxylic acid, tetrahydrofuran-3-ylmethylamine, 1 -[4-hydroxy-2-(hydroxymethyl)butyl]-3- methyl-2-nitroguanidine, and 3 -hydroxy dinotefuran.
Typically, the dinotefuran derivatives or analogs comprise all the compounds described in patent EP 0 649 845. More particularly, the dinotefuran derivatives or analogs comprise, without limitation, l-[{(tetrahydro-3-furanyl)methyl} amino]- l-methylamino- 2-nitroethylene, 1 -[ {(tetrahydro-3-furanyl)methyl} amino]- 1 -ethylamino-2- nitroethylene, 1 -[ {(tetrahydro-3-furanyl)methyl) amino]- 1 -dimethylamino-2- nitroethylene, 1 -[ {(tetrahydro-3-furanyl)methyl) amino]- 1 -(1 -pyrrolidinyl)-2- nitroethylene, l-[N- {(tetrahydro-3-furanyl)methyl} -N-methylamino]- 1 -methylamino-2- nitroethylene, l-[N- {(tetrahydro-3-furanyl)methyl} -N-propylamino]- 1 -methylamino-2- nitroethylene, l-[N- {(tetrahydro-3-furanyl)methyl} -N-propylamino]- 1 -ethylamino-2- nitroethylene, 1 - {(tetrahydro-3-furanyl)methyl} -2-nitro-3-methylguanidine,
N- {(tetrahydro-3-furanyl)methyl} -N-(methyl)nitroguanidine, 1 - {(tetrahydro-3- furanyl)methyl} - 1 -ethyl-2-nitro-3-methylguanidine, N-(tetrahydro-3-furanyl)methyl-N'- cyano(methylthio)formamidine, N-cyano-N'- {(tetrahydro-3- furanyl)methyl} acetamidine, N-cyano-N'- {(tetrahydro-3-furanyl)methyl} -N- methylacetamidine, N-[4-{(2-methyl)tetrahydrofuranyl}methyl]-N'-methyl-N"- nitroguanidine, 1 - {(tetrahydro-3-furanyl)methyl} - 1 ,2-dicyclohexylcarbonyl-2-methyl-3- nitroguanidine, 1 - {(tetrahydro-3-furanyl)methyl} - 1 ,2-diethylcarbonyl-2-methyl-3- nitroguanidine, 1 - {(tetrahydro-3-furanyl)methyl} - 1 ,2-dimethoxycarbonyl-2-methyl-3- nitroguanidine, and 1 - {(tetrahydro-3-furanyl)methyl} - 1 ,2-dibenzoyl-2-methyl-3- nitroguanidine.
The compounds of the pyrethroid family are compounds which act on the insect nervous system and disrupt neuron function by interacting with sodium channels. Compounds of the pyrethroid family include, without limitation, ethofenprox, permethrin, prallethrin, resmethrin, sumithrin, allethrin, alpha-cypermethrin, bifenthrin, beta-cypermethrin, cyfluthrin, cypermethrin, deltamethrin, flumethrin, esfenvalerate, lamda-cyhalothrin, zeta-cypermethrin, and the derivatives thereof or the pharmaceutically acceptable salts thereof
A preferred compound of the pyrethroid family is permethrin.
In one particular embodiment, the compositions of the invention further comprise an insect growth regulator.
Insect growth regulators are chemical substances which inhibit the lifecycle of insects. Among the insect growth regulators, mention may be made, without limitation, of azadirachtin, hydroprene, methoprene, pyriproxyfen, triflumuron, and the derivatives thereof or the pharmaceutically acceptable salts thereof.
A preferred insect growth regulator compound is pyriproxyfen or methoprene, and is preferably pyriproxyfen. The term“pharmaceutically acceptable salts” is intended to mean both organic salts and inorganic salts. Representative examples of inorganic salts comprise hydrochlorides, hydrobromides, iodates, sulfonates and phosphates. Representative examples of organic salts comprise formates, acetates, trichloroacetates, propionates, benzoates, cinnamates, fumarates, maleates and methanesulfonates.
In one particular embodiment, the composition comprises a compound of the neonicotinoid family, preferably dinotefuran, and a compound of the pyrethroid family, preferably permethrin, in weight amounts such that the weight ratio of the compound of the pyrethroid family to the compound of the neonicotinoid family is between 4 and 15, preferentially between 6 and 9, and even more preferentially between 7 and 8.
