Feed and method for controlling infection of central filaria in mammals

Abstract

An oral animal feed and a method of preventing and / or controlling parasites in a mammal in need thereof by orally administering to a mammal, such as a canine, a feed comprising an effective amount of a systemic anthelmintic having a relatively long half-life for an effective time, this results in an increase in the amount of anthelmintic in the blood of the mammal and maintained at a therapeutically effective level for preventing and / or controlling heart filarius.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 407,140, ​​filed on September 15, 2022, which is hereby incorporated by reference herein. Field of the Invention

[0003] The teachings of the present disclosure are generally directed to methods of administering active substances to control heartworms in mammals.

[0004] background

[0005] There are five main types of parasites or helminths that most commonly infect domestic dogs: roundworms, tapeworms, hookworms, whipworms, and heartworms. These worms can cause serious health problems, including gastrointestinal problems, abdominal pain, weight loss, dehydration, anemia, pneumonia, and death in severe cases. In addition, some worms, such as Dirofilaria immitis, more commonly known as heartworms, infect dogs, cats, ferrets, and some other animals, can be easily transmitted by insect bites and are usually fatal if untreated. In some cases, treatment for adult heartworm infection can itself be fatal to the animal. Therefore, dogs, cats, and ferrets kept as pets must receive appropriate veterinary care, including routine treatment, to prevent heartworm infection.

[0006] Therapies currently available for controlling helminth infections in animals are known to achieve varying degrees of success. Problems leading to ineffective control of heartworms, for example in dogs and cats, include improper oral dosing, which can further lead to anthelmintic resistance, and vomiting caused by the high doses required by some anthelmintics to achieve effectiveness.

[0007] Overview

[0008] Embodiment 1: A method for controlling heartworm infection, comprising:

[0009] administering to a mammal in need thereof a cumulative therapeutically effective amount of at least one systemic anthelmintic, the cumulative therapeutically effective amount comprising: a plurality of individual microdoses of the at least one systemic anthelmintic,

[0010] wherein said microdoses are administered daily or substantially daily to said mammal, wherein said at least one anthelmintic has a half-life in said 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.

[0011] Embodiment 2: The method of embodiment 1, wherein the systemic anthelmintic is a component of at least one of a medicated feed, chew, snack, tablet, capsule, powder, ointment, suspension, solution, and paste.

[0012] Embodiment 3: The method of embodiments 1-2, wherein the systemic anthelmintic is a component of a medicated pet food, and the medicated feed is a consumable product selected from the group consisting of kibbles, wet food, pastes, chews, and treats.

[0013] Embodiment 4: The method according to embodiments 1-3, wherein the mammal is selected from the group consisting of canines and felines.

[0014] Embodiment 5: The method according to embodiment 4, wherein the mammal is a domestic dog.

[0015] Embodiment 6: The method according to embodiment 4, wherein the mammal is a domestic cat.

[0016] Embodiment 7: The method of embodiments 1-6, wherein the cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Aelurostrongylus abstrusus, Angiostrongylus vasorum, Crenosoma vulpis, and Eucoleus aerophilu.

[0017] Embodiment 8: The method of embodiments 1-6, wherein the cumulative therapeutically effective amount is sufficient to control infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Ringworm venom and Eubacterium aerogenes.

[0018] Embodiment 9: The method according to embodiments 1-8, wherein the systemic antihelmintic is milbemycin.

[0019] Embodiment 10: The method according to embodiment 9, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0020] Embodiment 11: The method of embodiments 1-10, wherein the cumulative therapeutically effective amount of moxidectin administered to the mammal over the course of about a 30-day period does not exceed 48 μg moxidectin / kg body weight of the mammal.

[0021] Embodiment 12: The method according to embodiment 11, wherein the amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

[0022] Embodiment 13: The method of embodiments 11-12, 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.

[0023] Embodiment 14: The method of any one of Embodiments 10-13, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0024] Embodiment 15: The method of any one of Embodiments 10-13, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0025] Embodiment 16: The method according to embodiments 1-8, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0026] Embodiment 17: The method according to Embodiment 16, wherein the amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0027] Embodiment 18: The method of Embodiment 17, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over the course of about a 30-day period does not exceed 25 mg monepantel / kg body weight of the mammal.

[0028] Embodiment 19: The method of embodiments 17-18, wherein the amount of monepantel in the microdose is within 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.

[0029] Embodiment 20: The method of embodiments 17-19, wherein the amount of monepantel 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.

[0030] Embodiment 21: The method of embodiments 1-20, wherein the number of days between administration of any two microdoses is less than a period of 2, 3, 4, 5, 6, or 7 days.

[0031] Embodiment 22: The method of embodiments 1-21, wherein the at least one microdose is administered orally.

[0032] Embodiment 23: The method of embodiments 1-22, further comprising administering at least one additional anthelmintic.

[0033] Embodiment 24: The method of Embodiment 23, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0034] Embodiment 25: The method of embodiments 23-24, wherein the at least one additional anthelmintic has a half-life of less than 1 day.

[0035] Embodiment 26: The method according to 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-gated potassium channel SLO-1.

[0036] Embodiment 27: A method according to embodiment 23, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of: a macrolide 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 p-quinoline 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.

[0037] Embodiment 28: The method of embodiment 27, wherein the at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

[0038] Embodiment 29: The method of embodiment 27, wherein the at least one additional anthelmintic comprises cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of: emodepsin, PF1022, and a salt or derivative of any one of the foregoing.

[0039] 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.

[0040] Embodiment 31: The method of Embodiment 27, wherein the at least one additional anthelmintic comprises an ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octotel, and a salt or derivative of any of the foregoing.

[0041] Embodiment 32: The method of Embodiment 27, 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 a salt or derivative of any of the foregoing.

[0042] Embodiment 33: The method according to Embodiment 27, wherein the at least one additional anthelmintic comprises quinolinamide, and the quinolinamide is at least one compound selected from the group consisting of dequent, quinolinamide and a salt or derivative of any one of the foregoing.

[0043] Embodiment 34: A method according to Embodiment 27, wherein the at least one additional anthelmintic comprises aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of: amitraz, deacylated amitraz (dAMD), tripendimidine and salts or derivatives of any of the foregoing.

[0044] Embodiment 35: A method according to embodiment 27, wherein the at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of: coumaphos, fenvalerate, dichlorvos, haloxone, naphthalofos, trichlorfon, and salts or derivatives of any one of the foregoing.

[0045] Embodiment 36: 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 thiobisdichlorophenol, diiodonitrophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile, and a salt or derivative of any of the foregoing.

[0046] 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, escitalol, and a salt or derivative of any of the foregoing.

[0047] Embodiment 38: The method of embodiment 23, wherein the at least one additional anthelmintic is a compound selected from the group consisting of nitrothiocyanate, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride (Miracil), mirasan, niclosamide, niridazole, nitrothiocyanate, nitrothiocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resorcinol, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan, and salts or derivatives of any of the foregoing.

[0048] Embodiment 39: The method of Embodiment 23, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

[0049] Embodiment 40: A composition for controlling heartworm infection, comprising:

[0050] A microdose of at least one systemic anthelmintic that is active in a mammal and has a half-life in the system of 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, and a cumulative dose of a plurality of said microdoses is sufficient to control a heartworm infection.

