Feeds and methods for controlling heartworm infections in mammals - Patents.com

Abstract

An oral animal feed and method for preventing and / or controlling heartworms in a mammal in need of treatment, comprising orally administering to a mammal, such as a canid, feed containing an effective amount of a systemic anthelmintic drug with a relatively long half-life for an effective period of time to prevent and / or control heartworms, thereby increasing the amount of the anthelmintic drug in the mammal's blood to a therapeutically effective level and maintaining it thereat.

Description

Related Applications

[0001]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 407,140, ​​filed September 15, 2022, which is incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE

[0002] The teachings of this disclosure relate generally to methods of administering active agents for controlling heartworm in mammals. [Background technology]

[0003] There are five main types of parasites or helminths that most commonly infect domestic dogs: ascarid worms, tapeworms, hookworms, whipworms, and heartworms. These helminths can cause serious health problems, including gastrointestinal problems, abdominal pain, weight loss, dehydration, anemia, and pneumonia, and in severe cases, can be fatal. Furthermore, some helminths, such as Dirofilaria immitis (commonly known as heartworm), which infect dogs, cats, ferrets, and some other animals, are easily transmitted through insect bites and are often fatal if left untreated. In some cases, treatment for adult heartworm infections can itself be fatal to the animal. Therefore, it is essential that pet dogs, cats, and ferrets receive proper veterinary care, including regular treatment to prevent heartworm infection.

[0004]

[0004] Currently available treatments for controlling helminth infections in animals are known to have varying degrees of success. For example, problems contributing to ineffective control of heartworm in dogs and cats include inadequate oral dosing, which can further lead to anthelmintic resistance, and vomiting caused by the high doses required for some anthelmintics to be effective. Summary of the Invention

[0005] Embodiment 1: A method for controlling heartworm infection, comprising: administering a therapeutically effective cumulative amount of at least one systemic anthelmintic to a mammal in need of treatment, wherein the therapeutically effective cumulative amount comprises multiple discrete microdoses of the at least one systemic anthelmintic; The method, wherein the microdose is administered to the mammal daily or substantially daily, and wherein the at least one anthelmintic has a half-life in the mammal of at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days.

[0006]

[0006] Embodiment 2: The method described in embodiment 1, wherein the systemic anthelmintic is an integral part of at least one of medicated feed, chew treats, snacks, tablets, capsules, powders, ointments, suspensions, solutions, and pastes.

[0007]

[0007] Embodiment 3: The method described in embodiment 1 or 2, wherein the systemic anthelmintic is an integral part of medicated pet food, and the medicated food is a consumable product selected from the group consisting of kibble, wet pet food, paste, chew treats, and reward treats.

[0008]

[0008] Embodiment 4: The method of any one of embodiments 1 to 3, wherein the mammal is selected from the group consisting of canines and felines.

[0009] Embodiment 5: The method of embodiment 4, wherein the mammal is a domestic dog.

[0009]

[0010] Embodiment 6: The method of embodiment 4, wherein the mammal is a domestic cat.

[0011] Embodiment 7: The method of any one of embodiments 1 to 6, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0010]

[0012] Embodiment 8: The method of any one of embodiments 1 to 6, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0011]

[0013] Embodiment 9: The method of any one of embodiments 1 to 8, wherein the systemic anthelmintic is milbemycin.

[0014] Embodiment 10: The method of embodiment 9, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0012]

[0015] Embodiment 11: The method of any one of embodiments 1 to 10, wherein the cumulative therapeutically effective amount of moxidectin administered to the mammal over a period of about 30 days does not exceed 48 μg of moxidectin per kg of body weight of the mammal.

[0013]

[0016] Embodiment 12: The method of embodiment 11, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg, and about 0.8 μg / kg to about 0.9 μg / kg.

[0014]

[0017] Embodiment 13: The method of embodiment 11 or 12, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg, and about 1.6 μg / kg.

[0015]

[0018] Embodiment 14: The method of any one of embodiments 10 to 13, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0016]

[0019] Embodiment 15: The method of any one of embodiments 10 to 13, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0017]

[0020] Embodiment 16: The method of any one of embodiments 1 to 8, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0021] Embodiment 17: The method of embodiment 16, wherein the aminoacetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0018]

[0022] Embodiment 18: The method of embodiment 17, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over a period of about 30 days does not exceed 25 mg of monepantel per kg of body weight of the mammal.

[0019]

[0023] Embodiment 19: The method of embodiment 17 or 18, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of: about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; and about 0.125 mg / kg to about 0.25 mg / kg.

[0020]

[0024] Embodiment 20: The method of any one of embodiments 17 to 19, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

[0021]

[0025] Embodiment 21: The method of any one of embodiments 1 to 20, wherein the number of days between the administration of any two microdoses is less than 2, 3, 4, 5, 6, or 7 days.

[0022]

[0026] Embodiment 22: The method of any one of embodiments 1 to 21, wherein at least one microdose is administered orally.

[0027] Embodiment 23: The method of any one of embodiments 1 to 22, further comprising administering at least one additional anthelmintic.

[0023]

[0028] Embodiment 24: The method of embodiment 23, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0029] Embodiment 25: The method of embodiment 23 or 24, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

[0024]

[0030] Embodiment 26: The method of embodiment 23, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

[0025]

[0031] Embodiment 27: The method of embodiment 23, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphate or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

[0026]

[0032] Embodiment 28: The method of embodiment 27, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, and the macrocyclic lactone is at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

[0027]

[0033] Embodiment 29: The method of embodiment 27, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, and the cyclooctadepsipeptide is at least one compound selected from the group consisting of emodepside, PF1022, and salts or derivatives of any of the foregoing.

[0028]

[0034] Embodiment 30: The method of embodiment 27, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, and the amino-acetonitrile derivative is monepantel or a salt or derivative thereof.

[0029]

[0035] Embodiment 31: The method of embodiment 27, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, and the tetrahydropyrimidine is at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

[0030]

[0036] Embodiment 32: The method of embodiment 27, wherein the at least one additional anthelmintic comprises an imidazothiazole, wherein the imidazothiazole is at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

[0031]

[0037] Embodiment 33: The method of embodiment 27, wherein the at least one additional anthelmintic comprises paraherquamide, wherein the paraherquamide is at least one compound selected from the group consisting of delquantel, paraherquamide, and salts or derivatives of any of the foregoing.

[0032]

[0038] Embodiment 34: The method of embodiment 27, wherein the at least one additional anthelmintic comprises an aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

[0033]

[0039] Embodiment 35: The method of embodiment 27, wherein the at least one additional anthelmintic comprises an organophosphorus compound, and the organophosphorus compound is at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxon, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

[0034]

[0040] Embodiment 36: The at least one additional anthelmintic comprises a substituted phenol, wherein the substituted phenol is at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolan, meniclofolan, nitroxynil, and salts or derivatives of any of the foregoing.

[0035]

[0041] Embodiment 37: The method of embodiment 27, wherein the at least one additional anthelmintic comprises a piperazinone, and the piperazinone is at least one compound selected from the group consisting of praziquantel, epsiprantel, and salts or derivatives of any of the foregoing.