In another particular embodiment, the composition comprises a compound of the neonicotinoid family, preferably dinotefuran, and a compound of the pyrethroid family, preferably permethrin, and an insect growth regulator, preferably pyriproxyfen, in weight amounts such that the weight ratio of the insect growth regulator to the compound of the neonicotinoid family is between 0.05 and 0.12, preferentially between 0.06 and 0.1, and even more preferentially between 0.07 and 0.09.
In one preferred embodiment of the invention, the composition comprises about 60% to 95% of permethrin, about 6% to 22% of dinotefuran, and optionally about 0.8% to 4% of pyriproxyfen. In a more preferred embodiment of the invention, the composition comprises about 70% to 90% of permethrin, about 8% to 15% of dinotefuran, and optionally about 0.9% to 1.5% of pyriproxyfen. According to these preferred embodiments of the invention, the percentages are expressed by weight relative to the total weight of the compounds which are permethrin, dinotefuran and optionally pyriproxyfen.
In another preferred embodiment of the invention, the composition comprises:
- about 20% to 50%, preferably about 30% to 40%, and even more preferably about 34% to 38%, by weight of permethrin,
- about 1% to 20%, preferably about 1% to 10%, and more preferably about 3% to 7%, by weight of dinotefuran, and - optionally about 0.1% to 2%, preferably about 0.1% to 1%, and more preferably 0.2% to 0.6% by weight of pyriproxyfen, relative to the total weight of the composition.
The term“about” will be understood by those skilled in the art and can vary to a certain extent according to the context in which it is used. If some uses of this term are not clear for those skilled in the art depending on the context,“about” means plus or minus 20%, preferably plus or minus 10% of the specific term.
Application
The term“non-human mammal” is intended to mean any non-human mammal capable of being stung or bitten by mosquitoes and thus developing mosquito-bome diseases or being a reservoir for any of these diseases, meaning that already suffering from a vector-borne disease and able to contaminate another non-human mammal via mosquitoes. The non-human mammal may in particular be a member of the canine family, such as a dog, a fox, a coyote or a wolf, or a member of the feline family, such as a cat, a lion or a panther. In one preferred embodiment, the non-human mammal belongs to the pets group including for instance a dog, a cat, a rodent, a rabbit, etc. In one more preferred embodiment, the non-human mammal is a dog or a cat, more preferentially a dog.
The terms“control” and“controlling” are intended to mean, without limitation, the action of reducing, repelling (anti-feeding), eradicating, eliminating, killing and preventing mosquitoes in non-human mammals. The notion of “preventing” also comprises decreasing, reducing or preventing a mosquito blood meal in non-human mammals, which results in reducing the risks of infection of surrounding subjects and thus contributes to limiting the spread of the mosquito-bome disease.
The invention also relates to a method for controlling mosquitoes in non-human mammals, comprising the administration of an effective amount in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks of a composition as defined herein comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in non human mammals.
In the context of the present invention, the expression“effective amount” means the amount of the compound of the neonicotinoid family, of the compound of the pyrethroid family, and optionally of the insect growth regulator that is capable of causing sufficient mosquito control. It is accepted by those skilled in the art that sufficient control is obtained when at least 80% of mosquitoes are controlled.
The repellent effect (or anti-feeding efficacy) is evaluated using the Abbott formula (Abbott, W.S.: A method of computing the effectiveness of an insecticide; J. Econ. Entomol; 1925; 18; 265-267) calculating the percentage (%) corresponding to the difference between the number of engorged mosquitoes (or feeding mosquitoes) calculated in a non-treated non-human mammal (control group) and the number of engorged mosquitoes calculated in a treated non-human mammal (treated group) relative to the number of engorged mosquitoes calculated in a non-treated, non-human mammal, i.e.:
Anti-feeding efficacy (%) = ((Number of engorged mosquitoes of the control group - Number of engorged mosquitoes of the treated group) / Number of engorged mosquitoes of the control group) x 100.
An engorged mosquito (or fed with blood) corresponds to a mosquito that has already bitten or stung and fed on blood of the non-human mammal. For all calculations, the arithmetic and geometric means are used.