[0051] Embodiment 41: A composition according to Embodiment 40, wherein the systemic anthelmintic is a component of at least one formulation selected from the group consisting of: medicated feed, treats, chews, snacks, tablets, capsules, powders, ointments, suspensions, solutions, sachets and pastes, or components thereof.

[0052] Embodiment 42: A composition according to Embodiment 40, wherein the medicated feed comprises at least one feed ingredient, and wherein the microdose of the systemic anthelmintic is an integral part of the feed ingredient.

[0053] Embodiment 43: The composition of Embodiment 40, wherein the medicated feed is selected from the group of formulations consisting of kibbles, chews, wet food, pastes, and snacks.

[0054] Embodiment 44: The composition of Embodiments 40-43, wherein the mammal is selected from the group consisting of canines and felines.

[0055] Embodiment 45: The composition of Embodiment 44, wherein the mammal is a domestic dog.

[0056] Embodiment 46: A composition according to Embodiment 44, wherein the mammal is a domestic cat.

[0057] Embodiment 47: The composition of embodiments 40-46, wherein the cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Ringworm venom and Eubacterium aerogenes.

[0058] Embodiment 48: The composition of embodiments 40-46, wherein the cumulative therapeutically effective amount is sufficient to control infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Ringworm venom and Eubacterium aerophila.

[0059] Embodiment 49: The composition of embodiments 44-48, wherein the systemic anthelmintic is milbemycin.

[0060] Embodiment 50: The composition of Embodiment 49, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0061] Embodiment 51: A composition according to embodiment 50, wherein the amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

[0062] Embodiment 52: The composition of embodiments 50-51, 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.

[0063] Embodiment 53: The composition of any one of Embodiments 50-52, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0064] Embodiment 54: The composition of any one of Embodiments 50-53, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0065] Embodiment 55: The composition of embodiments 40-48, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0066] Embodiment 56: The composition of Embodiment 55, wherein the amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0067] Embodiment 57: A composition according to Embodiment 56, wherein the amount of monepantel in the microdose is within 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.

[0068] Embodiment 58: The composition of embodiments 56-57, wherein the amount of monepantel 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.

[0069] Embodiment 59: The composition of embodiments 40-58, wherein the at least one microdose is formulated to be administered orally.

[0070] Embodiment 60: The composition of embodiments 40-59, further comprising at least one additional anthelmintic.

[0071] Embodiment 61: The composition of Embodiment 60, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0072] Embodiment 62: The composition of Embodiments 60-61, wherein the at least one additional anthelmintic has a half-life of less than 1 day.

[0073] Embodiment 63: A composition according to 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-gated potassium channel SLO-1.

[0074] Embodiment 64: A composition according to embodiment 60, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of: a macrolide 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 p-quinoline 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.

[0075] Embodiment 65: A composition according to embodiment 64, wherein the at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

[0076] Embodiment 66: A composition according to Embodiment 64, wherein the at least one additional anthelmintic comprises cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of: emodepsin, PF1022, and a salt or derivative of any one of the foregoing.

[0077] 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.

[0078] Embodiment 68: The composition of Embodiment 64, wherein the at least one additional anthelmintic comprises an ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octotel, and a salt or derivative of any one of the foregoing.

[0079] Embodiment 69: A composition according to Embodiment 64, 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 a salt or derivative of any of the foregoing.

[0080] Embodiment 70: A composition according to Embodiment 64, wherein the at least one additional anthelmintic comprises quinolinamide, and the quinolinamide is at least one compound selected from the group consisting of dequent, quinolinamide and a salt or derivative of any one of the foregoing.

[0081] Embodiment 71: A composition according to Embodiment 64, wherein the at least one additional anthelmintic comprises aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of: amitraz, deacylated amitraz (dAMD), tripendimidine and salts or derivatives of any one of the foregoing.

[0082] Embodiment 72: A composition according to Embodiment 64, wherein the at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of: coumaphos, chlorpyrifos, dichlorvos, haloxone, naphthiophos, trichlorfon, and salts or derivatives of any one of the foregoing.

[0083] 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 thiobisdichlorophenol, diiodonitrophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile, and a salt or derivative of any of the foregoing.

[0084] Embodiment 74: The composition of Embodiment 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, escitalopram, and a salt or derivative of any of the foregoing.

[0085] Embodiment 75: The composition of embodiment 60, wherein the at least one additional anthelmintic is a compound selected from the group consisting of nitrosocyanamide, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride (Miracil), mirasan, niclosamide, niridazole, nitrothiocyanate, nitrosocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resorcinol, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan, and salts or derivatives of any of the foregoing.

[0086] Embodiment 76: A composition according to Embodiment 60, wherein the at least one additional anthelmintic is diethylcarbamazine or a salt or derivative thereof.

[0087] Embodiment 77: A medicated feed for use in a method of controlling heartworm infection, the method comprising: administering to a mammal in need thereof a cumulative therapeutically effective amount of at least one systemic anthelmintic, the cumulative therapeutically effective amount comprising: a plurality of individual microdoses of the at least one systemic anthelmintic,

[0088] wherein said microdoses are administered daily or substantially daily to said mammal, wherein said at least one anthelmintic has a half-life in said 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.

[0089] Embodiment 78: The medicated feed for use in the method according to Embodiment 77, wherein the systemic anthelmintic is a component of at least one of a medicated feed, chew, snack, tablet, capsule, powder, ointment, suspension, solution and paste.

[0090] Embodiment 79: The medicated feed for use in the method of embodiments 77-78, wherein the systemic anthelmintic is a component of a medicated pet food and the medicated feed is a consumable selected from the group consisting of kibble, wet food, paste, chews and treats.

[0091] Embodiment 80: The medicated feed for use in the method according to embodiments 77-79, wherein the mammal is selected from the group consisting of canines and felines.

[0092] Embodiment 81: The medicated feed for use in the method according to Embodiment 80, wherein the mammal is a domestic dog.

[0093] Embodiment 82: The medicated feed for use in the method according to Embodiment 80, wherein the mammal is a domestic cat.

[0094] Embodiment 83: The medicated feed for use in the method according to embodiments 77-82, wherein the cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of: Dirofilaria immitis, Strongyloides cati, Angiostrongylus vascularis, Ringworm fox and Eubacterium aerogenes.

[0095] Embodiment 84: The medicated feed for use in the method according to embodiments 77-82, wherein the cumulative therapeutically effective amount is sufficient to control infection by at least one helminth selected from the group consisting of: Dirofilaria immitis, Strongyloides cati, Angiostrongylus vascularis, Ringworm fox and Eubacterium aerogenes.

[0096] Embodiment 85: The medicated feed for use in the method according to embodiments 77-84, wherein the systemic anthelmintic is milbemycin.

[0097] Embodiment 86: The medicated feed for use in the method according to Embodiment 85, wherein the milbemycin is moxidectin or a therapeutically acceptable salt thereof.

