Systemic isoxazoline anthelmintics for the treatment or prevention of vector-borne and viral diseases

Abstract

The present invention provides a systemic isoxazoline-based anthelmintic for the treatment or prevention of vector-borne diseases and viral diseases. [Solution] This specification discloses methods for treating or preventing organism-associated infections, or for preventing vector-borne diseases, including malaria, by delivering one, two, or more systemic doses of an isoxazoline antiparasitic agent to individuals confirmed or suspected of being infected with and / or infected with malaria.

Description

Technical Field

[0001] Claims of Priority This application claims the benefit under 35 U.S.C.§ 119(e) of U.S. Provisional Patent Application No. 62 / 829,573, filed Apr. 4, 2019, the entire content of which is incorporated herein by reference in its entirety.

Background Art

[0002] In some aspects, embodiments of the present invention relate to the treatment and prevention of various arthropod-borne organisms and other infectious pathogens where new treatment and prevention modalities are sorely needed.

Summary of the Invention

Means for Solving the Problems

[0003] In some embodiments, formulations comprising pharmaceutical agents for the treatment and / or prevention of various arthropod-borne diseases and other pathogenic diseases and related organisms, including any number of features / elements disclosed herein, consisting essentially of, or consisting of, those features / elements, and methods of using the same are disclosed herein.

[0004] In some embodiments, formulations comprising pharmaceutical agents for the treatment and / or prevention of various pathogenic diseases and related organisms, including parasites, bacteria, viruses, fungi and / or other organisms, including any number of features / elements disclosed herein, consisting essentially of, or consisting of, those features / elements, and methods of using the same are disclosed herein.

[0005] In some embodiments, a method of treating malaria is disclosed, comprising administering to an individual in need of treatment a therapeutically effective amount of an isoxazoline-based antiparasitic formulation, the therapeutically effective amount being sufficient to have a systemic bioavailability sufficient to inhibit the health or life cycle of a species of the genus Plasmodium in the individual.

[0006] In some embodiments, the method includes administering an isoxazoline antiparasitic preparation multiple times within 30 days.

[0007] In some embodiments, the formulation is administered orally.

[0008] In some embodiments, the formulation is administered parenterally.

[0009] In some embodiments, the formulation is administered transdermally.

[0010] In some embodiments, species of the genus Plasmodium are selected from the group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi.

[0011] In some embodiments, the formulation is therapeutically effective in disrupting the health or life cycle of Plasmodium species in the liver of an individual.

[0012] In some embodiments, the method further includes administering another therapeutic agent that is therapeutically effective in disrupting the health or life cycle of a Plasmodium species in an individual.

[0013] In some embodiments, the administration of another therapeutic agent is carried out using the same formulation as the isoxazoline antiparasitic preparation.

[0014] 10. The method according to any one of claims 1 to 9, further comprising identifying the individual diagnosed with malaria.

[0015] In some embodiments, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, lotilaner, sarolaner, and afoxolaner.

[0016] In some embodiments, isoxazoline antiparasitic formulations for use in the treatment of malaria are disclosed, which are therapeutically effective in individuals requiring treatment and which have sufficient systemic bioavailability to disrupt the health or life cycle of Plasmodium species within the individual.

[0017] In some embodiments, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, lotilaner, sarolaner, and afoxolaner.

[0018] Also disclosed herein is a method for preventing vector-borne diseases, comprising administering a single therapeutic dose of an isoxazoline-based antiparasitic preparation to an individual in need of treatment, wherein the single therapeutic dose is sufficient to have sufficient systemic bioavailability to inhibit the health or life cycle of the vector or vector-borne disease organism for at least about one month.

[0019] In some embodiments, the method is sufficient to have sufficient systemic bioavailability to inhibit the health or life cycle of a vector or vector-borne disease organism for at least about three months.

[0020] In some embodiments, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, lotilaner, sarolaner, and afoxolaner.

[0021] In some embodiments, a method for preventing vector-borne diseases is disclosed herein, comprising administering therapeutically effective doses of an isoxazoline antiparasitic preparation to individuals in need of treatment in multiple doses at intervals, wherein the intervalted therapeutic doses include 2 to 7 doses within one week, but no more doses within a period of at least about one month, and the multiple intervalted therapeutic doses are sufficient to have sufficient systemic bioavailability to inhibit the health or life cycle of the vector or vector-borne disease organism for at least about one month.

[0022] In some embodiments, the multiple spaced treatment amounts are oral dosages of an isoxazoline-based antiparasitic agent, and each of the oral dosages is about 500 mg or less.

[0023] In some embodiments, the method further does not include additional dosages within at least about a three-month period.

[0024] In some embodiments, the method is sufficient to have systemic bioavailability sufficient to inhibit the health or life cycle of the vector or vector-borne disease organism for at least about three months.

[0025] In some embodiments, the vector-borne disease includes malaria.

[0026] In some embodiments, the vector-borne disease includes Lyme disease.

[0027] In some embodiments, the vector-borne disease includes dengue fever, West Nile virus, chikungunya, yellow fever, filariasis, tularemia , dirofilariasis, Japanese encephalitis, St. Louis encephalitis, Western equine encephalitis, Zika fever, EEE (eastern equine encephalitis), Lyme disease, anaplasmosis, ehrlichiosis, babesiosis, Borrelia miyamotoi infection, Rickettsia parkeri Rocky Mountain spotted fever, Pacific Coast tick fever, Ehrlichia muris-like infection, Heartland virus, Bourbon virus, B. mayonii infection, and one or more of the group consisting of other tick-borne diseases.

[0028] In some embodiments, disclosed herein is a method of treating or preventing a viral infection, comprising administering to a subject in need of treatment or prevention a pharmaceutical composition comprising an isoxazoline-based antiparasitic agent, the formulation being therapeutically effective to treat or prevent a viral infection in the subject.

[0029] In some embodiments, the method includes treating a viral infection.

[0030] In some embodiments, the pharmaceutical composition is a single-dose single administration.

[0031] In some embodiments, the viral infection includes a coronavirus infection.

[0032] In some embodiments, the viral infection includes SARS-CoV2 (COVID19).

[0033] In some embodiments, the pharmaceutical composition is sufficient to have a systemic bioavailability sufficient to inhibit the health or life cycle of the virus for at least about one month.

[0034] In some embodiments, the isoxazoline-based antiparasitic agent is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, flukxametamide, and isocycloseram.

[0035] In some embodiments, the isoxazoline-based antiparasitic agent is a single active drug agent in the pharmaceutical composition.

[0036] In some embodiments, the method further includes one or more of the following additional active agents: baricitinib; lopinavir and / or ritonavir, darunavir, favipiravir, remdesivir, ribavirin, galidseivir, BCX-4430, arbidol, chloroquine, hydroxychloroquine, mefloquine, and / or nitazoxanide.

[0037] In some embodiments, disclosed herein is a method of prevention against viral infection, comprising administering therapeutically effective doses of an isoxazoline antiparasitic preparation to an individual in need of treatment in multiple doses at intervals, wherein the intervals between doses include 2 to 7 doses within one week, but no more doses within a period of at least about one month, and the multiple intervals between doses are sufficient to have sufficient systemic bioavailability to inhibit the life cycle and / or replication of the virus for at least about one month.

[0038] In some embodiments, the viral infection includes coronaviruses.

[0039] In some embodiments, the viral infection includes SARS-CoV-2 (COVID-19).

[0040] In some embodiments, the interval-based therapeutic doses are oral doses of isoxazoline antiparasitic agents, each of which is approximately 500 mg or less.

[0041] In some embodiments, the method does not include any further doses within a period of at least about three months.

[0042] In some embodiments, this method is sufficient to have sufficient systemic bioavailability to inhibit viral replication or life cycle for at least about three months.

[0043] In some embodiments, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, fluxamethamide, and isocycloceram.

[0044] In some embodiments, the method further comprises one or more of the following additional active agents: baricitinib; lopinavir and / or ritonavir, darunavir, favipiravir, remdesivir, ribavirin, galidseivir, BCX-4430, arbidol, chloroquine, hydroxychloroquine, mefloquine, and / or nitazoxanides.