[0036]

[0042] Embodiment 38: The method of embodiment 23, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

[0037]

[0043] Embodiment 39: The method of embodiment 23, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

[0044] Embodiment 40: A composition for controlling heartworm infection, comprising a microdose of at least one systemic anthelmintic, wherein the at least one systemic anthelmintic is active in a mammal and has a half-life in the mammal's system of at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days, and wherein the cumulative dose of multiple microdoses is sufficient to control heartworm infection.

[0038]

[0045] Embodiment 41: The composition of embodiment 40, wherein the systemic anthelmintic is an integral part of at least one formulation selected from the group consisting of medicated feed, reward treat, chew treat, snack, tablet, capsule, powder, ointment, suspension, solution, sachet, and paste, or an integral part thereof.

[0039]

[0046] Embodiment 42: The composition of embodiment 40, wherein the medicated feed comprises at least one livestock feed and the microdose of the systemic anthelmintic is an integral part of the livestock feed.

[0047] Embodiment 43: The composition of embodiment 40, wherein the medicated feed is selected from the group of formulations consisting of pet food, chew treats, wet pet food, pastes and snacks.

[0040]

[0048] Embodiment 44: The composition of any one of embodiments 40 to 43, wherein the mammal is selected from the group consisting of canines and felines.

[0049] Embodiment 45: The composition of embodiment 44, wherein the mammal is a domestic dog.

[0041]

[0050] Embodiment 46: The composition of embodiment 44, wherein the mammal is a domestic cat.

[0051] Embodiment 47: The composition of any one of embodiments 40 to 46, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0042]

[0052] Embodiment 48: The composition of any one of embodiments 40 to 46, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulosstrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0043]

[0053] Embodiment 49: The composition of any one of embodiments 44 to 48, wherein the systemic anthelmintic is milbemycin.

[0054] Embodiment 50: The composition of embodiment 49, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0044]

[0055] Embodiment 51: The composition of embodiment 50, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg, and about 0.8 μg / kg to about 0.9 μg / kg.

[0045]

[0056] Embodiment 52: The composition of embodiment 50 or 51, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg, and about 1.6 μg / kg.

[0046]

[0057] Embodiment 53: The composition of any one of embodiments 50 to 52, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0047]

[0058] Embodiment 54: The composition of any one of embodiments 50 to 53, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0048]

[0059] Embodiment 55: The composition of any one of embodiments 40 to 48, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0060] Embodiment 56: The composition of embodiment 55, wherein the amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0049]

[0061] Embodiment 57: The composition of embodiment 56, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of: about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; and about 0.125 mg / kg to about 0.25 mg / kg.

[0050]

[0062] Embodiment 58: The composition of embodiment 56 or 57, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

[0051]

[0063] Embodiment 59: The composition of any one of embodiments 40 to 58, wherein at least one microdose is formulated and administered orally.

[0064] Embodiment 60: The composition of any one of embodiments 40 to 59, further comprising at least one additional anthelmintic.

[0052]

[0065] Embodiment 61: The composition of embodiment 60, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0066] Embodiment 62: The composition of embodiment 60 or 61, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

[0053]

[0067] Embodiment 63: The composition of embodiment 60, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

[0054]

[0068] Embodiment 64: The method of embodiment 60, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphorus compound or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

[0055]

[0069] Embodiment 65: The method of embodiment 64, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, and the macrocyclic lactone is at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

[0056]

[0070] Embodiment 66: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, and the cyclooctadepsipeptide is at least one compound selected from the group consisting of emodepside, PF1022, and salts or derivatives of any of the foregoing.

[0057]

[0071] Embodiment 67: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, and the amino-acetonitrile derivative is monepantel or a salt or derivative thereof.

[0058]

[0072] Embodiment 68: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, and the tetrahydropyrimidine is at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

[0059]

[0073] Embodiment 69: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises an imidazothiazole, wherein the imidazothiazole is at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

[0060]

[0074] Embodiment 70: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises paraherquamide, wherein paraherquamide is at least one compound selected from the group consisting of delquantel, paraherquamide, and salts or derivatives of any of the foregoing.

[0061]

[0075] Embodiment 71: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises an aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

[0062]

[0076] Embodiment 72: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises an organophosphorus compound, and the organophosphorus compound is at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxone, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

[0063]

[0077] Embodiment 73: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises a substituted phenol, and the substituted phenol is at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolan, meniclofolan, nitroxynil, and salts or derivatives of any of the foregoing.

[0064]

[0078] Embodiment 74: The composition of embodiment 64, wherein the at least one additional anthelmintic comprises a piperazinone, wherein the piperazinone is at least one compound selected from the group consisting of praziquantel, epsiprantel, and salts or derivatives of any of the foregoing.

[0065]

[0079] Embodiment 75: The composition of embodiment 60, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

[0066]

[0080] Embodiment 76: The composition of embodiment 60, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

[0081] Embodiment 77: A medicated feed for use in a method for controlling a canine heartworm infection, comprising administering to a mammal in need of treatment a therapeutically effective cumulative amount of at least one systemic anthelmintic, wherein the therapeutically effective cumulative amount comprises multiple discrete microdoses of the at least one systemic anthelmintic; The medicated feed, wherein the microdose is administered to the mammal daily or substantially daily, and wherein the half-life of the at least one anthelmintic drug in the mammal is at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days.

[0067]

[0082] Embodiment 78: A medicated feed for use in the method of embodiment 77, wherein the systemic anthelmintic is an integral part of at least one of a medicated feed, chew treat, snack, tablet, capsule, powder, ointment, suspension, solution, and paste.

[0068]

[0083] Embodiment 79: A medicated pet feed for use in the method of embodiment 77 or 78, wherein the systemic anthelmintic is an integral part of the medicated pet feed, and said medicated pet feed is a consumable product selected from the group consisting of pet food, wet pet food, paste, chew treats, and reward treats.

[0069]

[0084] Embodiment 80: A medicated feed for use in the method of any one of embodiments 77 to 79, wherein the mammal is selected from the group consisting of canines and felines.

[0070]

[0085] Embodiment 81: A medicated feed for use in the method of embodiment 80, wherein the mammal is a domestic dog.

[0086] Embodiment 82: A medicated feed for use in the method of embodiment 80, wherein the mammal is a domestic cat.

[0071]

[0087] Embodiment 83: A medicated feed for use in the method of any one of embodiments 77 to 82, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulosstrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0072]

[0088] Embodiment 84: A medicated feed for use in the method of any one of embodiments 77 to 82, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

[0073]

[0089] Embodiment 85: A medicated feed for use in the method of any one of embodiments 77 to 84, wherein the systemic anthelmintic is milbemycin.

[0090] Embodiment 86: A medicated feed for use in the method of embodiment 85, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0074]

[0091] Embodiment 87: A medicated feed for use in the method of embodiment 85 or 86, wherein the therapeutically effective cumulative amount of moxidectin administered to the mammal over a period of about 30 days does not exceed 48 μg moxidectin per kg body weight of the mammal.

[0075]

[0092] Embodiment 88: A medicated feed for use in the method of embodiment 87, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg, and about 0.8 μg / kg to about 0.9 μg / kg.

[0076]

[0093] Embodiment 89: A medicated feed for use in the method of any one of embodiments 85 to 88, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg and about 1.6 μg / kg.