[0098] Embodiment 87: The medicated feed for use in the method of Embodiments 85-86, wherein the cumulative therapeutically effective amount of moxidectin administered to the mammal over the course of a period of about 30 days does not exceed 48 μg moxidectin / kg body weight of the mammal.

[0099] Embodiment 88: The medicated feed for use in the method according to embodiment 87, wherein the amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

[0100] Embodiment 89: The medicated feed for use in the method according to embodiments 85-88, 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.

[0101] Embodiment 90: The medicated feed for use in the method of embodiments 85-89, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

[0102] Embodiment 91: The medicated feed for use in the method of Embodiments 85-89, wherein the administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

[0103] Embodiment 92: The medicated feed for use in the method according to embodiments 77-84, wherein the systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

[0104] Embodiment 93: The medicated feed for use in the method according to Embodiment 92, wherein the amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

[0105] Embodiment 94: The medicated feed for use in the method according to Embodiment 93, wherein the cumulative therapeutically effective amount of monepantel administered to the mammal over the course of a period of about 30 days does not exceed 25 mg monepantel / kg body weight of the mammal.

[0106] Embodiment 95: The medicated feed for use in the method according to embodiments 93-94, wherein the amount of monepantel in the microdose is within 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.

[0107] Embodiment 96: The medicated feed for use in the method according to embodiments 93-95, wherein the amount of monepantel 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.

[0108] Embodiment 97: The medicated feed for use in the method according to embodiments 77-96, wherein the number of days between the administration of any two microdoses is less than a period of 2, 3, 4, 5, 6 or 7 days.

[0109] Embodiment 98: The medicated feed for use in the method according to embodiments 77-97, wherein the at least one microdose is administered orally.

[0110] Embodiment 99: The medicated feed for use in the method according to embodiments 77-98, further comprising administering at least one additional anthelmintic.

[0111] Embodiment 100: The medicated feed for use in the method according to Embodiment 99, wherein the at least one additional anthelmintic is a systemic anthelmintic.

[0112] Embodiment 101: The medicated feed for use in the method of embodiments 99-100, wherein the at least one additional anthelmintic has a half-life of less than 1 day.

[0113] Embodiment 102: The medicated feed for use in the method according to 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-gated potassium channel SLO-1.

[0114] Embodiment 103: The medicated feed for use in the method according to Embodiment 99, wherein the at least one additional anthelmintic is at least one compound selected from the group consisting of: macrolides or salts or derivatives thereof; cyclooctadepsipeptide or salts or derivatives thereof; tetrahydropyrimidine or salts or derivatives thereof; imidazothiazole or salts or derivatives thereof; p-quinoline or salts or derivatives thereof; aminophenylamidine or salts or derivatives thereof; organophosphate or salts or derivatives thereof; substituted phenols or salts or derivatives thereof; piperazinone or salts or derivatives thereof; and octadepsipeptide or salts or derivatives thereof.

[0115] Embodiment 104: The medicated feed for use in the method according to embodiment 103, wherein the at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of: avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

[0116] Embodiment 105: The medicated feed for use in the method according to Embodiment 103, wherein the at least one additional anthelmintic comprises cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of: emodepsin, PF1022, and a salt or derivative of any one of the foregoing.

[0117] Embodiment 106: The medicated feed for use in the method according to 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.

[0118] Embodiment 107: The medicated feed for use in the method according to Embodiment 103, wherein the at least one additional anthelmintic comprises ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octotel and a salt or derivative of any one of the foregoing.

[0119] Embodiment 108: The medicated feed used in the method according to 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 a salt or derivative of any one of the foregoing.

[0120] Embodiment 109: The medicated feed used in the method according to Embodiment 103, wherein the at least one additional anti-helminthic drug includes quinolinamide, and the quinolinamide is at least one compound selected from the group consisting of dequent, quinolinamide and a salt or derivative of any one of the foregoing.

[0121] Embodiment 110: The medicated feed used in the method according to Embodiment 103, wherein the at least one additional anthelmintic comprises aminophenylamidine, and the aminophenylamidine is at least one compound selected from the group consisting of: amitraz, deacylated amitraz (dAMD), triphenamide and salts or derivatives of any of the foregoing.

[0122] Embodiment 111: The medicated feed used in the method according to Embodiment 103, wherein the at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of: coumaphos, chlorpyrifos, dichlorvos, haloxone, naphthiophos, trichlorfon and salts or derivatives of any one of the foregoing.

[0123] Embodiment 112: The medicated feed for use in the method according to 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: thiobisdichlorophenol, diiodonitrophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile and salts or derivatives of any of the foregoing.

[0124] Embodiment 113: The medicated feed used in the method according to Embodiment 103, wherein the at least one additional anthelmintic comprises piperazinone, and the piperazinone is at least one compound selected from the group consisting of: praziquantel, ethazitel and a salt or derivative of any one of the foregoing.

[0125] Embodiment 114: The medicated feed for use in the method according to embodiment 99, wherein the at least one additional anthelmintic is a compound selected from the group consisting of nitrosocyanamide, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride (Miracil), mirasan, niclosamide, niridazole, nitrothiocyanate, nitrosocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resorcinol, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan and salts or derivatives of any one of the foregoing.

[0126] Embodiment 115: The 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 DESCRIPTION OF THE DRAWINGS

[0127] FIG. 1 is a sample graph of the level of moxidectin in plasma over time (days) in mammals given different dosing regimens: a 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). Details

[0129] Surprisingly, the inventors have discovered that oral treatment with an anthelmintic can provide improved control of parasitic infections in mammals when administered orally in smaller, more frequent / chronic doses. Administration is discussed below as in conjunction with feed. However, it is also contemplated that the anthelmintic may 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. Advantageously, by using smaller, more frequent doses, less total anthelmintic is required to control heartworm infection over the same time period. For example, assume that according to prior art methods, a single oral dose of 24 μg / kg moxidectin / kg mammal body weight is required over a 30 day (1 month) period to achieve and maintain a therapeutically effective concentration of moxidectin in the blood of a canine for continued heartworm prevention and control. With smaller and more frequent dosing of the methods of the present invention, as little as 0.2-0.72 μg moxidectin / kg canine body weight per day may be required, or a cumulative requirement of 6-21.6 μg moxidectin / kg canine body weight over the same 30 day period.

[0130] Advantageously, by switching to a daily low-dose administration, the total amount of anthelmintic required for a therapeutically effective monthly dose can be reduced by 2%-87.5%. However, from a practical perspective, at least two problems arise: (1) producing a uniform feed; and (2) analytical control testing of very small doses of anthelmintic may be difficult to achieve. The analytical matrix from the feed can be very complex and difficult to assay. For some desired doses and feed concentrations, the assays will be in the parts per million to parts per billion range. Therefore, it is possible that one skilled in the art could choose to increase the daily dose so that the sum of the daily doses over the course of a month is equal to the prior art once-monthly dose or even higher, for example, 200% of the prior art once-monthly dose. Doing so can help ensure uniformity as well as increase assay accuracy and reduce analytical variability when the dose is administered as part of the feed. In the case of heartworm, the increased dose may also be effective against resistant isolates of heartworm.