[0045] Disclosed herein are isoxazoline antiparasitic agents used for the treatment or prevention of pathogens, wherein the agents are therapeutically effective in individuals requiring treatment, and the formulations are sufficient to have sufficient systemic bioavailability to inhibit the health or life cycle of the pathogens.

[0046] In some embodiments, the pathogen includes a virus.

[0047] In some embodiments, the virus includes coronaviruses.

[0048] In some embodiments, the virus includes SARS-CoV-2 (COVID-19).

[0049] In some embodiments, the drug is intended to treat a pathogen.

[0050] In some embodiments, the drug is intended to prevent pathogens.

[0051] In some embodiments, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, fluxamethamide, and isocycloceram. [Modes for carrying out the invention]

[0052] Malaria is a serious, sometimes life-threatening disease caused by the malaria parasite, and is transmitted to humans through the bite of an infected Anopheles mosquito, known as a malaria vector. According to the World Health Organization (WHO), there were an estimated 219 million cases of malaria in 87 countries in 2017, and an estimated 435,000 deaths from malaria in 2017.

[0053] The WHO Africa region is said to have a disproportionately high share of the global malaria burden. In 2017, the region accounted for 92% of malaria cases and 93% of malaria-related deaths. According to the WHO, five countries—Nigeria (25%), the Democratic Republic of Congo (11%), Mozambique (5%), India (4%), and Uganda (4%)—account for nearly half of all malaria cases worldwide. It is estimated that nearly half of the world's population is at risk of malaria. Most malaria cases and deaths occur in sub-Saharan Africa. However, Southeast Asia, the Eastern Mediterranean, the Western Pacific, and the Americas also experience significant cases. WHO regions are also at risk. In 2017, malaria infections continued in 87 countries and territories.

[0054] Total funding for malaria control and eradication reached an estimated $3.1 billion in 2017. Some population groups are significantly more susceptible to malaria and at considerably higher risk of developing serious illness than others. These include infants, children under five years of age, pregnant women, and people with HIV / AIDS, as well as unimmunized migrants, mobile populations, and travelers.

[0055] There are at least five species of parasites that cause malaria in humans, including Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium malariae. In 2017, Plasmodium falciparum accounted for 99.7% of estimated malaria cases in the WHO Africa region, and also accounted for the majority of cases in the WHO Southeast Asia region (62.8%), Eastern Mediterranean region (69%), and Western Pacific region (71.9%). Plasmodium vivax is the dominant parasite in the WHO regions of North and South America, accounting for 74.1% of malaria cases.

[0056] Malaria is an acute febrile illness. Symptoms usually appear about 10 to 15 days after being bitten by the causative mosquito. Initial symptoms, such as fever, headache, and chills, are generally mild and can be difficult to recognize as malaria. For example, malaria caused by Plasmodium falciparum can progress to a serious illness and, in many cases, be fatal if not treated within 24 hours.

[0057] Children with severe malaria often develop one or more symptoms of severe anemia, respiratory distress associated with metabolic acidosis, or cerebral malaria. In adults, multiple organ failure is also frequent. In malaria-endemic areas, people may acquire partial immunity, and asymptomatic infections can occur.

[0058] There are over 400 species of Anopheles mosquitoes, with approximately 30 species being the primary vectors of malaria. Typical vector mosquitoes bite at night. The severity of infection depends on factors related to the parasite, vector, human host, and environment.

[0059] Anopheles mosquitoes lay their eggs in water, which hatch into larvae that eventually emerge as adult mosquitoes. Female mosquitoes feed on blood to nourish their eggs. Mosquitoes have a long lifespan (giving the parasite time to fully develop inside the mosquito's body), and infection rates can be higher in areas where mosquitoes prefer to bite humans more than other animals. The long lifespan of African vector species and their strong tendency to bite humans are the main reasons why approximately 90% of malaria cases worldwide occur in Africa.

[0060] Infection also depends on climatic conditions that can affect the number and survival of mosquitoes, such as rainfall patterns, temperature, and humidity. In many places, infection is seasonal, with peaks during and immediately after the rainy season. Malaria outbreaks can occur in areas where people have little or no immunity to malaria, and where climate and other conditions suddenly promote infection. Malaria can also occur when immunocompromised individuals move to areas with high malaria rates, for example, in search of work or as refugees.

[0061] Human immunity is another important factor, especially among adults in areas with moderate or severe infection rates. Partial immunity develops after years of exposure and, while never providing complete protection, reduces the risk of malaria infection developing into serious illness. This is why, although most malaria deaths in Africa occur in infants, all age groups are at risk in areas with low infection rates and low immunity.

[0062] For at least the reasons stated herein, improved systems and methods for treating and / or preventing malaria, as well as other conditions including those disclosed herein, are required.

[0063] In some embodiments, disclosed herein are methods for treating malaria parasite infestation and / or malaria by delivering one, two, or more systemic doses of an isoxazoline antiparasitic agent to an individual confirmed or suspected of being infected with malaria parasites and / or malaria.

[0064] In some embodiments, disclosed herein are vector-borne organisms, such as Borrelia Burgdorferi, Borrelia mayonii, Borrelia miyamotoi, and other species of the genus Borrelia; Babesia microti, and other species of Babesia; Ehrlichia muris eauclairensis, Ehrlichia chaffeensis, Ehrlichia ewingii, and other species of the genus Ehrlichia; Anaplasma phagocytophilum, and other species of Anaplasma; and Francisella tularensis. A method of treating parasitic infections such as those caused by Francisella tularensis, other Francisella species, Rickettsia rickettsia, Rickettsia parkeri, other Rickettsia species, Poissant virus, Heartland virus, Bourbon virus, and / or Colorado tick fever virus by delivering one, two, or more systemic doses of an isoxazoline antiparasitic agent to individuals confirmed or suspected of being infected with and / or suffering from such animal-borne infections.

[0065] In some embodiments, disclosed herein are methods for preventing human and other animal-borne animal-borne diseases, such as Lyme disease, anaplasmosis, ehrlichiosis, babesiosis, Borrelia miyamotoi infection, relapsing fever, Poissant virus disease, tularemia, Heartland virus disease, Bourbon virus disease, Rocky Mountain spotted fever, R. parcheri rickettsial disease, Colorado tick-borne fever, tick-borne relapsing fever, southern tick-associated rash disease, or other such tick-borne diseases, by delivering one, two, or more systemic doses of an isoxazoline antiparasitic agent to an individual, as well as vectors that carry the organisms, such as mosquitoes of the genus Anopheles (including Anopheles gambiae, Anopheles stephensi, etc.), ticks (Ixodes scapularis), and Amblyomma americana. This method of preventing infection involves killing the ticks of the genus Ixodes (Ixodes americanum), Dermacentor variabilis, Rhipicephalus sanguineus, Ixodes cookie, Amblyomma maculatum, Dermacentor andersoni, Ornithodoros spp., Ixodes pacificus, or other related vector species before the organism is passed from the vector to a human, or before it bites another human in close proximity, for example, within about 1, 2, 4, 6, 8, 12, 15, 18, 24 or more hours, within about 5, 10, 15, 30, 45 minutes, or within about 4-8 hours), or within a range including any two of the aforementioned values.

[0066] In some embodiments, disclosed herein are methods for preventing human vector-borne diseases by delivering one, two, or more systemic doses of an isoxazoline antiparasitic agent to one or more individuals in geographically close proximity (e.g., within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more square miles, within about 10 to 50 square miles, or within about 100 square miles), and methods for preventing infection by killing disease-carrying vectors, such as mosquitoes of the genus Anopheles (e.g., Anopheles gambia, Anopheles steffens, etc.), after the one or more individuals have been bitten, thereby reducing local vector populations.

[0067] Also disclosed herein are isoxazoline antiparasitic formulations for use in the treatment of vector-borne diseases such as Lyme disease, anaplasmosis, or malaria, or other diseases disclosed elsewhere herein, wherein the formulations are therapeutically effective in individuals requiring treatment and have sufficient systemic bioavailability to disrupt the health or life cycle of vector-borne organisms such as Plasmodium species within the individual. These formulations may have any number of properties as disclosed elsewhere herein.