The insecticidal effect is evaluated by calculating the percentage (%) corresponding to the difference between the number of live mosquitoes observed in a non-treated, non human mammal (control group) and the number of live mosquitoes observed in a treated, non-human mammal (treated group) relative to the number of live mosquitoes observed in a non-treated, non-human mammal, i.e.:
Insecticidal efficacy (%) = ((Number of live mosquitoes of the control group - Number of live mosquitoes of the treated group) / Number of live mosquitoes of the control group) x 100.
For all calculations, the arithmetic and geometric means are used. The knock-down effect is evaluated by calculating the percentage (%) corresponding to the difference between the number of live and moribund mosquitoes observed in a non- treated, non-human mammal (control group) and the number of live and moribund mosquitoes observed in a treated, non-human mammal (treated group) relative to the number of live and moribund mosquitoes observed in a non-treated, non-human mammal, i.e.:
Knock-down efficacy (%) = ((Number of live and moribund mosquitoes of the control group - Number of live and moribund mosquitoes of the treated group) / Number of live and moribund mosquitoes of the control group) x 100.
A moribund mosquito exhibits uncoordinated movement, including under stimulation and is not able to fly. For all calculations, the arithmetic and geometric means are used.
A further object of the invention relates to a method for controlling at least about 80% of mosquitoes in a non-human mammal, comprising the administration of an effective amount in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks of a composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in said non-human mammals.
A further object of the invention is a composition as disclosed herein for use for preventing and/or controlling a mosquito-bome disease in a non-human mammal, preferably in cats and/or dogs, more preferably in a dog.
As used herein a “mosquito-bome disease” refers to any disease transmitted by mosquitoes. Typically, a“mosquito-bome disease” is due to the transmission of a pathogen in a non-human mammal by the mosquito. The“pathogen” includes for instance viruses (like West Nile vims), bacteriae, protozoae, endoparasites of mammals, more especially hookworms, flatworms, tapeworms, more especially gastro -intestinal nematodes, cardio-pulmonary nematodes and/or heartworms. In a particular embodiment, a mosquito-bome disease is heartworm disease, a Dirofilaria repens and/or Brugyia spp. infestation. The compositions as disclosed herein can thus be used to prevent and/or control an infection by a pathogen transmitted during the blood feeding of mosquitoes such as viruses (like West Nile virus), bacteriae, protozoae, endoparasites of mammals, more especially hookworms, flatworms, tapeworms, more especially gastro -intestinal nematodes, cardio-pulmonary nematodes and/or heartworms.
As briefly described in the introduction, mosquitoes are acknowledged to be disease vectors such as filariae.“Filariae” generally include nematodes that typically reside within the heart and lungs of a host during the final reproductive stages of its life cycle. Some specific filariae may include Dirofilaria immitis (heartworm) and Dirofilaria repens (the agent of cutaneous dirofilariosis) and any other similar nematode of the same class or subclass.“Heartworm disease” is typically a disease due to an infestation of a heartworm as above defined. In a particular embodiment,“Heartworm disease” is a Dirofilaria immitis infestation.
In a particular embodiment of the invention, the cat and dog endoparasite transmitted by mosquitoes is a nematode and/or a trematode in circulatory system. As cat and dog worms, those from the Filarioidae family may be cited such as Dirofilaria spp. ( immitis , repens ) and Brugia spp. (pahangi, malayi). A preferred circulatory system worm is Dirofilaria spp. (heartworm). In another particular embodiment of the invention, the cat and dog endoparasite transmitted by mosquitoes is a nematode in subcutaneous tissues, preferably Dirofilaria spp. {repens).
Mosquitoes are also acknowledged to be viruses vector. Arboviruses (means virus transmitted by mosquitoes) families Flaviviridae (genus Flavivirus ) and Togaviridae (genus Alphavirus ) are important in both humans and domestic animals, such as alphaviruses (Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus) and flaviviruses (Japanese encephalitis virus and West Nile virus), Alphaviridae, like chikungunya fever, Bunyaviridae like Rift-Valley fever, Dengue, Yellow fever, Zika virus, Usutu virus, etc.
Mosquitoes are further acknowledged to be bacteria and/or protozoa vector. As bacteria transmitted by mosquitoes, Tularemia and Rickettsia spp. may be cited. As protozoa transmitted by mosquitoes, malaria (. Plasmodium spp.: Plasmodium falciparum, ect.) may be cited.