[0131] The methods and compositions taught herein have the additional advantage of promoting compliance, since smaller doses of anthelmintics can be incorporated into the feed. This makes it less likely that the owner will forget or neglect to administer the anthelmintic, since the owner will naturally follow a daily feeding regimen in any case. Thus, the present disclosure provides methods for extended control of heartworms in a safer, more compliant, and more effective manner than achieved with previously known treatments. All the owner needs to remember is to feed their pet every day as they normally would. Furthermore, the method can be used to prevent the establishment of resistant isolates of heartworms.

[0132] Several classes of compounds with anthelmintic activity are known, including: macrolides, such as avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate, tricloban azoles; cyclooctadepsipeptides, such as emodepside and PF1022; amino-acetonitrile derivatives, such as monepantel; tetrahydropyrimidines, such as morantel, pyrantel, octadal; imidazothiazoles, such as butamidazole, levamisole, tetramisole; salicylanilides, such as bromoxanide, brotianide, ide), cloiosanil, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan; paraherquamides, such as dequinol, paraherquamide; aminophenylamidines, such as amitrail, deacylated amitrail (dAMD), triphenamide; organophosphates, such as coumaphos, fusophate, dichlorvos, haloxone, naphthiophos, trichlorfon; substituted phenols, such as thiobisdichlorophenol, diiodonitrophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitrothiophene; piperazinones such as praziquantel, escitalopram; and other classes, which include such examples as nitrothiocyanamide, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, miracil, mirasan, niclosamide, niridazole, nitrothiocyanate, oltipraz, omphalotin, oxamidine, paromomycin, piperazine and resortel.

[0133] Antihelmintics of particular interest for the prevention and control of filarial infections in mammals are the macrolides (avermectins and milbemycins).

[0134] Avermectins are a group of 16-membered macrolide derivatives. These naturally occurring compounds are fermentation products of Streptomyces avermitilis, a soil actinomycete. An example of an avermectin is ivermectin, as shown below:

[0135]

[0136] Milbemycins are a group of macrolides first isolated from Streptomyces hygroscopicus in 1972. They are fermentation products of Streptomyces species. They have a similar mechanism of action to avermectin and milbemycins generally have a longer half-life. For example, moxidectin has a terminal half-life of about 13.9 days compared to ivermectin's 1.8 day terminal half-life. Moxidectin, an example of a milbemycin, is shown below:

[0137]

[0138] 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 biologically active enantiomers thereof are amino-acetonitriles that may be suitable for use in the present disclosure.

[0139]

[0140] More particularly, anthelmintics having a half-life of at least 1 day are suitable for use in the methods and formulations of the present disclosure. More preferably, anthelmintics having a half-life of at least 3 days are suitable for use in the methods and formulations of the present disclosure. Even more preferably, anthelmintics having a half-life of at least 7 days are suitable for use in the methods and formulations of the present disclosure.

[0141] The formulations, feeds and methods of the present disclosure may further include one or more other active pharmaceutical substances with therapeutic efficacy against other types of parasites in combination with anthelmintics. Such active substances include agents effective against vectors of heartworm transmission, fleas, ticks and intestinal nematode species. Active substances may include, for example, isoxazolines, foramidines, spinosads, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs and juvenile hormones), benzimidazoles and tetrahydropyrimidines.

[0142] The method of the present disclosure is carried out by administering the anthelmintic to a mammal in small, frequent doses. For ease of conventional administration, the anthelmintic administration can be carried out using feed, chews, tablets, liquids, gels or other suitable forms for oral administration. Many different feeds are envisioned, provided that one or more manufacturing methods and feed compositions have no adverse effects on the chemical stability, efficacy and safety of the anthelmintic and (if applicable) other active substances. For example, feeds and snacks, chews, treats or supplementary feeds in the broad categories of dry, semi-wet, canned cooked feeds or fresh refrigerated feeds may be suitable for the present disclosure. Mammals receive a maintenance dose of anthelmintic by consuming feed products weekly, semi-weekly or daily.

[0143] By incorporating smaller doses of the anthelmintic into the animal feed composition and administering it at an effective rate (most preferably daily), the blood and tissue levels of the anthelmintic rise over time until it reaches an optimal steady state at which it can be maintained by daily or substantially daily dosing. In contrast, when the anthelmintic is orally administered in larger doses at a less frequent rate, for example, a single treatment of a large dose administered once over a 30 day period via a "treat or tablet," the levels of the anthelmintic in the blood and tissues rise sharply at the first dose, and then decline until the next dose is administered. Administration of large doses at a less frequent rate means that the mammal must consume more of the anthelmintic in each dose so that the blood and tissue levels of the anthelmintic do not drop below the necessary level for effective protection before the next dose.

[0144] Unless otherwise indicated, all ratios, percentages and parts discussed herein are "by weight."

[0145] The terms "controlling parasitic infections" and "controlling helminth infections" refer to preventing, treating, minimizing or eliminating an infection with parasites or helminths in mammals.

[0146] The term "controlling heartworm infection" means preventing, treating, minimizing or eliminating heartworm infection in mammals.

[0147] The terms "parasite" and "worm" are used interchangeably and refer to members of the phyla Annelida, Platyhelminthes, Nematoda, and Acanthocephala. The terms "parasite" and "worm" include egg, larval, and adult developmental stages.

[0148] The term "heartworm" is used to refer to members of the genus Dirofilaria. The term includes both larval and adult developmental stages.

[0149] The term "canid" refers to any member of the genus Canis, which includes species such as wolves, dogs, coyotes, and jackals.

[0150] The term "feline" refers to any member of the subfamily Felinae, which includes species such as domestic cats, bobcats, wildcats, ocelots, members of the genus Lynx, Pallas's cats, and cougars.

[0151] The term "mustard" refers to any member of the family Mustelidae, which includes species such as ferrets, American mink, European mink, mustelids, badgers, and wolverines.

[0152] In practicing the methods of the present disclosure, "feed" is animal feed, snacks, treats or other supplemental feed that can be administered daily or substantially daily. By using different forms of feed, e.g., kibble and treats, pet owners can change the diet and snacks of mammals from time to time while still conveniently administering a daily dose of an anthelmintic.

[0153] The term "chew" refers to a treat that generally has flavor and aroma properties that are attractive to mammals but typically has no nutritional value. In practicing the methods of the present disclosure, "feed" and / or "chew" may be used interchangeably.

[0154] For purposes of this disclosure, the term "effective time", also referred to herein as "effective duration", includes at least the duration of feed administration required to achieve a sufficiently high level of anthelmintic in the blood or tissues of a mammal for controlling 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 can be seven days or fifteen days or longer. As discussed below, the effective time will vary based on the frequency of administration of the feed or anthelmintic.

[0155] As just mentioned, the "effective time" will vary as a function of the frequency of administration of the feed. The term "effective frequency" as used herein means the number of feedings that produce a therapeutically effective concentration of the anthelmintic in the blood of a mammal over a given period of time. In all cases, the term "effective frequency" as used herein contemplates feedings that include the anthelmintic multiple times per month. Those skilled in the art will appreciate that the anthelmintic can be administered over a range of frequencies. For example, the anthelmintic can be administered daily, every other day, every three days, once a week, or even at inconsistent time intervals.