[0077]

[0094] Embodiment 90: A medicated feed for use in the method of any one of embodiments 85 to 89, wherein said administration results in a concentration of moxidectin in the blood of said mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0078]

[0095] Embodiment 91: A medicated feed for use in the method of any one of embodiments 85 to 89, wherein said administration results in a concentration of moxidectin in the blood of said mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0079]

[0096] Embodiment 92: A medicated feed for use in the method of any one of embodiments 77 to 84, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0080]

[0097] Embodiment 93: A medicated feed for use in the method of embodiment 92, wherein the aminoacetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0098] Embodiment 94: A medicated feed for use in the method of embodiment 93, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over a period of about 30 days does not exceed 25 mg of monepantel per kg of body weight of the mammal.

[0081]

[0099] Embodiment 95: A medicated feed for use in the method of embodiment 93 or 94, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of: about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; about 0.125 mg / kg to about 0.25 mg / kg.

[0082]

[0100] Embodiment 96: A medicated feed for use in the method of any one of embodiments 93 to 95, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

[0083]

[0101] Embodiment 97: A medicated feed for use in the method of any one of embodiments 77 to 96, wherein the number of days between the administration of any two microdoses is less than 2, 3, 4, 5, 6 or 7 days.

[0084]

[0102] Embodiment 98: A medicated feed for use in the method of any one of embodiments 77 to 97, wherein at least one microdose is administered orally.

[0103] Embodiment 99: A medicated feed for use in the method of any one of embodiments 77 to 98, further comprising administering at least one additional anthelmintic.

[0085]

[0104] Embodiment 100: A medicated feed for use in the method of embodiment 99, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0105] Embodiment 101: A medicated feed for use in the method of embodiment 99 or 100, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

[0086]

[0106] Embodiment 102: A medicated feed for use in the method of embodiment 99, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

[0087]

[0107] Embodiment 103: A medicated feed for use in the method of embodiment 99, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphorus compound or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

[0088]

[0108] Embodiment 104: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, and the macrocyclic lactone is at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

[0089]

[0109] Embodiment 105: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, and the cyclooctadepsipeptide is at least one compound selected from the group consisting of emodepside, PF1022, and salts or derivatives of any of the foregoing.

[0090]

[0110] Embodiment 106: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, and the amino-acetonitrile derivative is monepantel or a salt or derivative thereof.

[0091]

[0111] Embodiment 107: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, and the tetrahydropyrimidine is at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

[0092]

[0112] Embodiment 108: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises an imidazothiazole, and the imidazothiazole is at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

[0093]

[0113] Embodiment 109: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises paraherquamide, wherein paraherquamide is at least one compound selected from the group consisting of delquantel, paraherquamide, and salts or derivatives of any of the foregoing.

[0094]

[0114] Embodiment 110: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises an aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

[0095]

[0115] Embodiment 111: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises an organophosphorus compound, and the organophosphorus compound is at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxon, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

[0096]

[0116] Embodiment 112: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises a substituted phenol, and the substituted phenol is at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolan, meniclofolan, nitroxynil, and salts or derivatives of any of the foregoing.

[0097]

[0117] Embodiment 113: A medicated feed for use in the method of embodiment 103, wherein the at least one additional anthelmintic comprises a piperazinone, and the piperazinone is at least one compound selected from the group consisting of praziquantel, epsiprantel, and salts or derivatives of any of the foregoing.

[0098]

[0118] Embodiment 114: A medicated feed for use in the method of embodiment 99, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

[0099]

[0119] Embodiment 115: A medicated feed for use in the method of embodiment 99, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof. [Brief explanation of the drawings]

[0100] [Figure 1]

[0120] FIG. 1 shows sample graphs of moxidectin levels over time (days) in plasma of mammals given different dosing regimens: one bolus dose every 30 days (squares), a daily dose of 0.0008 mg / kg / day (solid line), or a daily dose of 0.0016 mg / kg / day (triangles). DETAILED DESCRIPTION OF THE INVENTION

[0101]

[0121] Surprisingly, the present inventors have discovered that oral anthelmintic treatment can improve the control of parasitic infections in mammals when administered orally in smaller, more frequent / more chronic doses. Administration in conjunction with feed is discussed below. However, it is also anticipated that the anthelmintic can be administered alone or in a dosage form other than feed, such as a chew, tablet, liquid, gel, or other suitable form for oral administration. By using smaller, more frequent doses, it is advantageous to reduce the total amount of anthelmintic required to control heartworm infection within the same period. For example, assume that a single oral dose of 24 μg of moxidectin per kg of mammalian body weight is required to achieve and maintain a therapeutically effective concentration of moxidectin in the canine's blood over a 30-day (1-month) period for continued heartworm prevention and control, according to a prior art approach. The smaller, more frequent dosing approach of the present invention may require only small amounts of moxidectin, 0.2 to 0.72 μg per kg of canine body weight per day, or a cumulative amount of 6 to 21.6 μg of moxidectin per kg of canine body weight over the same 30 day period.

[0102]

[0122] Advantageously, the total amount of anthelmintic required for a therapeutically effective monthly administration can be reduced by 2% to 87.5% by switching to a low-dose daily administration. However, from a practical standpoint, at least two problems arise: (1) creating a homogeneous feed; and (2) analytical control tests for very small amounts of anthelmintic can be difficult to perform. The analytical matrix derived from the feed can be quite complex and difficult to assay. Assays can range from parts per million to parts per billion for some required doses and feed concentrations. Therefore, one skilled in the art can choose to increase the daily dose so that the total amount per day for one month is equal to the monthly dose of the prior art, or even higher, e.g., 200% of the monthly dose of the prior art. This can help ensure homogeneity and improve assay precision and reduce analytical variability when the dose is administered as part of the feed. In the case of heartworm, increasing the dose can also be effective against drug-resistant heartworm isolates.

[0103]

[0123] The method and composition taught herein has the additional advantage of promoting compliance, since the smaller amount of anthelmintic drug can be incorporated into feed.In any case, owners naturally follow the daily feeding regimen, which reduces the possibility that owners will forget or neglect to administer anthelmintic drug.Therefore, the present disclosure provides a method for long-term control of heartworms in a safer, more compliant and effective manner than that achieved by known treatment methodologies.All owners need to remember is to feed their pets every day as usual.In addition, this method can be used to prevent the establishment of drug-resistant heartworm isolates.

[0104]

[0124] Some classes of anthelmintic active compounds include macrocyclic lactones, such as abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin, etc.; benzimidazoles and probenzimidazoles, such as albendazole, albendazole sulfoxide, cambandazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, triclabendazole, etc.; cyclooctadepsipeptides, such as emodepside, PF1022, etc.; amino-acetonitrile derivatives, such as monepantel, etc.; tetrahydropyrimidines, such as morantel, pyrantel, oxantel, etc.; imidazothiazoles. benzophenone, benzophenone-3, benzotriazole, benzophenone-4, benzotriazole ...and other classes such as amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetid, dichlorophen, diethylcarbamazine, emetine, hetolin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omphalotin, oxamniquine, paromomycin, piperazine, and rezolantel;

[0105]

[0125] Anthelmintics of particular interest for the prevention and control of heartworm infections in mammals are the macrocyclic lactones (avermectins and milbemycins).

[0126] Avermectins are a group of 16-membered macrocyclic lactone derivatives. These naturally occurring compounds are fermentation products of the soil actinomycete Streptomyces avermitilis. An example of an avermectin is ivermectin, shown below.