[0068] Furthermore, isoxazoline antiparasitic formulations for use in the prevention of vector-borne diseases are also disclosed herein, which have sufficient systemic bioavailability to cause death in vectors encountering the systemically circulating antiparasitic agent at a reasonable probability (e.g., about 50%, 60%, 70%, 80%, 90% or higher or lower vector mortality rates). These formulations may have any number of properties as disclosed elsewhere herein.

[0069] As used herein, “compound,” “compounds,” “chemical entity,” and “chemical entities” refer to compounds contained in the general formulas disclosed herein, any subgenera of those general formulas, and any form of compounds within the general and subgenera formulas, including racemates, stereoisomers, and tautomers of one or more compounds.

[0070] As used herein, the term “effective dose” means, for example, the amount of drug or pharmaceutical product required by a researcher or clinician to induce a biological or medical response in a tissue, system, human or non-human animal.

[0071] Furthermore, the term “therapeutically effective dose” means any dose that results in improved treatment, cure, prevention, or remission of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, compared to a corresponding subject who has not received such a dose. This term also includes doses that are effective in enhancing normal physiological function.

[0072] As used herein, the term “excipient” means a substance used to formulate a pharmaceutical active ingredient (API) into a pharmaceutical formulation. Excipients (e.g., mannitol, captisol®, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, etc.) are an integral part of drug development and, though not limited to, help achieve a desired product profile, including assisting in manufacturing and altering the stability and efficacy of the drug. Acceptable excipients are non-toxic and do not adversely affect the therapeutic benefits of at least one of the chemical entities described herein. Such excipients may be any solid, liquid, or semi-solid, or, in the case of aerosol compositions, may be commonly available gaseous excipients.

[0073] Furthermore, the term “excipients” encompasses solubilizers, stabilizers, carriers, diluents, fillers, pH buffers, tonicifying agents, antimicrobial agents, wetting agents, and emulsifiers (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.). Excipients are preferably approved for or considered safe for human and other animal administration. Generally, the intended dosage is considered. Depending on the formula, the pharmaceutical composition contains about 0.005% to 95% of the chemical entity; in certain embodiments, about 0.5% to 50% by weight. In this specification, “lyophilization,” “lyophilized,” and “freeze-dried” refer to a process in which the material to be dried is first frozen, and then the ice or freezing solvent is removed by sublimation in a vacuum environment. The terms “lyophilized powder” or “lyophilized preparation” refer to any solid material obtained by lyophilization, i.e., by lyophilization of an aqueous solution. The aqueous solution may include a non-aqueous solvent, i.e., a solution composed of aqueous solution and one or more non-aqueous solvents. Preferably, the lyophilized preparation is a preparation in which a solid material is obtained by lyophilizing a solution composed of water as a pharmaceutically acceptable excipient.

[0074] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and dosage form that, within reasonable medical judgment, is suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0075] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt derived from a variety of organic and inorganic counterions well known in the art, including, but not limited to, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and, if the molecule contains a basic functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.

[0076] pharmaceutically acceptable salts of the compound can be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or they may be prepared by separately reacting the purified compound in the form of its free acid or free base with a suitable base or acid, respectively.

[0077] Therefore, in the context of a compound or a pharmaceutically acceptable salt thereof, the word "or" is understood to refer to either the compound or a pharmaceutically acceptable salt thereof (a substitute), or the compound and a pharmaceutically acceptable salt thereof (a combination).

[0078] As used herein, the term “pharmaceutical composition” (also referred herein to as one or more formulations) refers to a compound and one or more pharmaceutically acceptable excipients. One or more excipients may be acceptable in the sense that they are compatible with the other components of the composition and are not harmful to its recipient. According to another aspect of the present invention, a process is also provided for preparing a pharmaceutical composition comprising a drug or a pharmaceutically acceptable salt thereof using one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be used for the treatment and / or prevention of any of the conditions described herein.

[0079] Pharmaceutical compositions adapted for parental administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the composition isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Compositions may be presented in unit-dose or multi-dose (multi-dose) containers, such as sealed ampoules and vials, and may be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0080] A "racemate" refers to a mixture of enantiomers. In embodiments of the present invention, a therapeutic agent, or a pharmaceutically acceptable salt thereof, is enantiomerically concentrated with one enantiomer in which all of the chiral carbons mentioned are present in one composition. Generally, the term "enantiomerically concentrated compound or salt" means that the specified enantiomer constitutes more than 50% by weight of the total weight of all enantiomers in that compound or salt.

[0081] A "solvate" of one or more compounds refers to a compound as defined above, bound to a stoichiometric or non-stoichiometric amount of solvent.

[0082] The solvates of compounds include solvates of all forms of the compound. In certain embodiments, the solvent is volatile, non-toxic, and / or acceptable in trace amounts for administration to humans. Suitable solvates include water.

[0083] One or more "stereoisomers" of a compound refers to one or more stereoisomers. This refers to compounds with different chiralities at the body center. Stereoisomers include enantiomers and diisomers. It contains astereomers.

[0084] Optically active (R) and (S) isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional methods. For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization using chiral auxiliaries, the resulting diastereomer mixture can be separated, and the auxiliary groups can be cleaved to obtain the pure, desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group, or an acidic functional group such as a carboxyl group, the diastereomer salt can be formed with a suitable optically active acid or base, and the diastereomer thus formed can then be separated by fractionation crystallization or chromatographic means known in the art, after which the pure enantiomer can be recovered. Furthermore, the separation of enantiomers and diastereomers is often achieved using chromatography with a chiral stationary phase, sometimes in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0085] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomers of heteroaryl groups that contain ring atoms bonded to both the ring-NH- and ring-N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0086] Such compounds in some embodiments may exist in specific geometric or stereoisomeric forms. The present invention intends to include all such compounds, including (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof such as enantiomerically concentrated mixtures, within the scope of the invention. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0087] The "treatment" or "treatment" of a patient's illness 1) The disease occurs in patients who have a predisposition to the disease or who have not yet shown symptoms of the disease. 1) To prevent; 2) To suppress a disease or prevent the onset of a disease; or 3) To treat a disease It also refers to relieving or regressing the symptoms.

[0088] Isoxazoline anthelmintics are a class of anthelmintics conventionally used as insecticides and acaricides for veterinary indications. One or more isoxazoline anthelmintics may be used alone or in combination with other therapeutic agents, in systems and methods such as those disclosed herein. In some embodiments, patients requiring treatment may be treated with active agents of the isoxazoline anthelmintics family of chemicals, including, but not limited to, isoxazoline-substituted benzamide derivatives. Without being limited to theory, isoxazoline anthelmintics may act as GABA-chloride antagonists that selectively target the nervous system of certain organisms. GABA-mediated chloride influx can cause hyperpolarization of the cell membrane and generate inhibitory postsynaptic potentials. This reduces the probability of action potential generation, leading to paralysis and eventual death of the organism. Examples of isoxazoline anthelmintics include any number of fluralaner, sarolaner, lotilaner, afoxolaner, isocycloceram, and / or fluxamethamide, which include their derivatives, analogues, and L and D isomers, which may include, but are not limited to, enantiomers, racemic compositions, and enantiomerically pure compositions. In some embodiments, the isoxazoline anthelmintic, or any other active ingredient disclosed herein, is the sole active ingredient used in the formulation and / or method. In some embodiments, the isoxazoline anthelmintic is an isoxazoline-substituted benzamide derivative. In some embodiments, the isoxazoline anthelmintic has one, two, three, or more fluorine groups in its chemical structure, such as a trifluorine group (e.g., R-CF3). In some embodiments, the formulation may contain, for example, in amounts / concentrations otherwise disclosed herein, a precursor compound for another isoxazoline anthelmintic agent (e.g., isoxazole carboxylic acid including isoxazole-4-carboxylic acid) or a decomposition compound (e.g., isoxazolethiopenecarboxylic acid) in place of or in addition to the isoxazoline anthelmintic agents otherwise disclosed herein.In some embodiments, the formulation does not contain any precursor compounds or degradation compounds, including those disclosed herein. In some embodiments, the formulation may contain a pyrazole-5-carboxamide comprising an arylisoxazoline moiety.