[0156] In addition, as discussed above, the effective frequency can affect the duration required to obtain therapeutically effective levels of the anthelmintic in the blood of the mammal. For example, if the mammal is fed the anthelmintic composition daily, the duration of feed administration required to achieve therapeutically effective levels of the anthelmintic in the blood of the mammal, and therefore the "effective time", will be relatively less than if the mammal is only fed the anthelmintic composition once or twice per week.

[0157] In addition, the effective frequency is affected by the amount of the daily dose in mg / kg mammal body weight. In particular, at slightly higher daily doses, the effect of missed doses on efficacy is smaller.

[0158] Furthermore, the effective frequency is affected by the duration of treatment. In the initial phase, e.g., before the amount of anthelmintic in the blood or tissues of the mammal has reached therapeutically effective levels, the animal feed may need to be administered more frequently than would be required after a longer period of use (i.e., once therapeutically effective levels have been achieved).

[0159] For the purposes of the present disclosure, "substantially daily" means a sufficiently regular basis that the concentration of the anthelmintic in the blood or tissue of the mammal rises and remains at a therapeutically effective level. For example, the disclosed daily feed composition can preferably be fed to the mammal every day indefinitely. However, as a practical matter, there are many reasons why doses may be missed or skipped on a regular basis. For example, the mammal may be sick or the owner may have run out of the daily medicated feed composition. The disclosed method is sufficiently robust that even in the case of occasional interruptions in the daily feeding of the medicated animal feed composition, the mammal will still be protected to a certain extent from parasites. When implementing the method of the present disclosure, the term "substantially daily" includes at least 10 days / month, more preferably at least 15 days / month, and even more preferably at least 20 days / month. All of these feeding frequencies, whether they are, for example, three times a week, every other day or every day, are suitable for being classified within the scope of substantially every day as long as they promote the anthelmintic to reach and maintain therapeutically effective levels in the blood of the mammal.

[0160] The term "subtherapeutic" refers to an amount of an anthelmintic that is, by itself, ineffective or suboptimal for controlling a parasitic infection in a mammal at a single dose.

[0161] The term "therapeutically effective" means that the dose or blood level of the anthelmintic or its physiologically acceptable derivative or metabolite thereof is sufficient to control helminth infection better than if the drug were not present. The anthelmintic or its physiologically acceptable derivative or metabolite thereof may be present by itself or together with one or more additional active substances. Preferably it controls helminth infection by about at least 50% better than if the drug were not present, and more preferably it controls helminth infection by about at least 90% better than if the drug were not present.

[0162] In practicing the methods of the present disclosure, an effective amount or therapeutically effective amount of an anthelmintic is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount required to control a helminth infection. As will be appreciated by those skilled in the art, this amount will vary depending on a number of factors. These factors include, for example, the type of mammal being treated and its weight and general physical condition, as well as the potency of the anthelmintic.

[0163] The effectiveness of anthelmintics varies. Therefore, the effective amount of each specific anthelmintic used in at least some of the methods according to the present disclosure can be calculated. Typically, the effective amount of the daily dose of the anthelmintic will be in the range of about 25%-90% of the approved label dose of the anthelmintic divided by the length of the dosing / retreatment interval (e.g., for a product administered once a month, the dose divided by 30). Those skilled in the art will recognize that for reasons such as, but not limited to, manufacturability, ease of testing and analysis, a higher dose of, for example, 90%-200% of the approved label dose of the anthelmintic may be selected. In some embodiments, the specific dose selected may be sufficient to increase the concentration of the anthelmintic in the blood of a mammal 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.

[0164] Although the present disclosure describes the concentration of anthelmintics in terms of feed such as kibble, it is also contemplated that the anthelmintics may be administered alone or in tablets, liquids, gels, or other suitable forms for oral administration. It will be appreciated by those skilled in the art that the concentration of the anthelmintics will vary depending on the particular dosage form. For example, in the case where the animal feed is a treat, the concentration of the anthelmintic in the treat will be greater than the concentration of the anthelmintic in the kibble. For example, if the daily dose of the anthelmintic based on the weight of the mammal is 10 mg, a typical 5 g treat may contain about 0.002% anthelmintic (by weight). Since the amount of kibble consumed in a day exceeds 5 g, the percentage of anthelmintics in the kibble will be smaller.

[0165] For example, an effective amount of moxidectin may be a daily dose or substantially a daily dose of about 0.2 to about 1.6 μg moxidectin / kg body weight of a mammal. Alternatively, an effective amount of moxidectin may be a daily dose or substantially a daily dose of about 0.4 to about 1.6 μg moxidectin / kg body weight of a mammal. Alternatively, an effective amount of moxidectin may be a daily dose or substantially a daily dose of about 0.8 to about 1.6 μg moxidectin / kg body weight of a mammal. Alternatively, an effective amount of moxidectin may be a daily dose or substantially a daily dose of about 0.2 to about 0.8 μg moxidectin / kg body weight of a mammal.

[0166] Animal feed will typically contain from about 0.0000001% to about 0.00008% moxidectin by weight in the feed. Preferably from about 0.0000002% to about 0.00005% moxidectin by weight in the feed. More preferably from about 0.000001% to about 0.0001% of one or more moxidectin components by weight in the feed.

[0167] In another example, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.025 to about 0.83 mg monepantel / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.05 to about 0.5 mg monepantel / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.125 to about 0.5 mg / kg mammal body weight. Alternatively, the effective amount of monepantel can be a daily dose or substantially a daily dose of about 0.125 to about 0.25 mg monepantel / kg mammal body weight.

[0168] Animal feed will typically contain 0.00005% to about 0.0001% monepantel by weight in the feed. Preferably about 0.0001% to about 0.005% monepantel by weight in the feed. More preferably about 0.0005% to about 0.001% of one or more monepantel components by weight in the feed.

[0169] In one aspect, the present disclosure relates to a method of controlling central filarial infections in mammals by administering a systemically active oral composition comprising an anthelmintic or a physiologically acceptable derivative or salt thereof and an animal feed at least once a week, more preferably three times a week, and most preferably substantially daily.

[0170] In another aspect, the present disclosure relates to a systemically active oral composition comprising an anthelmintic and an animal feed.

[0171] The present disclosure also relates to the use of an anthelmintic for preparing an animal feed for controlling central filarial infection in mammals.

[0172] The present disclosure also relates to a method of controlling heartworm infection in a mammal over an extended period of time, comprising orally administering to the mammal a daily dose or substantially a daily dose of an effective amount of an anthelmintic in a daily feed. A daily feed is a feed that is intended to be administered daily, but as described herein, it may be administered for an effective period of time. The method is particularly useful for controlling heartworms in a mammal over an extended period of time, comprising orally administering to the mammal a substantially daily dose of an effective amount of an anthelmintic.

[0173] An aspect of the present disclosure is oral administration of an amount of an anthelmintic that is ineffective or suboptimal for controlling heartworm infection in a mammal if administered at longer intervals, such as once a month. However, as described herein, by repeated administration at shorter intervals, such as substantially daily, effective control of heartworm infection is achieved. Ineffective or suboptimal means that a single administration, as well as multiple administrations, results in less than a 50% reduction in heartworm infection, including no or substantially no reduction, compared to administration of no drug at all. This reflects the chronic rather than acute administration aspect disclosed herein.