[0106] [ka]

[0107]

[0127] Milbemycins are a group of macrolides first isolated from Streptomyces hygroscopicus in 1972. Milbemycins are fermentation products of Streptomyces. Milbemycins have a mechanism of action similar to avermectin, and milbemycins often have a longer half-life. For example, moxidectin has a terminal half-life of approximately 13.9 days compared to ivermectin's terminal half-life of 1.8 days. An example of a milbemycin, moxidectin, is shown below.

[0108] [ka]

[0109]

[0128] Amino-acetonitrile derivatives, such as monepantel (N-[(2S)-2-cyano-1-[5-cyano-2-(trifluoromethyl)phenoxy]propan-2-yl]-4-(trifluoromethylsulfanyl)benzamide), are believed to act by interfering with parasite muscle function. Monepantel, its salts, derivatives, metabolites, and any of its biologically active enantiomers are amino-acetonitriles that may be suitable for use according to the present disclosure.

[0110] [ka]

[0111]

[0129] More particularly, anthelmintics with a half-life of at least 1 day are suitable for the disclosed methods and formulations. More preferably, anthelmintics with a half-life of at least 3 days are suitable for the disclosed methods and formulations. Even more preferably, anthelmintics with a half-life of at least 7 days are suitable for the disclosed methods and formulations.

[0112]

[0130] The formulations, feeds, and methods of the present disclosure can further include one or more other active pharmaceutical ingredients in combination with the anthelmintic that have therapeutic efficacy against other types of parasites. Such active agents include agents effective against vectors of heartworm infection, fleas, ticks, and intestinal nematode species. Active agents can include, for example, isoxazolines, foramidines, spinosyns, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), benzimidizoles, and tetrahydropyrimidines.

[0113]

[0131] The method of the present disclosure is carried out by administering small, frequent doses of an anthelmintic to a mammal. To facilitate routine dosing, the anthelmintic can be administered using feed, chew treats, tablets, liquids, gels, or other forms suitable for oral administration. Many different feeds are contemplated, provided that the manufacturing process and feed composition do not have adverse effects on the anthelmintic and, if applicable, other active substances in terms of chemical stability, efficacy, and safety. For example, feeds and snacks in the broad categories of dry feed, semi-moist feed, or canned-refrigerated feed, chew treats, reward treats, or supplemental feeds can be adapted for use according to the present disclosure. The mammal is administered a maintenance dose of the anthelmintic by consuming the feed product weekly, twice weekly, or daily.

[0114]

[0132] By incorporating smaller amounts of anthelmintic into animal feed compositions and administering them at an effective rate (most preferably daily), the blood and tissue levels of the anthelmintic will increase over time until they reach an optimal steady state that can be maintained by daily or substantially daily administration.On the other hand, when anthelmintic is orally administered infrequently in large amounts, for example, in a large single treatment administered via "reward treats or tablets" once every 30 days, the levels of the anthelmintic in blood and tissue will rise sharply when the first dose is administered, and then decline until the next dose is administered.Administering infrequently in large amounts means that the mammal must consume more anthelmintic with each administration, so that the blood and tissue levels of the anthelmintic do not fall below the level required for effective protection before the next dose is administered.

[0115]

[0133] All ratios, percentages and parts discussed herein are "weight ratios," "weight percents" and "weight parts," respectively, unless otherwise specified.

[0134] The terms "controlling a parasitic infection" and "controlling a helminth infection" refer to the prevention, treatment, minimization or elimination of a parasitic or helminth infection in a mammal.

[0116]

[0135] The term "controlling heartworm infection" refers to the prevention, treatment, minimization or elimination of infection by heartworm in a mammal.

[0136] The terms "parasite" and "helminth" are used interchangeably to refer to members of the phyla Annelida, Platyhelminthes, Nematoda, and Acanthocephalina. The terms "parasite" and "helminth" include egg, larval, and adult developmental stages.

[0117]

[0137] The term "heartworm" is used to refer to members of the genus Dirofilaria. The term includes larval and adult development stages.

[0138] The term "canid" refers to any member of the genus Canis, which includes species such as wolves, dogs, coyotes, and jackals.

[0118]

[0139] The term "feline" refers to any member of the subfamily Felinae, and includes species such as the domestic cat, bobcat, wildcat, ocelot, members of the lynx genus, Pallas's cat, and cougar.

[0119]

[0140] The term "mustelid" refers to any member of the family Mustelidae, which includes species such as ferrets, American minks, European minks, weasels, badgers, and wolverines.

[0120]

[0141] In carrying out the method of the present disclosure, "feed" refers to animal feed, snacks, reward treats or other nutritional supplements that can be administered daily or substantially daily.By using different forms of feed, such as pet food and reward treats, pet owners can change the diet and snacks of mammals from time to time while conveniently administering the daily dose of anthelmintic drug.

[0121]

[0142] The term "chew treat" refers to a reward treat that typically has flavor and aroma characteristics that are appealing to mammals, but generally lacks nutritional value. In practicing the methods of the present disclosure, "food" and / or "chew treat" may be used interchangeably.

[0122]

[0143] For purposes of this disclosure, the term "effective time," also referred to herein as "effective duration," includes at least the period of administration of the feed necessary to achieve a level of anthelmintic drug in the mammal's blood or tissues high enough to control heartworms, i.e., a "therapeutically effective" level. In some embodiments, the effective time can be as short as three days. In other cases, the effective time may be seven days, or fifteen days, or longer. As discussed below, the effective time will vary depending on how frequently the feed or anthelmintic drug is administered.

[0123]

[0144] As previously mentioned, "effective time" varies as a function of the frequency with which the feed is administered. As used herein, the term "effective frequency" refers to the number of feedings over a given period of time that results in a therapeutically effective concentration of the anthelmintic drug in the mammal's blood. In any case, as used herein, the term "effective frequency" contemplates multiple feedings per month that contain the anthelmintic drug. Those skilled in the art will understand that the anthelmintic drug can be administered at various frequencies. For example, the anthelmintic drug may be administered daily, every other day, every three days, once a week, or at irregular intervals.

[0124]

[0145] Furthermore, as discussed above, the frequency of effectiveness can affect the period of time required to achieve therapeutically effective levels of the anthelmintic in the mammal's blood. For example, if a mammal is fed the anthelmintic composition daily, the period of feed administration required to achieve therapeutically effective levels of the anthelmintic in the mammal's blood, and therefore the "effective time," will be relatively shorter than if the mammal were fed the anthelmintic composition only once or twice a week.

[0125]

[0146] Furthermore, the frequency of effectiveness is affected by the daily dose (mg / kg mammalian body weight), with missed doses having less impact on effectiveness, especially at slightly higher daily doses.

[0126]

[0147] Furthermore, the effective frequency is affected by the duration of treatment: for example, in the early stages before therapeutically effective levels of anthelmintic drug are reached in the mammal's blood or tissues, the animal feed may need to be administered more frequently than is required after longer periods of use, i.e., after therapeutically effective levels are achieved.