In the context of the invention,“mosquitoes” include any mosquito able to bite or stung a non-human mammal such as a dog or a cat.
More particularly, mosquitoes feeding on the blood of cat and dogs are from the family Culicidae:
- Aedes spp. (or Stegomyia spp.): A. cinereus, A. esoensis, A. rossicus, A. vexans, A. vittatus, A. aegypti, A. albopictus, A. stricticus, A. cantans, A. communis, A. punctor, A. japonicus, A. geniculatus, A. detritus, A. africanus, A. furcifer, A. niveus, A. taylori, A. luteocephalus, A. simpsoni, and A. scapularis;
- Anopheles spp.: A. anopheles, A. cellia, kerteszia, A. gambiae, A. lophodomyia, A. nyssorhynchus, A. stethomyia, A. baimaia, A. messeae, A. maculipennis, A. claviger, A. plumbeus, A. aquasalis, A. belator, A. darlingi, A. funestus, A. arabiensis, A. bwanbae, A; melas, A. merus, A. nili, and A. pauliania;
- Culex spp.: C. pipiens, C. anips, C. annulirostris, C. apicalis, C. conservator, C. corniger, C. pilosus, C. reevesi, C. adami, C. rubinotus, C. tar sails, C. tritaeniorhynchus, C. modestus, C. antennatus, C. bahamensis, C. erraticus, C. nigripalpus, C. quinquefasciatus, C. restuans, C. salinarius, C. theileri, C. tritaeniorhynchus, C. univittatus, and C. vishnui
- Ochlerotatus spp.: O. acartomyia, O. culicelsa, O. gilesia, O. protoculex, O. empihals, O. pholeomyia, O. sallumia, O. buvirillia, and O. caspius
- Uranotaenia spp.: abdita, nigerrima, nigerrima, harrisoni, yunnanensis, pifanoi, leucoptera, gerdae, campestris, grasse, mayottensis, mashonaensis, madagascarensis and
- Coquillettidia spp: Coquillettidia richiardii.
In a preferred embodiment, the mosquitoes are Aedes aegypti, Aedes albopictus and Culex pipiens.
The invention thus also relates to a veterinary composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for use for controlling a mosquito-bome disease in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks.
The invention also relates to the use of a veterinary composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, in manufacturing of a drug for controlling a mosquito-bome disease in a non-human mammal, said composition being intended to be administered in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks.
The invention also relates to a method for controlling a mosquito-bome disease in non human mammal, comprising the administration of an effective amount of a composition comprising a compound of the neonicotinoid family, a compound of the pyrethroid family and optionally an insect growth regulator, in a non-human mammal which may or may not be suffering from heartworm disease, said composition being intended to be administered in a single dose, at least every five weeks.
In the context of the invention, the expressions“controlling mosquito-bome diseases”, “mosquito-bome diseases treatment” and “mosquito-bome prevention” denote the protection of the non-human mammal against mosquito-bome diseases, i.e. the protection of the non-human mammal by controlling mosquitoes. According to one particular embodiment, these expressions include the preventive treatment of the non human mammal against mosquito-bome diseases.
According to a first aspect, a preventive treatment denotes a treatment carried out before the non-human mammal has been exposed to or has been in contact with the causative agent of a mosquito-bome disease, i.e. mosquitoes. A preventive treatment therefore reduces the risks of the non-human mammal developing a mosquito-bome disease. According to a second aspect, a preventive treatment also denotes a treatment carried out in a non-human mammal suffering from a mosquito-bome disease. The treatment carried out in a sick subject makes it possible to control the mosquitoes in its environment and to reduce the risks of infection in the surrounding healthy subjects, contributing thereby to limit the spread of the mosquito-bome disease. According to one preferred embodiment of the invention, the composition is intended to be administered in a single dose, at least every five weeks. According to this embodiment, the composition is administered to the non-human mammal at a time TO and is then again administered at a time Tl, at least 5 weeks later, such as 5, 6, 7, or 8 weeks later. In a further preferred embodiment, the composition is administered every 5 to 8 weeks, every 6 to 8 weeks, or every 7 to 8 weeks. Particularly, the treatment can be repeated every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. Accordingly, the composition is administered to the non-human mammal every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In a particular embodiment, the duration of the treatment is 5 weeks, 8 weeks, 16 weeks, 32 weeks, 1 year, 64 weeks, 2 years, 5 years, and more preferably until the death of the non-human mammal.