[0174] In a first embodiment, a method for controlling centriole worms in a mammal is disclosed by orally administering to the mammal a daily feed comprising an effective amount of an anthelmintic for an effective period of time.

[0175] In a second embodiment, an anthelmintic for use in controlling heartworms in a mammal in need thereof is disclosed. The anthelmintic may be present in an effective amount in a daily feed to be administered to the mammal for an effective period of time to control heartworms.

[0176] In a third embodiment, a daily feed for controlling centriole worms in a mammal is disclosed, comprising an effective amount of an anthelmintic when administered for an effective period of time.

[0177] In aspects of any one of the embodiments, the mammal can be a canine. More particularly, the canine can be a wolf, a coyote or a dog.

[0178] In aspects of any one of the embodiments, the mammal can be a feline. More particularly, the feline can be a domestic cat, a bobcat, a wild cat, an ocelot, a member of the genus Lynx, a Pallas's cat, or a puma.

[0179] In aspects of any one of the embodiments, the mammal can be a mustelid. More particularly, the mustelid can be a ferret, mink, ferret, badger or wolverine.

[0180] In an aspect of any of the embodiments, the anthelmintic is a macrolide or a salt thereof. Example

[0181] The following examples illustrate the methods of the present disclosure:

[0182] Example 1

[0183] Moxidectin administered orally (ie, by the mouth) to dogs is effective for the treatment and control of heartworms.

[0184] Methods: On day -35, groups of 12 dogs will undergo an initial examination to ensure satisfactory body condition. On day -34, a modified Knott's test and / or adult antigen test may be performed to verify the absence of circulating microfilariae or adult antigens of Dirofilaria immitis in the blood. Dogs exposed to anthelmintics or internal and external anthelmintics with activity against Dirofilaria immitis within 60 days prior to day -28 will be excluded.

[0185] Between Days -32 and -30, dogs will be weighed and randomized by weight to 1 of 4 treatment groups.

[0186] Dogs will be housed indoors in a mosquito-free area to help prevent naturally occurring heartworm infections. Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on Days -32 to -30. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercially available dog diet at the recommended intake rate and should be allowed ad libitum access to drinking water.

[0187] Dogs assigned to Groups 1 and 2 will be vaccinated with 50 ± 5 third stage infective Dirofilaria immitis larvae on Day -28. Groups 1 and 2 will be given moxidectin orally daily starting on Day 0 and continuing until Day 179.

[0188] Dogs assigned to Groups 3 and 4 will receive daily doses of moxidectin starting on Day -28 and continuing through Day -1. On Day 0, after the dogs have reached steady-state drug levels, the dogs will be inoculated with 50 ± 5 third-stage infective Dirofilaria immitis larvae. Moxidectin will continue to be administered daily from Day 0 to Day 179.

[0189] The daily moxidectin dose for each of the study groups (1-4) should be in accordance with Table 1:

[0190] Table 1

[0191]

[0192]

[0193] *The selected mg / kg dose levels represent approximately 1 / 30 (Groups 1 and 3) and 1 / 15 (Groups 2 and 4) of the therapeutic dose levels (approximately 24 μg / kg) of moxidectin for monthly oral administration to prevent the development of adult heartworm disease and for the management of intestinal nematode infections in dogs.

[0194] Treatments on each dosing day can be administered by oral gavage to dogs in the fed or fasted state. Each dog in all groups will receive a dose of moxidectin based on each dog's pre-treatment or most recent body weight on Day -28 (Groups 3 and 4) or Day 0 (Groups 1 and 2) through Day 179. Dogs in all groups can be re-weighed on Days 0, 30, 60, 90, 120, 150 and their daily oral moxidectin oral liquid volume adjusted based on their most recent body weight.

[0195] If heartworms were found, they were recovered from all study dogs on or after Day 180 and counted.

[0196] This study demonstrates that the doses of moxidectin (0.8 μg / kg and 1.6 μg / kg) administered to dogs exposed to heartworms and dogs not exposed to heartworms will be effective in treating and / or preventing heartworms. The expected result was that 0 heartworms were recovered from all 12 dogs.

[0197] Using the same study methods as described above, but continuing daily administration of moxidectin for 90 days in treatment groups 2 and 3, blood can be drawn approximately daily after administration of the initial dose of moxidectin. The average concentration of moxidectin in the blood can then be determined for the different dose levels.

[0198] The predicted results for the average plasma concentration of moxidectin in the blood of a mammal at different dose levels are shown in the following graphs. The approximate plasma concentration for a daily dose of 0.0008 mg moxidectin / kg mammal body weight is shown as a solid line, and the approximate plasma concentration for a daily dose of 0.0016 mg moxidectin / kg mammal body weight is shown as a triangle. For comparison, the approximate plasma concentration for a mammal administered a single bolus dose once every 30 days (squares) is also shown in FIG1 :

[0199]

[0200] Example 2

[0201] Efficacy of monepantel administered orally (ie, by the mouth) to dogs for the treatment and control of heartworms.

[0202] Methods: On day -35, groups of 12 dogs will undergo an initial examination to ensure satisfactory body condition. On day -34, a modified Knott's test and / or adult antigen test may be performed to verify the absence of circulating microfilariae or adult antigens of Dirofilaria immitis in the blood. Dogs exposed to anthelmintics or internal and external anthelmintics with activity against Dirofilaria immitis within 60 days prior to day -28 will be excluded.

[0203] Between Days -32 and -30, dogs will be weighed and randomized by weight to 1 of 4 treatment groups.

[0204] Dogs will be housed indoors in a mosquito-free area to help prevent naturally occurring heartworm infections. Dogs may be housed in pairs, if compatible, or individually until assigned to a treatment group on Days -32 to -30. Thereafter, the dogs will be housed individually. Dogs will be fed a standard commercially available dog diet at the recommended intake rate and should be allowed ad libitum access to drinking water.

[0205] Dogs assigned to Groups 1 and 2 will be vaccinated with 50 ± 5 third stage infective Dirofilaria immitis larvae on Day -28. Groups 1 and 2 will receive daily oral administration of monepantel starting on Day 0 and continuing until Day 179.

[0206] Dogs assigned to Groups 3 and 4 will receive daily doses of monepantel starting on Day -28 and continuing through Day -1. On Day 0, after the dogs have reached steady-state drug levels, the dogs will be inoculated with 50 ± 5 third-stage infective Dirofilaria immitis larvae. Monepantel will continue to be administered daily from Day 0 to Day 179.

[0207] The daily monepantel dose for each of the study groups (1-4) should conform to Table 2.

[0208] Table 2

[0209]

[0210]

[0211] The treatment on each dosing day can be administered to dogs in the fed or fasted state by oral gavage. At each scheduled administration date from -28 days (Group 3 and Group 4) or Day 0 (Group 1 and Group 2) to Day 179, each dog in all groups will receive a dose of monepantel based on the treatment before or the nearest body weight of each dog. Dogs in all groups can be re-weighed and adjusted their daily monepantel oral liquid volume based on their nearest body weight at Day 0, 30, 60, 90, 120, 150.