[0089] In some embodiments, the system and method may be therapeutically effective in killing disease-carrying vectors, which may require only a single oral dose of an isoxazoline anthelmintic, for example, less than about 500 mg, or in the range of about 100 to 1,000 mg, or in the range of about 1,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 75, 50, 25 mg or less, or in a range including any two of the aforementioned values, to provide protection for vectors for at least about 45, 60, 75, 90 days or longer. In some embodiments, if it is desirable to reduce the duration or magnitude of systemic exposure, the dose may require only a single oral dose of less than 100 mg, for example, 50 to 100 mg. In some embodiments, multiple doses may be utilized to deliver preferred plasma levels to individuals with different body weights. In some embodiments, the dosage may be lower, more effective, and better absorbed by the intestines if administered within 30, 60, or 90 minutes before or after food intake. In some embodiments, disclosed herein, but not limited to, providing relatively low doses of isoxazoline anthelmintics for vector control, including malaria vector control. Such low doses can result in very low systemic exposure for safety reasons, and a high mosquito killing rate is not necessarily required. Such formulations can provide a range of weakening (or killing part of) vectors so that they cannot bite or otherwise transmit the organism to the next person. Generally, a higher dose, e.g., 2, 3, 4, or 5 times higher, is required to kill ticks than to kill mosquitoes. In some embodiments, a formulation may include a single oral dose followed by no subsequent doses or a limited number of small follow-up doses (e.g., one, two, three, four, five, six, seven or more follow-up doses (or a range including any two of the aforementioned values) administered daily, weekly, or at other intervals as disclosed elsewhere herein).In some embodiments, the therapeutic agent is provided in a single low dose administered at some intervals (e.g., monthly or more), such as every 2-3 weeks, every 1, 2, 3, 4, 5, or 6 months, or more or less, or within a range including any of the aforementioned values. In some embodiments, administration every 3-4 months may ultimately mean once a year in areas with seasonal malaria infection. In some embodiments, the formulation or method results in a peak or random blood, plasma, serum, or other fluid level in a patient of isoxazoline anthelmintics, or other therapeutic agents including those otherwise disclosed herein, which is approximately 1,000, 750, 500, 250, 200, 175, 150, 125, 100, 75, 50, 25, 20, 15, 10, 5, 4, 3, 2, 1 ng / ml or less or even less.

[0090] In some embodiments, administration at therapeutically effective doses may result in systemic exposure / plasma concentrations of isoxazoline anthelmintics sufficient to not only provide protection for vectors but also further disrupt the health and / or life cycle (e.g., replication) of malaria parasites or other species, including anthelmintic activity. Other such species may include tick-borne organisms such as Borrelia burgdorferi, Borrelia mayonii, Borrelia miyamotoi, and other Borrelia species; Babesia microti, and other Babesia species; Ehrlichia muris eauclairensis, Ehrlichia shafensis, Ehrlichia ewingii, and other Ehrlichia species; Anaplasma phagocytophyllum, and other Anaplasma species; Francisella tularensis, and other Francisella species; Rickettsia rickettsia, Rickettsia parcheri, and other Rickettsia species; Poissant virus, Heartland virus, Bourbon virus, and Colorado tick fever virus. While not limited to theory, this may require multiple and / or higher doses than the vector control indications discussed above. In some embodiments, the dosage may be more than a single oral dose over a period of 45, 60, 75, 90 days or longer, for example, at least two, three, four, five, six, seven, or more doses. The dosage may be, for example, once, two, three, four, five, six, or more times per week, or once, two, three, or more times per day. In some embodiments, the cumulative dose of isoxazoline antiparasitic agents administered during the course of treatment may be at least about 500 mg, 1 g, 1.5 g, 2 g, 3 g, 4 g, 4 g, 4 g, 4 g, 6 g, 6 g, 7 g, 9 g, or more, divided into periods of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 5 days, 6 weeks, 4 weeks, 4 g, 6 g, 6 g, 7 g, 8 g, 9 g, 10 g, or more. In some embodiments, the dose may be greater than a single oral dose, and the dose may vary.In some embodiments, the number of malaria parasites at target sites on an individual may decrease by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more on days 1, 2, 3, 4, 5, 6, 7, 10, 14, or more after treatment compared to before treatment initiation.

[0091] In some embodiments, therapeutic agents, such as isoxazoline antiparasitic agents and / or other agents, can be administered to generate peak, trough, or random plasma concentrations over 1, 2, 3, 4, 5, 6, 7, or more days, in ranges such as approximately 1 ng / mL to approximately 50,000 ng / mL, approximately 10 ng / mL to approximately 10,000 ng / mL, approximately 100 ng / mL to approximately 5,000 ng / mL, approximately, at least approximately, or just approximately 1, 5, 10, 50, 100, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 5,000, 10,000, 25,000, or 50,000 ng / mL, or any two of the aforementioned values. In some embodiments, isoxazoline antiparasitic agents can be administered to generate peak, trough, or random plasma concentrations over 1, 2, 3, 4, 5, 6, 7, or more days, in ranges such as approximately 1 nM to approximately 50,000 nM, approximately 10 nM to approximately 10,000 nM, approximately 100 nM to approximately 5,000 nM, approximately, at least approximately, or just approximately 1, 5, 10, 50, 100, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 5,000, 10,000, 25,000, or 50,000 nM, or any two of the aforementioned values.

[0092] In some embodiments, therapeutic agents, such as isoxazoline anthelmintics and / or other agents, can be administered in a manner that produces relatively constant plasma exposure over a long-acting period (e.g., 1, 2, 3, 4, 5, 6, 7 days, or more days; 2, 3, 4, or more weeks; 2, 3, 4, 5, 6 months, or more months; or more or less months). In a non-limiting example, the anthelmintic may be delivered weekly at 3-week intervals via solid oral tablets, with no further treatment with the anthelmintic for approximately 1, 2, 3, 4, 5, 6 months, or more or less, in which case each tablet delivers isoxazoline systemically to maintain relatively constant plasma levels (e.g., less than approximately 10% or less than approximately 20%) over a period of approximately 1, 2, 3, 4, 5, 6 months, or more or less, or any two of the aforementioned values.

[0093] In some embodiments, therapeutic agents, such as isoxazoline antiparasitic agents and / or other agents, may be administered in a single dose, or in doses of approximately, at least approximately, or just approximately 1, 23, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 doses, or in a range including any two of the aforementioned values.

[0094] In some embodiments, a therapeutically effective dose can inhibit the replication of the malaria parasite in target organs of mammals such as humans, thereby improving the signs and / or symptoms of malaria. The target organ may be the liver, spleen, bone marrow, or other parts of the body.

[0095] In some embodiments, the system and method can treat various Plasmodium species, including, but not limited to, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium malariae.

[0096] In some embodiments, the dose may result in a higher systemic exposure / plasma concentration than is meaningful to treat an individual with infection / parasitism, in order to reduce the possibility of parasitic resistance evolution.

[0097] In some embodiments, isoxazoline antiparasitic preparations can be delivered in doses sufficient to achieve therapeutically effective systemic bioavailability by oral administration (e.g., tablets, chewable tablets, capsules, syrups, sublingual tablets, dispersants, crushable preparations, soluble preparations, or other formulations), by injection (e.g., intramuscular, subcutaneous, intravenous, intraosseous), percutaneously (e.g., via patches, creams, ointments, oils, etc.), orally or via nasal spray without transdermal absorption (e.g., via bandages, films, clothing, etc.), or topically via rectal or vaginal suppositories or eye drops. In some embodiments, isoxazoline antiparasitic preparations may be administered in two or more forms or routes of administration, for example, as both oral tablets and perdermal applications via patches, creams, ointments, etc., to achieve some desired effect.