[0127]

[0148] For purposes of this disclosure, "substantially daily" means sufficiently regularly that the concentration of the anthelmintic drug in the mammal's blood or tissues rises to and is maintained at a therapeutically effective level. For example, a daily supply of the disclosed dietary composition can preferably be given to a mammal daily indefinitely. However, as a practical matter, there are many reasons why doses may be periodically missed or omitted. For example, the mammal may become ill, or the owner may use up the daily supply of medicated feed composition. The disclosed methods are robust enough to provide some degree of parasite protection to a mammal even with occasional interruptions in the daily feeding of the medicated animal feed composition. In practicing the methods of the present disclosure, the term "substantially daily" includes at least 10 days per month, more preferably at least 15 days per month, and even more preferably at least 20 days per month. All of these feeding frequencies, whether three times per week, every other day, or daily, qualify as substantially daily if they facilitate the anthelmintic drug to reach and be maintained at a therapeutically effective level in the mammal's blood.

[0128]

[0149] The term "sub-therapeutic" refers to an amount of an anthelmintic drug that, in a single administration, is in itself ineffective or suboptimal for controlling a parasitic infection in a mammal.

[0150] The term "therapeutically effective" means that the dose or blood level of the anthelmintic drug or its physiologically acceptable derivative or metabolite thereof is sufficient to control the helminth infection better than in the absence of the drug. The anthelmintic drug or its physiologically acceptable derivative or metabolite thereof may be naturally occurring or may be present together with one or more additional active substances. Preferably, the helminth infection is controlled by at least about 50% better than in the absence of the drug, and more preferably, the helminth infection is controlled by at least about 90% better than in the absence of the drug.

[0129]

[0151] In carrying out the method of the present disclosure, an effective amount or a therapeutically effective amount of an anthelmintic drug is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount necessary to control helminth infection. As can be understood by those skilled in the art, this amount will vary depending on many factors. These factors include, for example, the type and weight and general health of the mammal being treated, and the efficacy of the anthelmintic drug.

[0130]

[0152] Anthelmintics vary in potency. Accordingly, an effective amount of an anthelmintic can be calculated for each particular anthelmintic used in at least a portion of the methods of the present disclosure. Generally, an effective daily dose of an anthelmintic will be in the range of about 25% to 90% of the approved label dose of the anthelmintic divided by the length of the dosing / retreatment interval (e.g., for a monthly product, the dose divided by 30). Those skilled in the art will recognize that higher doses, e.g., 90% to 200% of the approved label dose of the anthelmintic, may be selected for reasons including, but not limited to, ease of manufacturability, testing, and analysis. In some embodiments, the particular dose selected may be sufficient to raise the concentration of the anthelmintic in the mammal's blood to a therapeutically effective level within about 7 days of substantially daily administration, more preferably within about 5 days of substantially daily administration, and most preferably within about 3 days of substantially daily administration.

[0131]

[0153] This disclosure describes the concentration of the anthelmintic in relation to feed, such as pet food, and also contemplates administration using other dosage forms, such as reward treats or chew treats. It is also contemplated that the anthelmintic may be administered by itself or in a tablet, liquid, gel, or other suitable form for oral administration. Those skilled in the art will understand that the concentration of the anthelmintic will vary depending on the particular dosage form. For example, if the animal feed is the reward treat, the concentration of the anthelmintic in the reward treat will be higher than the concentration of the anthelmintic in, for example, pet food. For example, if the daily dose of the anthelmintic relative to the mammal's body weight is 10 mg, a typical 5 g reward treat may contain about 0.002 percent anthelmintic (by weight). As the amount of pet food consumed per day exceeds 5 g, the percentage of the anthelmintic in the pet food will be smaller.

[0132]

[0154] For example, an effective amount of moxidectin can be a daily or substantially daily amount of about 0.2 to about 1.6 μg of moxidectin per kg of mammalian body weight. Alternatively, an effective amount of moxidectin can be a daily or substantially daily amount of about 0.4 to about 1.6 μg of moxidectin per kg of mammalian body weight. Alternatively, an effective amount of moxidectin can be a daily or substantially daily amount of about 0.8 to about 1.6 μg of moxidectin per kg of mammalian body weight. Alternatively, an effective amount of moxidectin can be a daily or substantially daily amount of about 0.2 to about 0.8 μg of moxidectin per kg of mammalian body weight.

[0133]

[0155] Animal feeds typically contain between about 0.0000001 and about 0.00008 percent moxidectin by weight. Preferably, the moxidectin content in the feed is between about 0.0000002 and about 0.00005 percent by weight. Most preferably, the one or more moxidectin components in the feed are between about 0.000001 and about 0.0001 percent by weight.

[0134]

[0156] In another example, an effective amount of monepantel can be a daily or substantially daily amount of about 0.025 to about 0.83 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.05 to about 0.5 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.125 to about 0.5 mg of monepantel per kg of mammalian body weight. Alternatively, an effective amount of monepantel can be a daily or substantially daily amount of about 0.125 to about 0.25 mg of monepantel per kg of mammalian body weight.

[0135]

[0157] Animal feed typically contains about 0.00005 to about 0.0001 percent by weight of monepantel in the feed. Preferably, the monepantel content in the feed is between about 0.0001 and about 0.005 percent by weight. Most preferably, the monepantel content in the feed is between about 0.0005 and about 0.001 percent by weight.

[0136]

[0158] In one aspect, the present disclosure relates to a method of controlling heartworm infection in a mammal by administering a systemically active oral composition comprising an anthelmintic, or a physiologically acceptable derivative or salt thereof, and animal feed at least once a week, more preferably three times a week, and most preferably substantially daily.

[0137]

[0159] In another aspect, the present disclosure relates to a systemically active oral composition comprising an anthelmintic and an animal feed.

[0160] The present disclosure also relates to the use of an anthelmintic agent for the manufacture of animal feed for controlling heartworm infection in mammals.

[0138]

[0161] The present disclosure also relates to a method for long-term control of heartworm infection in a mammal, comprising orally administering to the mammal a daily or substantially daily amount of an effective amount of an anthelmintic drug in a daily feed. A daily feed is a feed intended to be administered daily, but which can be administered at an effective time, as described herein. The method comprises orally administering to the mammal an effective amount of an anthelmintic drug in a substantially daily amount, and is particularly useful for long-term control of heartworm in a mammal.

[0139]

[0162] One aspect of the present disclosure is that when administered at longer intervals, such as once a month, oral administration of an amount of anthelmintic drug is ineffective or suboptimal for controlling heartworm infection in mammals.However, as described herein, by administering at shorter intervals, for example, repeatedly at substantially daily intervals, effective control of heartworm infection is achieved.Ineffective or suboptimal means that single administration and multiple administrations reduce heartworm infection by less than 50%, including no reduction or substantial reduction compared to no drug administration at all.This reflects the chronic administration aspect disclosed herein, not acute administration.

[0140]

[0163] In a first embodiment, a method for controlling heartworm in a mammal by orally administering to the mammal a daily diet containing an effective amount of an anthelmintic drug for an effective period of time is disclosed.

[0141]

[0164] In a second embodiment, an anthelmintic drug is disclosed for use in controlling heartworm in a mammal in need thereof. The anthelmintic drug may be present in an effective amount in a daily feed, the daily feed being administered to the mammal at a time effective to control heartworm.

[0142]

[0165] In a third embodiment, a daily feed for controlling heartworm in a mammal is disclosed, the daily feed comprising an effective amount of an anthelmintic when administered at an effective time.

[0143]

[0166] In any aspect of the embodiment, the mammal can be a canine. More particularly, the canine can be a wolf, coyote, or dog.

[0167] In any aspect of the embodiment, the mammal can be a feline. More particularly, the feline can be a domestic cat, a bobcat, an ocelot, a member of the genus Lynx, a Pallas's cat, or a cougar.