In another particular embodiment, the composition is intended to be administered in a single dose to the non-human mammal at a time TO and is not repeated later. According to this particular embodiment, the term“every” means a unique treatment in with the composition is efficient up to 5, 6, 7, and preferably up to 8 weeks. Thus, the present invention also relates to a 5, 6, 7, or 8 weeks long acting veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes in a non-human mammal.
According to another particular embodiment, the compositions as defined above are intended to be applied topically to the skin of the non-human mammal. Typically, the compositions used in the present invention can be in the form of solutions, emulsions or gels. The compositions of“spot-on” or“line-on” type are particularly suitable for a topical application.
In one preferred embodiment of a topical application, the compositions are applied to the skin of the non-human mammal, against the direction of the coat. The expression “an application against the direction of the coat” is intended to mean an application to the skin of the non-human mammal, in the opposite direction to the implantation of the hairs. For the non-human mammals to which the invention relates, the application against the direction of the coat is generally carried out in the direction starting from the base of the tail toward the shoulder blades of the non-human mammal. Advantageously, the veterinary compositions used in the invention are and continuously applied against the direction of the coat. The continuous application of the composition is carried out by keeping the composition in contact with the animals’ skin, this being until all of the desired dose of the composition is administered externally to the skin of the non-human mammal. The notion“continuously” can also be defined as an infinite succession of spots.
The continuous application of the composition can be carried out along a rectilinear path. In one preferred embodiment, the compositions used are continuously applied against the direction of the coat, starting from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal. In particular, the user holds the animal against himself with one of his hands and continuously applies the composition against the direction of the coat using his other hand starting from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
The compositions used in the invention are preferentially formulated in unit dose form adjusted to the weight and/or to the size of the non-human mammal, all of the dose being applied to the non-human mammal. Typically, the doses of composition range from 0.1 to 100 mL, preferentially from 0.5 to 20 mL, and even more preferentially from 0.5 to 10 mL. When the non-human mammals to which the invention relates are dogs and cats, the doses of composition typically range from 0.5 to 10 mL. According to certain particular embodiments, the compositions are applied at a dose between 0.05 and 0.6 mL/kg of body weight of the non-human mammal, preferably 0.12 mL/kg BW.
According to another aspect of the invention, the compound of the neonicotinoid family, the compound of the pyrethroid family and optionally the insect growth regulator, as defined previously and including the preferred embodiments, are in compositions distinct from one another.
Another subject of the invention therefore relates to the use of a combination intended to be administered in a single dose, at least every five weeks, six weeks, seven weeks, preferably at least every eight weeks, and comprising a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for controlling mosquitoes in a non- human mammal. A further object of the invention relates to such a combination for use for controlling a mosquito-bome disease in a non human mammal.
The present invention also provides a kit comprising one or more compartments, said compartments comprising a combination of a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for simultaneous use of said composition at least every five weeks, preferably at least every eight weeks, for controlling mosquitoes and/or a mosquito-bome disease in a non human mammal, preferably in a dog.
The expression “simultaneous use” means that the compounds present in the combination as defined above are administered at the same time in the non-human mammal.
According to one specific embodiment, the kit also comprises an instruction sheet or notice and the procedure of the combination for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog. A product for implementing the use of the compositions of the invention for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal can in particular be the product comprising the dinotefuran-permethrin-pyriproxyfen combination such as the product sold under the name Vectra®3D by Ceva Sante Animale. Other aspects and advantages of the invention will emerge on reading the examples which follow, which should be considered to be illustrative and no limiting. EXAMPLES
Example 1: Material and Methods:
Sixteen dogs were enrolled and allocated to 2 groups based on the pre-treatment feeding rate of mosquitoes: a control untreated group (n=8) and a Vectra 3D (36.08% w/w permethrin, dinotefuran 4.95% w/w, pyriproxyfen 0.44% w/w, DPP) treated group (n=8). Treatment was administered in a line-on on day 0 and at the minimum recommended dose rate (0.12 mL/kg BW). On days 1, 7, 14, 21, 28, 35, 42, 49 and 56, dogs were sedated and challenged with 80 unfed female mosquitoes for 60 min. The mosquitoes were classified as fed/unfed and live/moribund/dead. All the live and moribund mosquitoes were incubated for 24h until viability assessment. Anti-feeding (repellency), knock-down effect and insecticidal efficacy of DPP was calculated using the Abbott formula.