[0212] Heartworms, if found, will be recovered from all study dogs on or after Day 180 and counted.

[0213] The expected result was that 0 heartworms were recovered from all 12 dogs, indicating that the doses of monepantel (0.083 mg / kg and 0.83 mg / kg) administered to heartworm-exposed dogs and non-heartworm-exposed dogs would be effective in treating and / or preventing heartworms.

[0214] Although the present invention has been described as having an exemplary design, the present invention can be further modified within the spirit and scope of the present disclosure. Therefore, this application is intended to cover any changes, uses, or adaptations of the present invention using its general principles.

Claims

1. A method for controlling heartworm infection, comprising: administering to a mammal in need thereof a cumulative therapeutically effective amount of at least one systemic anthelmintic, the cumulative therapeutically effective amount comprising a plurality of individual microdoses of the at least one systemic anthelmintic, wherein said microdoses are administered daily or substantially daily to said mammal, wherein said at least one anthelmintic has a half-life in said 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. The method according to claim 1, wherein: The systemic anthelmintic is a component of at least one of a medicated feed, chew, snack, tablet, capsule, powder, ointment, suspension, solution and paste.

3. The method according to claim 1-2, wherein: The systemic anthelmintic is a component of a medicated pet food, and the medicated feed is a consumable product selected from the group consisting of kibbles, wet food, pastes, chews, and treats.

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

5. The method according to claim 4, wherein: The mammal is a domestic dog.

6. The method according to claim 4, wherein: The mammal is a domestic cat.

7. The method according to claims 1-6, wherein: The cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

8. The method according to claims 1-6, wherein: The cumulative therapeutically effective amount is sufficient to control infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

9. The method according to claims 1-8, wherein: The systemic anthelmintic is milbemycin.

10. The method according to claim 9, wherein: The milbemycin is moxidectin or a therapeutically acceptable salt thereof.

11. The method according to claims 1-10, wherein: The cumulative therapeutically effective amount of moxidectin administered to the mammal over the course of about a 30 day period does not exceed 48 μg moxidectin / kg body weight of the mammal.

12. The method according to claim 11, wherein: The amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

13. The method according to claims 11-12, 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. The method according to any one of claims 10 to 13, wherein: The administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

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

16. The method according to claims 1-8, wherein: The systemic anthelmintic is an amino-acetonitrile derivative or a therapeutically acceptable salt thereof.

17. The method according to claim 16, wherein: The amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

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

19. The method according to claims 17-18, wherein: The amount of monepantel in the microdose is within 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.

20. The method according to claims 17-19, wherein: The amount of monepantel 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. The method according to claims 1-20, wherein: The number of days between administration of any two microdoses is less than a 2, 3, 4, 5, 6 or 7 day period.

22. The method according to claims 1-21, wherein: The at least one microdose is administered orally.

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

24. The method according to claim 23, wherein: The at least one additional anthelmintic is a systemic anthelmintic.

25. The method according to claims 23-24, wherein: The at least one additional anthelmintic has a half-life of less than 1 day.

26. 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-gated potassium channel SLO-1.

27. The method according to claim 23, wherein: The at least one additional anthelmintic is at least one compound selected from the group consisting of: a macrolide or a salt or derivative thereof; a cyclooctanoic acid peptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a p-quinoline 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 a cyclooctanoic acid peptide or a salt or derivative thereof.

28. The method according to claim 27, wherein: The at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

29. The method according to claim 27, wherein: The at least one additional anthelmintic includes cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of emodepside, PF1022, and a salt or derivative of any one of the foregoing.

30. The method of claim 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.

31. The method of claim 27, wherein: The at least one additional anthelmintic comprises an ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octahydrol, and a salt or derivative of any of the foregoing.

32. The method of claim 27, 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 a salt or derivative of any of the foregoing.

33. The method of claim 27, wherein: The at least one additional anthelmintic comprises quinolinamide, and the quinolinamide is at least one compound selected from the group consisting of dequent, quinolinamide, and salts or derivatives of any one of the foregoing.

34. The method of claim 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 amitraz, deacylated amitraz (dAMD), tripendimidine, and salts or derivatives of any of the foregoing.

35. The method of claim 27, wherein: The at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of coumaphos, chlorpyrifos, dichlorvos, halokone, naphthiophos, trichlorfon, and salts or derivatives of any of the foregoing.

36. The method of claim 27, 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 thiobisdichlorophenol, diiodophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile, and salts or derivatives of any of the foregoing.

37. The method of claim 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 and ecitalopram and salts or derivatives of any of the foregoing.

38. The method of claim 23, wherein: The at least one additional anthelmintic is a compound selected from the group consisting of nitrothiocyanate, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride, mirasan, niclosamide, niridazole, nitrothiocyanate, nitrothiocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resortel, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan, and a salt or derivative of any one of the foregoing.

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

40. A composition for controlling heartworm infection, comprising: A microdose of at least one systemic anthelmintic that is active in a mammal and has a half-life in the system of 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, and a cumulative dose of a plurality of said microdoses is sufficient to control a heartworm infection.

41. The composition according to claim 40, wherein The systemic anthelmintic is a component of at least one formulation selected from the group consisting of medicated feed, treats, chews, snacks, tablets, capsules, powders, ointments, suspensions, solutions, sachets and pastes, or a component thereof.

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

43. The composition according to claim 40, wherein The medicated feed is selected from the group of formulations consisting of kibbles, chews, wet food, pastes and snacks.

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

45. The composition according to claim 44, wherein The mammal is a domestic dog.

46. ​​The composition according to claim 44, wherein The mammal is a domestic cat.

47. The composition according to claims 40-46, wherein The cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

48. The composition according to claims 40-46, wherein The cumulative therapeutically effective amount is sufficient to control infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

49. The composition according to claims 44-48, wherein The systemic anthelmintic is milbemycin.

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

51. The composition according to claim 50, wherein The amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

52. The composition according to claims 50-51, 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. A composition as described in any one of claims 50-52, wherein The administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

54. A composition as described in any one of claims 50-53, wherein The administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

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

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

57. The composition according to claim 56, wherein The amount of monepantel in the microdose is within 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.

58. The composition according to claims 56-57, wherein The amount of monepantel 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. The composition according to claims 40-58, wherein The at least one microdose is formulated to be administered orally.

60. The composition of claims 40-59 further comprising at least one additional anthelmintic.

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

62. The composition according to claims 60-61, wherein The at least one additional anthelmintic has a half-life of less than 1 day.

63. The composition according to 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-gated potassium channel SLO-1.

64. The composition according to claim 60, wherein The at least one additional anthelmintic is at least one compound selected from the group consisting of: a macrolide or a salt or derivative thereof; a cyclooctanoic acid peptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a p-quinoline 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 a cyclooctanoic acid peptide or a salt or derivative thereof.

65. The composition according to claim 64, wherein The at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

66. The composition according to claim 64, wherein The at least one additional anthelmintic includes cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of emodepside, PF1022, and a salt or derivative of any one of the foregoing.

67. The composition according to claim 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.

68. The composition of claim 64, wherein The at least one additional anthelmintic comprises an ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octahydrol, and a salt or derivative of any of the foregoing.