[0144]

[0168] In any aspect of the embodiment, the mammal can be a mustelid. More particularly, the mustelid can be a ferret, mink, weasel, badger, or wolverine.

[0145]

[0169] In one aspect of any embodiment, the anthelmintic is a macrocyclic lactone or a salt thereof. Example

[0170] The following examples illustrate the methods of the present disclosure. [Example]

[0146]

[0171] Efficacy of moxidectin administered orally, i.e., via the mouth, to dogs for the treatment and control of Dirofilaria immitis.

[0172] Methods: - A cohort of 12 dogs is required to be pre-tested to ensure good health on day 35. - On day 34, a modified Knott's test and / or adult antigen test can be performed to verify the absence of circulating D. immitis microfilariae or adult antigen in the blood. - Dogs exposed to anthelmintics or endectocides with activity against D. immitis within the 60 days prior to day 28 will be excluded.

[0147]

[0173] Dogs are weighed between days -32 and -30 and randomized by weight to one of four treatment groups.

[0174] Dogs are housed indoors in a mosquito-free environment to promote prevention of naturally occurring heartworm infection. Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on days -32 to -30. Thereafter, dogs are housed individually. Dogs should be fed a standard commercial dog food at the recommended rate and have free access to drinking water.

[0148]

[0175] Dogs assigned to groups 1 and 2 will be inoculated with 50±5 third-stage infective D. immitis larvae on day −28. Daily oral dosing with moxidectin will begin on day 0 and continue through day 179 for groups 1 and 2.

[0149]

[0176] Dogs assigned to groups 3 and 4 will receive a daily dose of moxidectin starting on day -28 and continuing until day -1. On day 0, once the dogs have reached steady-state drug levels, they will be inoculated with 50 ± 5 third-stage infective D. immitis larvae. Daily dosing with moxidectin will continue from day 0 to day 179.

[0150]

[0177] The daily dose of moxidectin for each test group (Groups 1 to 4) should follow Table 1.

[0151] [Table 1]

[0152]

[0178] Treatment on each dosing day may be administered by oral gavage to fed or fasted dogs. On each scheduled dosing day from Day -28 (Groups 3 and 4) or Day 0 (Groups 1 and 2) through Day 179, each dog in all groups will receive a moxidectin dose based on their pretreatment or most recent body weight. Dogs in all groups will be reweighed on Days 0, 30, 60, 90, 120, and 150, and the daily volume of oral moxidectin liquid formulation may be adjusted based on their most recent body weight.

[0153]

[0179] If heartworms are found, they will be collected and counted from all test dogs after 180 days.

[0180] Rapid-acting trials have demonstrated that moxidectin is effective in treating and / or preventing heartworm disease when administered at doses of 0.8 μg / kg and 1.6 μg / kg to heartworm-exposed and heartworm-unexposed dogs. The expected outcome is zero heartworms recovered from all 12 dogs.

[0154]

[0181] Using the same test method as described above, but continuing daily administration of moxidectin in treatment groups 2 and 3 for 90 days, blood samples may be taken approximately daily after the initial dose of moxidectin is administered. The mean concentrations of moxidectin in the blood at different dose levels can then be determined.

[0155]

[0182] The predicted mean plasma concentrations of moxidectin in mammalian blood at different dosage levels are shown in the chart below. The solid line represents the approximate plasma concentration for a daily dose of 0.0008 mg of moxidectin per kg of mammalian body weight, and the triangles represent the approximate plasma concentration for a daily dose of 0.0016 mg of moxidectin per kg of mammalian body weight. For comparison, the approximate plasma concentrations for mammals receiving a single bolus dose once every 30 days are also shown in Figure 1 (squares). [Example]

[0156]

[0183] Efficacy of monepantel administered orally, i.e., via mouth, to dogs for the treatment and control of Dirofilaria immitis.

[0184] Methods: - A cohort of 12 dogs is required to be pre-tested to ensure good health on day 35. - On day 34, a modified Knott's test and / or adult antigen test can be performed to verify the absence of circulating D. immitis microfilariae or adult antigen in the blood. - Dogs exposed to anthelmintics or endoectocides with activity against D. immitis within the 60 days prior to day 28 will be excluded.

[0157]

[0185] Dogs are weighed between days -32 and -30 and randomized by weight to one of four treatment groups.

[0186] Dogs are housed indoors in a mosquito-free environment to promote prevention of naturally occurring heartworm infection. Dogs may be housed in pairs, if compatible, or individually until assigned to treatment groups on days -32 to -30. Thereafter, dogs are housed individually. They should be fed a standard commercial dog food at the recommended rate and have free access to drinking water.

[0158]

[0187] Dogs assigned to groups 1 and 2 will be inoculated with 50±5 third-stage infective D. immitis larvae on day −28. Daily oral dosing with monepantel will begin on day 0 and continue through day 179 for groups 1 and 2.

[0159]

[0188] Dogs assigned to groups 3 and 4 will begin receiving a daily dose of monepantel on day -28 and continue until day -1. On day 0, once the dogs have reached steady-state drug levels, they will be inoculated with 50±5 third-stage infective D. immitis larvae. Daily dosing with monepantel will continue from day 0 to day 179.

[0160]

[0189] The daily dose of monepantel for each study group (Groups 1 to 4) should follow Table 2.

[0161] [Table 2]

[0162]

[0190] Treatment on each dosing day may be administered by oral gavage to dogs in a fed or fasted state. On each scheduled dosing day from Day -28 (Groups 3 and 4) or Day 0 (Groups 1 and 2) through Day 179, each dog in all groups will receive a monepantel dose based on the dog's pretreatment or most recent body weight. Dogs in all groups will be reweighed on Days 0, 30, 60, 90, 120, and 150, and the daily volume of oral monepantel liquid formulation may be adjusted based on the most recent body weight.

[0163]

[0191] If heartworms are found, they will be collected and counted from all test dogs after 180 days.

[0192] The expected results showed that zero heartworms were recovered from all 12 dogs, demonstrating that the doses of monepantel (0.083 mg / kg and 0.83 mg / kg) administered to heartworm-exposed and heartworm-unexposed dogs were effective in treating and / or preventing heartworm.

[0164]

[0193] While this invention has been described as having an exemplary design, the invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.

Claims

1. 1. A method for controlling heartworm infection, comprising: administering a therapeutically effective cumulative amount of at least one systemic anthelmintic to a mammal in need of treatment, wherein said therapeutically effective cumulative amount comprises multiple discrete microdoses of at least one systemic anthelmintic; The method wherein the microdose is administered to the mammal daily or substantially daily, and wherein the at least one anthelmintic has a half-life in the mammal of at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days.

2. 10. The method of claim 1, wherein the systemic anthelmintic is an integral part of at least one of a medicated feed, chew, snack, tablet, capsule, powder, ointment, suspension, solution, and paste.

3. 3. The method of claim 1 or 2, wherein the systemic anthelmintic is an integral part of a medicated pet feed, said medicated feed being a consumable product selected from the group consisting of pet food, wet pet food, paste, chew treats, and reward treats.

4. 4. The method of any one of claims 1 to 3, wherein the mammal is selected from the group consisting of canines and felines.

5. 5. The method of claim 4, wherein the mammal is a domestic dog.