[0098] In some embodiments, the formulation is configured for systemic use rather than topical use. In some embodiments, the formulation is configured to be delivered via an ophthalmic route. In some embodiments, the formulation is configured to be delivered transdermally.

[0099] In some embodiments, isoxazoline anthelmintics may be used in combination with one, two, or more additional antimalarial agents, antibiotics, and / or antiparasitic agents to treat other diseases or conditions such as malaria, scabies, lice, or nematode infestations, to reduce the possibility of resistance, to enhance the effect of killing or, in other cases, inactivating vectors, or for other beneficial effects, seeking unexpected synergistic effects. The additional one or more antimalarial agents may be different isoxazoline anthelmintics (for example, as one non-limiting example, fluralaner and lotilaner together via the same or different routes of administration). Additional antimalarial agents include, for example, chloroquine, hydroxychloroquine, coartem, mefloquine, proguanil, chlorproguanil, chlorguanide, biguanide, pyrimidine, trimethoprim, chloroquine, lumefantrine, atovaquone, pyrimethamine, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, cinconin, cinconidine, quinimax (nine-quinidine-cinconin), amodiaquine, amopiroquine, sulfonamide, and Other sulfonamides (e.g., sulfadoxine, trimethoprim-sulfamethoxazole), artemisinin, ASAQ (artesunate-amodiaquine), artefren, artemether, artesunate, primaquine, pyronarizine, clindamycin, and one or more combinations thereof may be present. One or more additional agents may be antiparasitic agents, e.g., ivermectin, moxidectin, selamectin, doramectin, eprinomectin, abamectin, or any other agent of the avermectin class. In other embodiments, the isoxazoline anthelmintic may be combined with antibiotics such as doxycycline, amoxicillin, cefuroxime axetil, azithromycin, clarithromycin, or erythromycin. In other embodiments, the isoxazoline anthelmintic may be the sole active agent in the systemic formulation. In other embodiments, any two of the aforementioned active agents can be used with or without the isoxazoline antiparasitic agent.

[0100] Furthermore, a method for simultaneously treating malaria in infected individuals and creating population resistance to malaria is disclosed herein, by administering isoxazoline anthelmintics to both infected and uninfected individuals in a selected area. The isoxazoline anthelmintics may be in a therapeutically effective dose sufficient to treat malaria parasite infection in infected individuals and to kill mosquitoes that feed on the blood of the administered individuals. Dosing the population is effective in treating malaria parasites within infected individuals and can also reduce the mosquito population in the area.

[0101] In some embodiments, disclosed herein are methods for treating and / or preventing vector-borne diseases by combining isoxazoline antiparasitic agents with methods or techniques for vector control. These methods or techniques may include one, two, or more, such as nets, pest control / insecticide sprays or other formulations, education, waterlogging, traps, smoke / incense, etc. In some embodiments, isoxazoline antiparasitic agents can be used to coat, cover, saturate, or otherwise administer any articles that may come into contact with the relevant vectors, such as nets, indoor and outdoor walls, floors, ceilings, furniture, clothing (including shoes, boots, gloves, hats, glasses, etc.), fences, railings, etc.

[0102] In some embodiments, the dosage of isoxazoline antiparasitic preparations is therapeutically effective in treating malaria parasite infestation in infected individuals, but is not high enough to produce / induce undesirable and / or unacceptable side effects.

[0103] In some embodiments, sustained-release formulations and / or drug device configurations are disclosed herein that are utilized to reduce the frequency of administration, and / or increase the duration of effect, and / or improve drug compliance, and / or reduce the potential and / or rate of resistance in vectors to isoxazoline antiparasitic agents and / or other therapeutic agents used in combination therapy. Long-half-life isoxazoline antiparasitic formulations can be used in combination with delayed / sustained-release technologies to provide very long-lasting, sustained plasma drug concentrations. The duration may range, for example, from about or at least about 1, 2, or 3 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24 months, 3, 4, 5 years, or more years, or any two of the aforementioned values. The sustained-release formulation may include any of the embodiments described herein, including skin patches, creams, ointments, gels (including any type of hydrogel containing isoxazoline, which may be delivered transdermally, rectally, by injection, or by other routes of administration depending on the desired effect), oral dosage forms, or any other formulations.

[0104] In some embodiments, isoxazoline antiparasitic agents may be administered via formulations that induce release into the systemic circulation at specific sites in the body. For example, depending on the desired performance, antiparasitic agents may become available for systemic absorption by being absorbed in the stomach or intestines after oral administration. Such absorption may be enhanced if administered in close proximity to food intake.

[0105] In some embodiments, the efficacy of isoxazoline anthelmintics described in other embodiments disclosed herein may be supported, enhanced, or otherwise improved by the activity of metabolites of the isoxazoline anthelmintics.

[0106] In some embodiments, isoxazoline antiparasitic agents can be administered to the tap water of a specific area to maintain a therapeutically effective concentration of the isoxazoline antiparasitic agent for providing population prevention.

[0107] In some embodiments, animals may be administered isoxazoline anthelmintics to maintain a therapeutically effective concentration of the isoxazoline anthelmintics to provide, support, or enhance vector control. Such animals may include livestock (e.g., cattle, pigs, sheep), horses or other animals used for transporting people and / or goods, other domesticated animals including indoor and / or outdoor pets, and undomesticated animals such as mice, birds and / or deer, which may be useful in supporting further reduction of vector populations.

[0108] In some embodiments, patients may be treated with gene therapy (e.g., a virus or plasmid vector) that causes the treated individual to synthesize an isoxazoline anthelmintic agent sufficient to induce natural malaria resistance. In some embodiments, animals, including livestock, may be treated with gene therapy (e.g., a virus or plasmid vector) that causes the treated animal to synthesize an isoxazoline anthelmintic agent that can be excreted in milk or other means in sufficient quantities to function as a bioreactor.

[0109] In some embodiments, the formulation and / or packaging may be specially configured to withstand extreme environmental conditions (e.g., exposure to high heat or UV light). Packaging may include opaque or reflective packaging, such as waterproof packaging. In some embodiments, flavorings and / or sweeteners may be added to the oral formulation to improve the taste.

[0110] In some embodiments, isoxazoline antiparasitic formulations can be used to treat other indications / diseases via systems and methods disclosed elsewhere herein. These diseases may also be transmitted through insect vectors, such as mosquitoes. These diseases may include, for example, dengue fever, West Nile virus, chikungya, yellow fever, filiarisis, tularemia, dilofilariasis, Japanese encephalitis, St. Louis encephalitis, Western equine encephalitis, and Zika fever. In some embodiments, this disease may include, for example, EEE (Eastern Equine Encephalitis) and other tick-borne diseases / pathogens: Lyme disease, anaplasmosis, ehrlichiosis, babesiosis, Borrelia miyamotoi infection, Rickettsia parcheri spotted fever, Pacific Coast tick fever, Ehrlichia muris-like infection, Heartland virus, Bourbon virus, B. mayonii infection, and other tick-borne diseases.

[0111] In some embodiments, isoxazoline antiparasitic formulations can be used to treat other endoparasitic conditions (or protozoan or amoebic diseases), including river blindness (onchoceriasis), leishmaniasis, cryptosporidiosis, amoebiasis, Chagas disease, and African trypanosomiasis.

[0112] In some embodiments, though not limited to theory, isoxazoline antiparasitic agents used systemically for the treatment or prevention of malaria may include several of the following properties: the mechanism of action may include inhibition or activation of one, two, or more of the 5HT3 receptor, GABA Cl- channels, glutamatergic Cl- channels, serpentin receptors, or depolarization of Plasmodium species or other neuronal activity; the mechanism of action may include blockade of nuclear translocation of malaria parasite signal-recognizing particles (SRPs), or involvement of farnesoid X receptors for regulation of glucose homeostasis; they may control the hepatic stage of malaria parasite infection by inhibiting parasite development in hepatocytes and mitigating the resulting parasitemia, thereby reducing disease severity and increasing patient survival; and / or may be used in combination with avermectin, e.g., ivermectin, and / or other therapeutic agents whose activity against malaria parasites is considered herein.