Results:
The results are presented in table 1 and figure 1. Table 1:
Figure imgf000019_0001
Feeding and viability of mosquitoes in the control group was high (62-87%) all along the study.
Only 24h after administration, the anti-feeding efficacy was already 88%, knock-down effect was 96.9% and insecticidal efficacy was 99.9%. Most of the mosquitoes incubated from this first challenge did not survived (99.9%).
Repellency of DPP was >92% from day 7 to 28. It was maintained >85% until day 56. Knock-down effect was >82% from day 7 to 28. It was maintained >59% until day 56. Insecticidal was >99% from day 7 to 28. It was maintained >93% until day 56.
Conclusion:
The study confirms the rapid onset of activity and demonstrates the long-lasting efficacy of Vectra 3D for at least 8 weeks against mosquitoes that may carry various pathogens such as heartworm. In real-life situations, compliance is a recurrent issue and pet owners may not follow the monthly administration schedule. This dataset provides the evidence of the high efficacy standard of the product and additional piece of mind for the prescribing veterinarian.

Claims

1. A veterinary composition comprising a compound of the neonicotinoid family and a compound of the pyrethroid family, for use for controlling mosquitoes in a non-human mammal, wherein the composition is intended to be administered in a single dose, at least every five weeks.
2. The veterinary composition for use according to claim 1, wherein the composition is intended to be administered at least every six weeks, preferably at least every seven weeks, more preferably at least every eight weeks.
3. The veterinary composition for use according to claim 1 or 2, wherein the weight ratio of the compound of the pyrethroid family to the compound of the neonicotinoid family is between 4 and 15, preferably between 6 and 9, and more preferably between 7 and 8.
4. The veterinary composition for use according to any one of claims 1 to 3, wherein the compound of the neonicotinoid family is dinotefuran.
5. The veterinary composition for use according to any one of claims 1 to 4, wherein the compound of the pyrethroid family is permethrin.
6. The veterinary composition for use according to any one of claims 1 to 5, wherein the composition further comprises an insect growth regulator.
7. The veterinary composition for use according to claim 6, wherein the weight ratio of the insect growth regulator to the compound of the neonicotinoid family is between 0.05 and 0.12, preferably between 0.06 and 0.1, and more preferably between 0.07 and 0.09.
8. The veterinary composition for use according to claim 6 or 7, wherein the insect growth regulator is methoprene or pyriproxyfen, preferably pyriproxyfen.
9. The veterinary composition for use according to any one of claims 1 to 8, wherein the composition is intended to be applied topically to the skin of the non-human mammal, preferably against the direction of the coat.
10. The veterinary composition for use according to any one of claims 1 to 9, wherein the composition is intended to be applied continuously against the direction of the coat starting from the base of the tail, along the dorsal spine up to the shoulder blades of the non-human mammal.
11. The veterinary composition for use according to any one of claims 1 to 10, wherein the non-human mammal is a dog or a cat, preferably a dog.
12. The veterinary composition for use according to any one of claims 1 to 11, wherein the mosquitoes are of the Aedes genus, preferably are Aedes aegypti, Aedes albopictus, and/or of the Culex genus, preferably Culex pipiens.
13. The veterinary composition as defined in any one of claims 1 to 10, for use for controlling a mosquito-bome disease in a non-human mammal, preferably in cats and/or dogs, more preferably in a dog.
14. A kit comprising one or more compartments, said compartments comprising a combination of a compound of the neonicotinoid family, a compound of the pyrethroid family, and optionally an insect growth regulator, for simultaneous use of said combination at least every five weeks, preferably at least every eight weeks, for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog.
15. The kit according to claim 14, further comprising an instruction sheet or notice regarding the method of administration and the procedure of the combination for controlling mosquitoes and/or a mosquito-bome disease in a non-human mammal, preferably in a dog.
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