6. The method of claim 4, wherein the mammal is a domestic cat.

7. 7. The method of any one of claims 1 to 6, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

8. 7. The method of any one of claims 1 to 6, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

9. 9. The method of any one of claims 1 to 8, wherein the systemic anthelmintic is milbemycin.

10. 10. The method of claim 9, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

11. 11. The method of any one of claims 1 to 10, wherein the cumulative therapeutically effective amount of moxidectin administered to the mammal over a period of about 30 days does not exceed 48 μg of moxidectin per kg of mammal body weight.

12. 12. The method of claim 11, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg; and about 0.8 μg / kg to about 0.9 μg / kg.

13. 13. The method of claim 11 or 12, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg and about 1.6 μg / kg.

14. 14. The method of any one of claims 10 to 13, wherein the administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

15. 14. The method of any one of claims 10 to 13, wherein the administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

16. 9. The method of any one of claims 1 to 8, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

17. 17. The method of claim 16, wherein the aminoacetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

18. 18. The method of claim 17, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over a period of about 30 days does not exceed 25 mg of monepantel per kg of body weight of the mammal.

19. 19. The method of claim 17 or 18, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of: about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; and about 0.125 mg / kg to about 0.25 mg / kg.

20. 20. The method of any one of claims 17 to 19, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

21. 21. The method of any one of claims 1 to 20, wherein the number of days between administration of any two microdoses is less than 2, 3, 4, 5, 6, or 7 days.

22. 22. The method of any one of claims 1 to 21, wherein at least one microdose is administered orally.

23. 23. The method of any one of claims 1 to 22, further comprising administering at least one additional anthelmintic.

24. 24. The method of claim 23, wherein the at least one additional anthelmintic is a systemic anthelmintic.

25. 25. The method of claim 23 or 24, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

26. 24. The method of claim 23, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

27. 24. The method of claim 23, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphorus compound or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

28. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, and said macrocyclic lactone is at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

29. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, wherein the cyclooctadepsipeptide is at least one compound selected from the group consisting of emodepside, PF1022, and salts or derivatives of any of the foregoing.

30. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, said amino-acetonitrile derivative being monepantel or a salt or derivative thereof.

31. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, and the tetrahydropyrimidine is at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

32. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises an imidazothiazole, said imidazothiazole being at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

33. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises paraherquamide, said paraherquamide being at least one compound selected from the group consisting of delquantel, paraherquamide, and salts or derivatives of any of the foregoing.

34. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises an aminophenylamidine, wherein the aminophenylamidine is at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

35. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises an organophosphorus compound, said organophosphorus compound being at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxon, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

36. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises a substituted phenol, said substituted phenol being at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolane, meniclofolane, nitroxynil, and salts or derivatives of any of the foregoing.

37. 28. The method of claim 27, wherein the at least one additional anthelmintic comprises a piperazinone, said piperazinone being at least one compound selected from the group consisting of praziquantel, and epsiprantel, and salts or derivatives of any of the foregoing.

38. 24. The method of claim 23, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

39. 24. The method of claim 23, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

40. 1. A composition for controlling heartworm infection in dogs, comprising a microdose of at least one systemic anthelmintic drug, wherein the at least one systemic anthelmintic drug is active in a mammal and has a half-life in the mammal's system of at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days, and wherein the cumulative dose of multiple microdoses is sufficient to control heartworm infection in dogs.

41. 41. The composition of claim 40, wherein the systemic anthelmintic is an integral part of at least one formulation selected from the group consisting of medicated feed, reward treats, chew treats, snacks, tablets, capsules, powders, ointments, suspensions, solutions, sachets, and pastes, or integral parts thereof.

42. 41. The composition of claim 40, wherein the medicated feed comprises at least one livestock feed and the microdose of the systemic anthelmintic is an integral part of said livestock feed.

43. 41. The composition of claim 40, wherein the medicated feed is selected from the group of formulations consisting of pet foods, chew treats, wet pet foods, pastes and snacks.

44. 44. The composition of any one of claims 40 to 43, wherein the mammal is selected from the group consisting of canines and felines.

45. 45. The composition of claim 44, wherein the mammal is a domestic dog.

46. 45. The composition of claim 44, wherein the mammal is a domestic cat.

47. 47. The composition of any one of claims 40 to 46, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulosstrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

48. 47. The composition of any one of claims 40 to 46, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilus.

49. 49. The composition of any one of claims 44 to 48, wherein the systemic anthelmintic is milbemycin.

50. 50. The composition of claim 49, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

51. 51. The composition of claim 50, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg; and about 0.8 μg / kg to about 0.9 μg / kg.

52. 52. The composition of claim 50 or 51, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg and about 1.6 μg / kg.

53. 53. The composition of any one of claims 50 to 52, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

54. 54. The composition of any one of claims 50 to 53, wherein said administration results in a moxidectin concentration in the mammal's blood of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

55. 49. The composition of any one of claims 40 to 48, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

56. 56. The composition of claim 55, wherein the amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

57. The composition of claim 56, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; and about 0.125 mg / kg to about 0.25 mg / kg.

58. 58. The composition of claim 56 or 57, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

59. 59. The composition of any one of claims 40 to 58, wherein at least one microdose is formulated and administered orally.

60. 60. The composition of any one of claims 40 to 59, further comprising at least one additional anthelmintic.

61. 61. The composition of claim 60, wherein the at least one additional anthelmintic is a systemic anthelmintic.

62. 62. The composition of claim 60 or 61, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

63. 61. The composition of claim 60, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

64. 61. The method of claim 60, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphorus compound or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

65. 65. The method of claim 64, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, and said macrocyclic lactone is at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

66. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, wherein the cyclooctadepsipeptide is at least one compound selected from the group consisting of emodepside, PF1022, and salts or derivatives of any of the foregoing.

67. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, said amino-acetonitrile derivative being monepantel or a salt or derivative thereof.

68. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, and the tetrahydropyrimidine is at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

69. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises an imidazothiazole, wherein the imidazothiazole is at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

70. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises paraherquamide, wherein the paraherquamide is at least one compound selected from the group consisting of delquantel, paraherquamide, and salts or derivatives of any of the foregoing.

71. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises an aminophenylamidine, wherein the aminophenylamidine is at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

72. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises an organophosphorus compound, and the organophosphorus compound is at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxon, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

73. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises a substituted phenol, wherein the substituted phenol is at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolane, meniclofolane, nitroxynil, and salts or derivatives of any of the foregoing.

74. 65. The composition of claim 64, wherein the at least one additional anthelmintic comprises a piperazinone, and the piperazinone is at least one compound selected from the group consisting of praziquantel, epsiprantel, and salts or derivatives of any of the foregoing.

75. 61. The composition of claim 60, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

76. 61. The composition of claim 60, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

77. 1. A medicated feed for use in a method for controlling canine heartworm infection, comprising administering to a mammal in need of treatment a therapeutically effective cumulative amount of at least one systemic anthelmintic, wherein said therapeutically effective cumulative amount comprises multiple discrete microdoses of said at least one systemic anthelmintic; The medicated feed, wherein the microdose is administered to the mammal daily or substantially daily, and wherein the half-life of the at least one anthelmintic in the mammal is at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days, or at least 10 days.

78. 78. A medicated feed for use in the method of claim 77, wherein the systemic anthelmintic is an integral part of at least one of a medicated feed, chew treat, snack, tablet, capsule, powder, ointment, suspension, solution, and paste.