[0113] In some embodiments, the pharmaceutical formulations and methods disclosed herein can be used to treat or prevent infection by one, two, or more pathogens and can directly affect the pathogens (not just the vectors that may harbor the pathogens). Pathogens may include, for example, any number of the following: viruses (including, but not limited to, coronaviruses, human immunodeficiency viruses, herpes simplex viruses, papillomaviruses, influenza viruses, parainfluenza viruses, hepatitis viruses, coxsackieviruses, herpes zoster viruses, measles viruses, mumps viruses, rubella, rabies viruses, hemorrhagic viral fevers, H1N1, etc.), prions, parasites, fungi, molds, yeasts, and bacteria (including both Gram-positive and Gram-negative bacteria, anaerobic bacteria, and acid-fast bacteria, etc.).

[0114] In some embodiments, the pathogen is a virus, such as a DNA or RNA virus. In some embodiments, the virus is an RNA virus, such as a single-stranded or double-stranded virus. In some embodiments, the RNA virus is a positive-sense single-stranded RNA virus. In some embodiments, the virus is part of the order Nidovirales. In some embodiments, the virus belongs to the family Coronaviridae. In some embodiments, the virus belongs to the genus Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Deltacoronavirus. In some embodiments, Alphacoronavirus is, but is not limited to, human coronavirus 229E, human coronavirus NL63, or infectious gastroenteritis virus (TGEV). In some embodiments, Betacoronavirus is, but is not limited to, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 (COVID-19), Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus HKU1, or human coronavirus OC43. In some embodiments, Gammacoronavirus is infectious bronchitis virus (IBV). In some embodiments, coronaviruses are animal viruses that cause feline enteroperitonitis (FIP), canine respiratory coronavirus (CRCoV), bovine coronavirus, or equine enterocoronavirus.

[0115] The formulation can be administered, for example, to humans and / or other non-human animals, such as dogs, cats, livestock, primates, and bats.

[0116] Without limiting the theory, but in some embodiments, pharmaceutical formulations comprising isoxazoline antiparasitic agents and / or other therapeutic agents disclosed elsewhere herein may bind to, inhibit the expression of, or otherwise directly or indirectly affect, any number of the following:

[0117] Spike (S) glycoprotein contained on the surface of the virus;

[0118] The receptor-binding domain (RBD) on S1, which is involved in transmembrane angiotensin-converting enzyme 2 (ACE2) binding;

[0119] ACE2 (angiotensin-converting enzyme 2) - a viral receptor protein on host cells that binds to the viral S protein;

[0120] Angiotensin AT2 receptor;

[0121] S2 protein (involved in viral fusion with the cell membrane);

[0122] Envelope nucleoprotein (E protein);

[0123] Membrane protein (N protein);

[0124] 3CLpro (coronavirus main protease 3CLpro) and / or PLpro (papain-like protease PLpro) - proteases for the protein degradation of viral polyproteins into functional units;

[0125] RdRp (RNA-dependent RNA polymerase for replicating viral genomes);

[0126] TMPRSS2 (a transmembrane protein, a host cell-produced protease that primes serine 2-S protein to facilitate its binding to ACE2) and / or

[0127] Hemagglutinin esterase (HE) for treating or preventing viral infections.

[0128] In some embodiments, but not limited to them, formulations comprising isoxazoline antiparasitic agents (e.g., fluralaner, sarolaner, lotilaner, afoxolaner, fluxamethamide, and isocycloceram) and / or other therapeutic agents disclosed elsewhere herein can be used as single active agents and, but not limited to them, can be used in combination with additional agents for treating pathogenic infections such as viral infections including SARS-CoV-2 (COVID-19) to obtain unexpected synergistic effects. In some embodiments, other forms, including those disclosed herein, such as their derivatives, analogues, and L and D isomers (including, but not limited to, enantiomers, racemic compositions, and enantiomerically pure compositions), can also be used.

[0129] In some embodiments, but not limited to them, formulations containing spinosine and / or other therapeutic agents disclosed elsewhere herein can be used as a single active agent and, but not limited to them, can be used in combination with additional agents to treat pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), to obtain unexpected synergistic effects. Spinosines may include, for example, spinosine A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, Y, etc. Spinosines are a family of macrocyclic lactones with insecticidal activity against a variety of pests. The spinosines initially identified were found to be fused with a 12-membered macrocyclic lactone, a neutral sugar (rhamnose), and an amino sugar (phorosamine) in a 5,6,5-tricylic ring system. Spinosine is also disclosed in U.S. Patent Nos. 5,496,931, 5,670,364, 5,591,606, 5,571,901, 5,202,242, 5,767,253, 5,840,861, 5,670,486 and 5,631,155, as well as in U.S. Patent Application Publication 2020 / 0031859 ​​to Santos et al., each of which is incorporated herein by reference in its entirety. In some embodiments, other forms including those disclosed herein, such as derivatives, analogues, and L and D isomers (including, but not limited to, enantiomers, racemic compositions, and enantiomerically pure compositions), may also be used.

[0130] In some embodiments, but not limited to, albendazole, cambendazole, fenbendazole, flubeiidazole, mebendazole, oxfendazole, parabendazole, thiabendazole, triclabendazole, amitraz, demiditraz, chlorthrone, closantel, oxyclonazide, lafoxanide, cyphenothrin, flumethrin, permethrin, promazine, dercantel, diamphenetide, dicycianil, dinotefuran, imidacloprid, nitenpyram, thiamethoxam, abamectin, doramectin, emamectin, epnomectin, ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside, epsiplantel, fipronil Formulations containing fluazuron, fluhexaphon, indoxacarb, levamisol, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide, nitroscanate, nitroxynii, novaron, oxantel, praziquantel, pyrantel, pynprole, pvriproxyfen, sisaproml, spinosad, spinetram, lindane, picrotoxin, dieldrin, alpha-endosulfan, and / or triflumezopyrim can be used as a single active agent, and, though not limited to, may produce unexpected synergistic effects when used in combination with additional agents for treating pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), as disclosed elsewhere herein.

[0131] In some embodiments, but not limited to, metadiamides (e.g., broflanilide, tetraniliprole, or cyclaniliprole), cyclodienes, and / or macrocyclic lactones (including avermectin and milbemycin); formulations that may be active agents for treating Alzheimer's disease, such as galantamine, donepezil and other piperidine analogs, rivastigmine and other carbamate analogs, tacrine, 7-methoxytacrine, other pyridine analogs, huperzine A and other alkaloid analogs, etc., can be used as single active agents and, but not limited to, can be used in combination with additional agents for treating pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), to obtain unexpected synergistic effects.

[0132] In some embodiments, but not limited to them, formulations containing formamidine-based antiparasitic agents can be used as single active agents and, but not limited to them, can be used in combination with additional agents to treat pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), to obtain unexpected synergistic effects. A formamidine-based antiparasitic agent may be, for example, amitraz. N-(2,4-dimethylphenyl)-N-methiformamidine (DPMF), a metabolite of amitraz, can be another effective therapeutic agent, either alone or in addition. 2,4-dimethylanaline, a hydrolytic metabolite of DPMF, can also be an effective therapeutic agent in other embodiments. In some embodiments, other forms, including those disclosed herein, such as their derivatives, analogues, and L and D isomers (including, but not limited to, enantiomers, racemic compositions, and enantiomerically pure compositions), may also be available.

[0133] In some embodiments, but not limited to them, formulations containing formamidine-based anthelmintics can be used as a single active agent and, but not limited to them, can be used in combination with additional agents to treat pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), to obtain unexpected synergistic effects. The chemical structure of these insecticides is characterized by a central pyrazole ring in which a phenyl group is bonded to one of the nitrogen atoms of the pyrazole ring. Some non-exclusive examples of phenylpyrazole anthelmintics include, for example, acetoprole, ethiprole, fipronil, flufiprole, pyraclofos, pyraflprole, pyriprole, pyroran, and vaniliprole.