69. The composition according to claim 64, 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 a salt or derivative of any of the foregoing.

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

71. The composition of claim 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 amitraz, deacylated amitraz (dAMD), tripendimidine, and salts or derivatives of any of the foregoing.

72. The composition of claim 64, wherein The at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of coumaphos, chlorpyrifos, dichlorvos, halokone, naphthiophos, trichlorfon, and salts or derivatives of any of the foregoing.

73. The composition of claim 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 thiobisdichlorophenol, diiodophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile, and salts or derivatives of any of the foregoing.

74. 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, ecitalopram, and a salt or derivative of any of the foregoing.

75. The composition of claim 60, wherein The at least one additional anthelmintic is a compound selected from the group consisting of nitrothiocyanate, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride, mirasan, niclosamide, niridazole, nitrothiocyanate, nitrothiocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resortel, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan, and a salt or derivative of any one of the foregoing.

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

77. A medicated feed for use in a method for controlling heartworm infection, the method comprising: administering to a mammal in need thereof a cumulative therapeutically effective amount of at least one systemic anthelmintic, the cumulative therapeutically effective amount comprising: a plurality of individual microdoses of the at least one systemic anthelmintic, wherein said microdoses are administered daily or substantially daily to said mammal, wherein said at least one anthelmintic has a half-life in said 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.

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

79. The medicated feed for use in the method according to claims 77-78, wherein The systemic anthelmintic is a component of a medicated pet food, and the medicated feed is a consumable product selected from the group consisting of kibbles, wet food, pastes, chews, and treats.

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

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

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

83. The medicated feed for use in the method according to claims 77-82, wherein: The cumulative therapeutically effective amount is sufficient to prevent infection by at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

84. The medicated feed for use in the method of claims 77-82, wherein: The cumulative therapeutically effective amount is sufficient to control infection with at least one helminth selected from the group consisting of Dirofilaria immitis, Strongyloides cati, Angiostrongylus vasculi, Angiostrongylus vulgaris, and Eubacterium aerophila.

85. The medicated feed for use in the method according to claims 77-84, wherein The systemic anthelmintic is milbemycin.

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

87. The medicated feed for use in the method according to claims 85-86, wherein The cumulative therapeutically effective amount of moxidectin administered to the mammal over the course of about a 30 day period does not exceed 48 μg moxidectin / kg body weight of the mammal.

88. The medicated feed for use in the method of claim 87, wherein The amount of moxidectin in the microdose is within 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, about 0.8 μg / kg to about 0.9 μg / kg.

89. The medicated feed for use in the method according to claims 85-88, 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. The medicated feed for use in the method as claimed in any one of claims 85 to 89, wherein The administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 190 ng / mL for at least 30 days.

91. The medicated feed for use in the method as claimed in any one of claims 85 to 89, wherein The administration provides a concentration of moxidectin in the blood of the mammal of greater than about 7.8 ng / mL and less than about 100 ng / mL for at least 30 days.

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

93. The medicated feed for use in the method of claim 92, wherein: The amino-acetonitrile derivative is monepantel or a therapeutically acceptable salt thereof.

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

95. The medicated feed for use in the method according to claims 93-94, wherein: The amount of monepantel in the microdose is within 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.

96. The medicated feed for use in the method according to claims 93-95, wherein: The amount of monepantel 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. The medicated feed for use in the method of claims 77-96, wherein: The number of days between administration of any two microdoses is less than a 2, 3, 4, 5, 6 or 7 day period.

98. The medicated feed for use in the method of claims 77-97, wherein: The at least one microdose is administered orally.

99. The medicated feed for use in the method of claims 77-98 further comprising administering at least one additional anthelmintic.

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

101. The medicated feed for use in the method according to claims 99-100, wherein: The at least one additional anthelmintic has a half-life of less than 1 day.

102. The 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-gated potassium channel SLO-1.

103. The 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 macrolide or a salt or derivative thereof; a cyclooctanoic acid peptide or a salt or derivative thereof; a tetrahydropyrimidine or a salt or derivative thereof; an imidazothiazole or a salt or derivative thereof; a p-quinoline 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 a cyclooctanoic acid peptide or a salt or derivative thereof.

104. The medicated feed for use in the method of claim 103, wherein: The at least one additional anthelmintic comprises a macrolide, and the macrolide is at least one compound selected from the group consisting of avermectin, doramectin, emamectin, eprimectin, ivermectin, milbemycin oxime, moxidectin, nemaketin, and selamectin; benzimidazoles and probenzimidazoles, such as albendazole, albendazole-sulfoxide, cambendazole, cyclobendazole, febantel, fenbendazole, flubendazole, mebendazole, nevirapine, oxfendazole, oxibendazole, parbendazole, thiabendazole, thiophanate and triclabendazole, and salts or derivatives of any of the foregoing.

105. The medicated feed for use in the method of claim 103, wherein: The at least one additional anthelmintic includes cyclosporin, and the cyclosporin is at least one compound selected from the group consisting of emodepside, PF1022, and a salt or derivative of any one of the foregoing.

106. The medicated feed for use in the method of claim 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.

107. The medicated feed for use in the method of claim 103, wherein: The at least one additional anthelmintic comprises an ectoine, and the ectoine is at least one compound selected from the group consisting of morantel, pyrantel, octahydrol, and a salt or derivative of any of the foregoing.

108. The medicated feed for use in the method of claim 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 a salt or derivative of any of the foregoing.

109. The medicated feed for use in the method of claim 103, wherein: The at least one additional anthelmintic comprises quinolinamide, and the quinolinamide is at least one compound selected from the group consisting of dequent, quinolinamide, and salts or derivatives of any one of the foregoing.

110. The medicated feed for use in the method of claim 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 amitraz, deacylated amitraz (dAMD), tripendimidine, and salts or derivatives of any of the foregoing.

111. The medicated feed for use in the method of claim 103, wherein: The at least one additional anthelmintic comprises an organophosphate, and the organophosphate is at least one compound selected from the group consisting of coumaphos, chlorpyrifos, dichlorvos, halokone, naphthiophos, trichlorfon, and salts or derivatives of any of the foregoing.

112. The medicated feed for use in the method of claim 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 thiobisdichlorophenol, diiodophenol, hexachlorophenol, nitrochlorophenol, meniclopholan, nitroiodophenol nitrile, and salts or derivatives of any of the foregoing.

113. The medicated feed for use in the method of claim 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, ecitalopram, and a salt or derivative of any of the foregoing.

114. The 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 nitrothiocyanate, benzphenicol, butyralidone, clonazepam, clorsulon, diaminophen, dichlorophen, diethylcarbamazine, emetine, hetoline, hynthone, lucanthone, lugansone hydrochloride, mirasan, niclosamide, niridazole, nitrothiocyanate, nitrothiocyanate, oltipraz, omphalotin, oxamniquin, paromomycin, piperazine, resortel, salicylanilide, brosanide, brotinide, cloiosanide, closantel, niclosamide, hydroxychlorosalanide, clobeniosamide, tribromosalan, and a salt or derivative of any one of the foregoing.

115. The 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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