79. 79. A medicated pet feed for use in the method of claim 77 or 78, wherein the systemic anthelmintic is an integral part of the medicated pet feed, and the medicated pet feed is a consumable product selected from the group consisting of pet food, wet pet food, paste, chew treats, and reward treats.

80. 80. A medicated feed for use in the method of any one of claims 77 to 79, wherein the mammal is selected from the group consisting of canines and felines.

81. 81. A medicated feed for use in the method of claim 80, wherein the mammal is a domestic dog.

82. 81. A medicated feed for use in the method of claim 80, wherein the mammal is a domestic cat.

83. 83. A medicated feed for use in the method of any one of claims 77 to 82, wherein the therapeutically effective cumulative amount is sufficient to prevent infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulosstrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis and Eucoleus aerophilus.

84. 83. A medicated feed for use in the method of any one of claims 77 to 82, wherein the therapeutically effective cumulative amount is sufficient to control an infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Aerulosstrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis and Eucoleus aerophilus.

85. 85. A medicated feed for use in the method of any one of claims 77 to 84, wherein the systemic anthelmintic is milbemycin.

86. 86. A medicated feed for use in the method of claim 85, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

87. 87. A medicated feed for use in the method of claim 85 or 86, wherein the therapeutically effective cumulative amount of moxidectin administered to the mammal over a period of about 30 days does not exceed 48 μg of moxidectin per kg of mammal body weight.

88. 88. The medicated feed for use in the method of claim 87, wherein the amount of moxidectin in the microdose is in a range selected from the group consisting of: about 0.2 μg / kg to about 1.6 μg / kg; about 0.4 μg / kg to about 1.2 μg / kg; about 0.6 μg / kg to about 1.0 μg / kg; and about 0.8 μg / kg to about 0.9 μg / kg.

89. 89. A medicated feed for use in the method of any one of claims 85 to 88, wherein the amount of moxidectin in the microdose is selected from the group consisting of about 0.2 μg / kg, about 0.4 μg / kg, about 0.6 μg / kg, about 0.8 μg / kg and about 1.6 μg / kg.

90. 90. A medicated feed for use in the method of any one of claims 85 to 89, wherein said administration results in a concentration of moxidectin in the mammal's blood of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

91. 90. A medicated feed for use in the method of any one of claims 85 to 89, wherein said administration results in a concentration of moxidectin in the mammal's blood of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

92. 85. A medicated feed for use in the method of any one of claims 77 to 84, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

93. 93. A medicated feed for use in the method of claim 92, wherein the aminoacetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

94. 94. A medicated feed for use in the method of claim 93, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over a period of about 30 days does not exceed 25 mg of monepantel per kg of mammal body weight.

95. 95. A medicated feed for use in the method of claim 93 or 94, wherein the amount of monepantel in the microdose is in a range selected from the group consisting of: about 0.025 mg / kg to about 0.83 mg / kg; about 0.05 mg / kg to about 0.5 mg / kg; and about 0.125 mg / kg to about 0.25 mg / kg.

96. 96. A medicated feed for use in the method of any one of claims 93 to 95, wherein the amount of Montepantel in the microdose is selected from the group consisting of about 0.025 mg / kg; about 0.05 mg / kg; about 0.125 mg / kg; about 0.25 mg / kg; about 0.5 mg / kg; and about 0.83 mg / kg.

97. 97. A medicated feed for use in the method of any one of claims 77 to 96, wherein the number of days between the administration of any two microdoses is less than 2, 3, 4, 5, 6 or 7 days.

98. 98. A medicated feed for use in the method of any one of claims 77 to 97, wherein at least one microdose is administered orally.

99. 99. A medicated feed for use in the method of any one of claims 77 to 98, further comprising the step of administering at least one additional anthelmintic.

100. 100. A medicated feed for use in the method of claim 99, wherein the at least one additional anthelmintic is a systemic anthelmintic.

101. 101. A medicated feed for use in the method of claim 99 or 100, wherein the half-life of the at least one additional anthelmintic is less than 1 day.

102. 100. A medicated feed for use in the method of claim 99, wherein the at least one additional anthelmintic is selected from the group consisting of at least one compound that blocks acetylcholine receptors; at least one compound that acts on the nicotinic acetylcholine receptor ACR-23; and at least one compound that acts on the calcium-activated potassium channel SLO-1.

103. 100. A medicated feed for use in the method of claim 99, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of a macrocyclic lactone or a salt or derivative thereof; a cyclooctadepsipeptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; paraherquamide or a salt or derivative thereof; an aminophenylamidine or a salt or derivative thereof; an organophosphorus compound or a salt or derivative thereof; a substituted phenol or a salt or derivative thereof; a piperazinone or a salt or derivative thereof; and an octadepsipeptide or a salt or derivative thereof.

104. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises a macrocyclic lactone, said macrocyclic lactone being at least one compound selected from the group consisting of abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, nemadectin, selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, netobimin, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, and triclabendazole, and salts or derivatives of any of the foregoing.

105. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises a cyclooctadepsipeptide, said cyclooctadepsipeptide being at least one compound selected from the group consisting of emodepside, PF1022 and salts or derivatives of any of the foregoing.

106. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises an amino-acetonitrile derivative, said amino-acetonitrile derivative being monepantel or a salt or derivative thereof.

107. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises a tetrahydropyrimidine, said tetrahydropyrimidine being at least one compound selected from the group consisting of morantel, pyrantel, and oxantel, and salts or derivatives of any of the foregoing.

108. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises an imidazothiazole, said imidazothiazole being at least one compound selected from the group consisting of butamisole, levamisole, tetramisole, and salts or derivatives of any of the foregoing.

109. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises paraherquamide, said paraherquamide being at least one compound selected from the group consisting of delquantel, paraherquamide and salts or derivatives of any of the foregoing.

110. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises an aminophenylamidine, said aminophenylamidine being at least one compound selected from the group consisting of amidantel, deacylated amidantel (dAMD), tribendimidine, and salts or derivatives of any of the foregoing.

111. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises an organophosphorus compound, said organophosphorus compound being at least one compound selected from the group consisting of coumaphos, crufomate, dichlorvos, haloxon, naphthalophos, trichlorfon, and salts or derivatives of any of the foregoing.

112. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises a substituted phenol, said substituted phenol being at least one compound selected from the group consisting of bithionol, disophenol, hexachlorophene, niclofolane, meniclofolane, nitroxynil, and salts or derivatives of any of the foregoing.

113. 104. A medicated feed for use in the method of claim 103, wherein the at least one additional anthelmintic comprises a piperazinone, said piperazinone being at least one compound selected from the group consisting of praziquantel, epsiprantel, and salts or derivatives of any of the foregoing.

114. 100. A medicated feed for use in the method of claim 99, wherein the at least one additional anthelmintic is a compound selected from the group consisting of amoscanate, bephenium, bunamidine, clonazepam, clorsulon, diamfenetide, dichlorophen, diethylcarbamazine, emetine, hetrin, hycanthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitroxynil, nitrosucanate, oltipraz, omfalotin, oxamniquine, paromomycin, piperazine, rezolantel, salicylanilides, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide, tribromsalan, and salts or derivatives of any of the foregoing.

115. 100. A medicated feed for use in the method of claim 99, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

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