[0134] In some embodiments, but not limited to them, formulations containing organophosphates can be used as a single active agent and, but not limited to them, can be used in combination with additional agents for treating pathogenic infections, such as viral infections including SARS-CoV-2 (COVID-19), as disclosed elsewhere herein, to obtain unexpected synergistic effects. Organic phosphates include, for example, acephate, azamethiphos, azinophos-ethyl, azinophos-methyl, bromophos, bromophos-ethyl, kazusaphos, carbophenythion, chlormephos, chlorphoxime, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chlorvinophos, croumaphos, clotoxyphos, clufomate, cyanophenphos, cyanophos, demephron-O, demephron-S, demeton-O, demeton-S, demeton-S-methyl, demeton-S-methylsulfone, dialiphos, diazinon, diclofenthion, dichlorvos, diclotophos, dimephox (dime fphox), dimethoate, dioxabenzophos, dioxathione, disulfon, digitalmifos, edifenphos, EPBP, EPN, ESP, ethione, etopropos, etrimphos, femfur, phenamiphos, fenchlorphos, fenitrothion, fensulfothion, fenthion, fenofos, formothion, fosmethilane, heptenophos, isazofos, isofenphos, isothioate, isoxathione, jodofenphos, leptophos, metrifonate, malathion, menazone, mephosphorane, methacryphos, methamidophos, methidathione, mevinphos, monoclotophos, naledomethoate, oxydemethone-methyl, parathion, parathion-methyl, fente This may include dichlorvos, pholate, phosalon, phosmet, phosphamidone, phosphamidoneamide, phospholane, phoxime, pirimiphos-ethyl, pirimiphos-methyl, profenophos, propaphos, propethamphos, prothiophos, protoate, pyraclophos, pyridaphenthion, quinylphos, schlardan, sulfotep, sulprophos, temephos, TEPP, terbuphos, tetrachlorvinphos, thiometon, thionazine, triazophos, trichlorfon, bamidothion, their prodrugs, and one or more of their pharmaceutically acceptable salts or esters. In some embodiments, the organophosphate may be dichlorvos or its prodrug or a pharmaceutically acceptable salt or ester. In some embodiments, the organophosphate may be metrifonate or its prodrug or a pharmaceutically acceptable salt or ester. In some embodiments, other forms including those disclosed herein, such as derivatives, analogues, and L and D isomers (including, but not limited to, enantiomers, racemic compositions, and enantiomerically pure compositions), may also be used.

[0135] Additional agents may include, for example, other agents with antiviral activity, including, but not limited to, baricitinib or other JAK inhibitors; lopinavir and / or ritonavir, darunavir, favipiravir, remdesivir, ribavirin, galidseivir, BCX-4430 (a salt form of galidesivir), arbidol, chloroquine, hydroxychloroquine, mefloquine, nitazoxanide, acyclovir, famciclovir, ganciclovir, foscarnet, idoxuridine, sorivudine, trifluorothymidine, valacyclovir, vidarabine, didanosine, dideoxyinosine, stabudine, zalcitabine, zidovudine, amantadine, interferon alfa, rimantadine, oseltamivir, zanamivir, and / or baloxavir, as well as other agents disclosed elsewhere herein.

[0136] In some embodiments, the therapeutic agent is provided in a single, low dose administered at some intervals (e.g., monthly or more), such as every 2-3 weeks, every 1, 2, 3, 4, 5, or 6 months, or more or less, or within a range including any of the aforementioned values. In some embodiments, administration every 3-4 months may ultimately mean once a year in places with seasonal pathogen infections. In some embodiments, the formulation or method results in a peak or random blood, plasma, serum, or other fluid level in a patient of isoxazoline antiparasitic agents, or other therapeutic agents including those otherwise disclosed herein, which is approximately 1,000, 750, 500, 250, 200, 175, 150, 125, 100, 75, 50, 25, 20, 15, 10, 5, 4, 3, 2, 1 ng / ml or less or even less. In some embodiments, single-dose or multiple-dose formulations may be provided, with each dose having a half-life of approximately or at least approximately 20, 25, 30, 35, 40, 45, 50, 55, 60 days, or more. In some cases, such long-acting dosing offers several advantages over promising alternative drugs, given their relatively long half-lives, in terms of infection prevention or extension of therapeutic effect, reduction of viral load, or prevention of secondary complications such as pneumonia, acute respiratory distress syndrome (ARDS), septic shock, cardiomyopathy, and renal failure. However, in some embodiments, dosing may be, for example, approximately or at least approximately 1, 2, 3, 4, 5, 6, 7, 8 times daily, or more, for example, 1 to 2 times daily. In some embodiments, treatment may also be once weekly, a single dose, or a limited course of treatment.

[0137] In some embodiments, the medication may be administered more frequently than a single oral dose over a period of 45, 60, 75, 90 days, or longer, for example, at least two, three, four, five, six, seven, or more doses. The dose may be, for example, once, two, three, four, five, six, or more times per week, or, for example, once, two, three, or more times per day. In some embodiments, the cumulative dose of an active agent, such as an isoxazoline antiparasitic agent or any other agent disclosed herein, administered in the course of treatment may be about, at least about, or just about 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 1 g, 1.5 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, or more, divided into periods of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 weeks, 45 days, 60 days, 75 days, 90 days, or more. In some embodiments, the dose may be greater than a single oral dose, and the dose may vary. In some embodiments, the viral load in an individual may decrease by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more on days 1, 2, 3, 4, 5, 6, 7, 10, 14, or more after treatment compared to before the start of treatment.

[0138] In some embodiments, an active agent, such as an isoxazoline antiparasitic agent or any other agent or a combination of agents disclosed herein, can be administered to generate peak, trough, or random plasma concentrations over 1, 2, 3, 4, 5, 6, 7, or more days, in ranges such as approximately 1 ng / mL to approximately 50,000 ng / mL, approximately 10 ng / mL to approximately 10,000 ng / mL, approximately 100 ng / mL to approximately 5,000 ng / mL, approximately, at least approximately, or just approximately 1, 5, 10, 50, 100, 500, 1,000, 5,000, 10,000, 25,000, or 50,000 ng / mL, or any two of the aforementioned values. In some embodiments, an isoxazoline antiparasitic agent is administered over 1, 2, 3, 4, 5, 6, 7, or more days, for example, about 1 nM to about 50,000 nM, about 10 nM to about 10,000 nM, about 100 nM to about 5,000 nM, about, at least about, or just about 1, 10, 50, 100, 200, 250, 300, 350, 400, 450, 500, 6 Peak, trough, or random plasma concentrations can be generated in ranges including 0, 700, 800, 900, 1,000, 5,000, 10,000, 25,000, or 50,000 nM, or any two of the aforementioned values. In some embodiments, active agents, such as isoxazoline antiparasitic agents, can be administered in a manner that produces relatively constant plasma exposure over a long period (e.g., 1, 2, 3, 4, 5, 6, 7 days, or more days, 2, 3, 4 weeks, or more weeks, 2, 3, 4, 5, 6 months, or more months, or less). As a non-limiting example, an active agent, such as an isoxazoline antiparasitic agent, may be delivered via solid oral tablets once a week at three-week intervals, and thereafter no further treatment with the antiparasitic agent may be given for a period of approximately 1, 2, 3, 4, 5, 6 months or more or less, during which each tablet delivers isoxazoline systemically to maintain relatively constant plasma levels (e.g., fluctuations of less than approximately 10% or less than approximately 20%) over a period of approximately 1, 2, 3, 4, 5, 6 months or more or less, or within a range including any two of the aforementioned values.

[0139] In some embodiments, the active agent, for example, an isoxazoline antiparasitic preparation or any other agent or combination of agents disclosed herein, can be delivered in a dose sufficient to achieve therapeutically effective systemic bioavailability, etc., by oral administration (e.g., tablets, chewables, capsules, syrups, sublinguals, dispersants, crushable preparations, soluble preparations, or other preparations), by injection (e.g., intramuscular, subcutaneous, intravenous, intraosseous), percutaneous administration (e.g., via patches, creams, ointments, oils, etc.), oral or nasal spray, or topically via rectal or vaginal suppositories or eye drops. In some embodiments, the isoxazoline antiparasitic preparation may be administered in two or more forms or routes of administration, for example, as both oral tablets and percutaneous applications, to obtain some desired effect.

[0140] In some embodiments, the active agent, for example, isoxazoline antiparasitic preparations or any other agent or combination of agents disclosed herein, is, for example, about, at least about, or just about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg The drug may be administered in individual doses ranging from g, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, or more, or less, or within a range including any two of the aforementioned values. Dosing may be at least about, about, or just about 1, 2, or 3 times per day; once every 2 days, once every 3 days, once every 1, 2, 3, 4, 5, 6, or 7 times per week; once every 2 weeks, once every 1 month, once every 2 months, once every 3 months, a single dose, or within a range including any two of the aforementioned values. This treatment plan can be administered for a total of approximately, at least approximately, or just approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28 days, or more or less, or any two of the aforementioned values.

[0141] Various other modifications, adaptations, and alternative designs are naturally possible based on the teachings above. Therefore, it should be understood at this point that, within the scope of the appended claims, the present invention may be carried out in ways other than those specifically described herein. Various combinations or subcombinations of the particular features and aspects of the embodiments disclosed above may be created, and it is intended that they still be included in one or more of the present invention. Furthermore, any particular function, aspect, method, characteristic, feature, quality, attribute, element, etc., disclosed herein relating to one embodiment can be used in all other embodiments described herein. Therefore, it should be understood that various functions and aspects of the disclosed embodiments can be combined with each other or substituted for each other to form various forms of the disclosed invention. Accordingly, it is intended that the scope of the present invention disclosed herein should not be limited by the particular disclosed embodiments described above. Furthermore, the present invention is susceptible to various modifications and alternative forms, specific examples of which are shown in the drawings and described in detail herein. However, it should be understood that the present invention is not limited to any particular form or method disclosed, but rather encompasses all modifications, equivalents, and substitutes that fall within the spirit and scope of the various embodiments and appended claims described herein. None of the methods disclosed herein need to be performed in the order described herein. The methods disclosed herein include specific actions performed by a practicing physician. However, these methods may also explicitly or implicitly include instructions from a third party for those actions. For example, an action such as "oral administration of a pharmaceutical formulation of an isoxazoline antiparasitic agent" includes "instructions for oral administration of a pharmaceutical formulation of an isoxazoline antiparasitic agent." The scope disclosed herein also includes all possible overlaps, sub-scopes, and combinations thereof. Words such as "up to," "at least," "greater than," "less than," and "between" include the numbers listed.In this specification, numbers preceded by terms such as “approximately,” “about,” and “substantially” include the listed numbers (for example, approximately 10% = 10%) and represent an amount close to the stated amount that still performs the desired function or achieves the desired result. For example, the terms “approximately,” “about,” and “substantially” may refer to amounts within the range of less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount.

Claims

1. Rotilaner used to eliminate one or more ticks attached to humans, A first oral dose of the composition containing lotiraner is adapted to be administered to a human at a first time point. A second oral dose of the composition containing lotiraner is adapted for administration to a human at a second time point. The first oral dose is 50 mg to 400 mg of lotilaner. The second oral dose mentioned above is 30 mg to 100 mg of lotilaner. The second time point is approximately one month after the first time point, Rotiranel.

2. If one or more ticks attach to the human within one month after the first time point, the first oral dose is sufficient to eliminate one or more ticks, according to claim 1.

3. The rotilaner according to claim 1, wherein if one or more ticks attach to a human within three months from the first time point, the first oral dose and the second oral dose are sufficient to kill one or more ticks.

4. The rotilaner according to claim 1, wherein rotilaner is the sole active ingredient in the composition.

5. The rotilaner according to claim 1, wherein the one or more ticks are selected from the group consisting of the genera Ixodes, Amblyoma, Adenia, Lathyrus, and Ornithodorus.

6. The rotilaner according to claim 5, wherein the one or more ticks include the genus Ixodes.

7. The rotilaner according to claim 1, wherein the first oral dose and the second oral dose are sufficient to prevent transmission of tick-borne diseases by the control of ticks, and the tick-borne diseases are selected from the group consisting of tularemia, Lyme disease, anaplasmosis, ehrlichiosis, ehrlichia muris-like infection, babesiosis, Borrelia miyamotoi disease, B. mayoni infection, Rickettsia parkeri spotted fever, R. parkeri rickettsiasis, Pacific tick-borne fever, tick-borne relapsing fever, Rocky Mountain spotted fever, Colorado tick-borne fever, Pawashan virus disease, Heartland virus disease, Bourbon virus disease, and Southern tick-associated rash.

8. The rotilaner according to claim 7, wherein the tick-borne disease is Lyme disease.

9. The rotilaner according to claim 7, wherein the tick-borne disease is babesiosis.

10. The rotilaner according to claim 7, wherein the tick-borne disease is anaplasmosis.

11. The lotilaner according to claim 1, wherein an additional oral dose of the composition containing lotilaner is administerable to a human at the time of the additional dose, the additional oral dose is 30 mg to 100 mg of lotilaner, and the time of the additional dose is one month after the preceding time.

12. The lotilaner according to claim 11, wherein the first oral dose is 400 mg of lotilaner, and the second oral dose and additional oral dose are 40 mg to 100 mg of lotilaner.

13. The lotilaner according to claim 12, wherein the first oral dose is 400 mg of lotilaner, and the second oral dose and additional oral dose are 100 mg of lotilaner.

14. The lotilaner according to claim 11, wherein the first oral dose is 300 mg of lotilaner, and the second oral dose and additional oral dose are 40 mg to 60 mg of lotilaner.

15. The lotilaner according to claim 11, wherein the first oral dose is 250 mg of lotilaner, and the second oral dose and additional oral dose are 50 mg to 80 mg of lotilaner.

16. The lotilaner according to claim 15, wherein the first oral dose is 250 mg of lotilaner, and the second oral dose and additional oral dose are 50 mg of lotilaner.

17. The lotilaner according to claim 11, wherein the first oral dose is 100 mg to 400 mg of lotilaner, and the second oral dose and additional oral dose are 100 mg of lotilaner.

18. The lotilaner according to claim 17, wherein the first oral dose is 100 mg of lotilaner, and the second oral dose and additional oral dose are 100 mg of lotilaner.

19. The lotilaner according to claim 11, wherein the first oral dose is 75 mg of lotilaner, and the second oral dose and additional oral dose are 75 mg of lotilaner.

20. Rotilaner used to eliminate one or more ticks attached to humans, A first oral dose of the composition containing lotiraner is adapted to be administered to a human at a first time point. A second oral dose of the composition containing lotiraner is adapted to be administered to humans at one or more additional time points. The first oral dose is 100 mg to 400 mg of rotilaner. The second oral dose is 25 mg to 100 mg of lotilaner. Lotilaner, wherein the amount of lotilaner in a second oral dose adapted for administration to a human at the first time point is less than 50% of the amount of lotilaner at the first time point.

21. The rotilaner according to claim 20, wherein the one or more additional time points include 2 to 11 additional time points.

22. The lotilaner according to claim 21, wherein the amount of lotilaner administered to the human is the same at each of the 2 to 11 additional time points.

23. The rotilaner according to claim 20, wherein the one or more additional time points include 6 to 10 additional time points.

24. The rotilaner according to claim 20, wherein the sole active ingredient in the composition is rotilaner.

25. The rotilaner according to claim 20, wherein the one or more ticks are selected from the group consisting of ticks, ambryo ticks, scaber ticks, chestnut ticks, and ornithodrolo ticks.

26. The lotilaner according to claim 20, wherein the first oral dose is 200 mg to 300 mg of lotilaner.

27. The lotilaner according to claim 20, wherein the first oral dose is 250 mg of lotilaner.

28. The lotilaner according to claim 20, wherein the second oral dose is 40 mg to 60 mg of lotilaner.

29. The lotilaner according to claim 20, wherein the second oral dose is 60 mg to 100 mg of lotilaner.