Methods for treating and preventing non-viral tick-borne diseases and symptoms thereof

Abstract

Disclosed are methods and compositions for treating or preventing non-viral tick-borne diseases and symptoms thereof by administering a long half-life 8-aminoquinoline such as tafenoquine. The present invention discloses a kit, including a device for detecting non-viral tick-borne diseases and / or symptoms thereof, as well as long half-life 8-aminoquinolines, such as tafenoquine.

Description

BACKGROUND

[0001] 8-aminoquinolines have the ability to inhibit or kill pathogens within and outside of cells by inducing oxidative stress, thereby preventing or treating diseases caused by these pathogens, provided that: (i) the pathogen is inherently susceptible to the mechanism of action of the heptofenequin or a peroxide; (ii) the 8-aminoquinoline has appropriate substituents to confer a long half-life, so that the dosing time is infrequent; (iii) they can be safely dosed at high enough levels to achieve the desired antibacterial or antiparasitic effect for a sufficient period of time; and / or (iv) the selected dose is appropriate for treating immunocompetent and immunocompetent patients without the need for dose adjustment. As described below, standard medical and treatment protocols for human diseases caused by specific microorganisms transmitted by ticks are inadequate and can be improved by the use of long half-life 8-aminoquinolines alone or in combination with other agents.

[0002] Ticks found throughout the United States include American dog ticks, lone star ticks, brown dog ticks, woodchuck ticks, Gulf Coast ticks, Rocky Mountain wood ticks, soft ticks, and western blacklegged ticks. Some ticks carry pathogens such as Anaplasma spp., Babesia spp., Borrelia spp., Ehrlichia spp., Rickettsia spp., and Francisella spp. that can cause human diseases including African tick bite fever, anaplasmosis (previously known as human granulocytic ehrlichiosis (“HGE”)), babesiosis, ehrlichiosis, Lyme disease, Mediterranean spotted fever (also known as South European spotted fever), Pacific Coast tick fever (PCTF), Rocky Mountain spotted fever, southern tick-associated rash illness, tick-borne relapsing fever, tularemia, and 364D rickettsiosis (a relatively new disease found in California, USA). The infectious organisms (except Borrelia spp.) all have obligate intracellular life cycles within mammalian hosts and are all gram-negative spirochetes. From 2004 to 2019, the total number of reported cases of tick-borne diseases in the United States increased from 20,000 to as high as 60,000. The estimated number of unreported cases is 9 to 30 times higher, i.e., 180,000 to 1,800,000. Diseases caused by ticks vary in severity. Anaplasma Babesia Borrelia Ehrlichia Rickettsia Francisella Rickettsia Rickettsia parkeri rickettsiosis Babesiosis

[0003] Babesiosis ​​​​​​Babesiosis, caused by various Babesia species, has a 1-9 week or longer incubation period, and signs and symptoms of babesiosis include fever, chills, sweating, malaise, fatigue, myalgias, arthralgias, headache, gastrointestinal symptoms (such as decreased appetite and nausea, less commonly abdominal pain and vomiting), and dark urine. Less common signs and symptoms include cough, sore throat, emotional lability, depression, photophobia, conjunctival injection, mild splenomegaly, mild hepatomegaly, and jaundice. Routine laboratory findings in babesiosis include decreased hematocrit due to hemolytic anemia, thrombocytopenia, elevated serum creatinine and blood urea nitrogen, and mild elevation of liver transaminases.

[0004] Routine treatment of babesiosis is for at least 7-10 days with a combination of two drugs, usually atovaquone and azithromycin, or clindamycin and quinine. These regimens usually cure most immunocompetent patients, but do not prevent a high complication rate (>30%) in hospitalized patients, and about 10% and 25% of immunocompetent and immunocompromised hospitalized patients, respectively, require additional rounds of therapy. Mortality in the general hospitalized population is 1-2%, but can be much higher in immunocompromised populations. In contrast, malaria is a disease caused by protozoan parasites that invade red blood cells, leading to anemia and severe organ failure, and has an effective 3-day oral and intravenous treatment in the United States, with a mortality rate of 0.35% (Mace et al., 2021).

[0005] Lyme disease and borreliosis Lyme disease and borreliosis are associated with infection by the genus Borrelia, of which the most important are Borrelia burgdorferi in the United States B. burgdorferiThe incubation period is 3–30 days, and signs and symptoms vary depending on the stage of the disease. For the localized stage, signs and symptoms include erythema migrans (“EM”) – a red, annular, or uniformly expanding rash, flu-like symptoms (e.g., malaise, headache, fever, myalgia, and arthralgia), and lymphadenopathy. For the disseminated stage, signs and symptoms include multiple secondary annular rashes, flu-like symptoms, lymphadenopathy, rheumatic manifestations, cardiac manifestations, neurological manifestations, conjunctivitis, keratitis, uveitis, mild hepatitis, and splenomegaly. Typical laboratory findings include elevated erythrocyte sedimentation rate, mildly elevated liver transaminases, and microscopic hematuria or proteinuria; in Lyme disease meningitis, cerebrospinal fluid typically shows lymphocytosis, mildly elevated protein, and normal glucose levels. For Lyme disease, post-exposure prophylaxis involves a single dose of 200 mg doxycycline within 72 hours of tick bite (Lantos et al., 2021). Treatment for erythema migraine involves 10–14 days of oral antibiotic therapy, including doxycycline, cefuroxime axetil, and amoxicillin, with azithromycin for 5–10 days as a second-line alternative (Lantos et al., 2021). Treatment of established infections and their complications is complex and may involve oral or intravenous antibiotics (including those mentioned above and penicillin G) and corticosteroids, depending on the specific circumstances (Lantos et al., 2021).

[0006] Lyme disease is not associated with high mortality; a review of US mortality records from 1993–2003 revealed only one case with clinically consistent Lyme disease presentation (Kugeler et al., 2010). However, although standard antibiotic treatment successfully alleviates clinical symptoms in >80% of cases, Lyme disease can persist in other syndromes with various symptoms associated with post-treatment Lyme disease syndrome (PTLDS, Cabello et al., 2022). The etiology of PTLDS remains unclear (Cabello et al., 2022), but antimicrobial resistance is a proposed mechanism. It has also been suggested that transient intracellular localization of *Borrelia* organisms allows them to evade immune defenses (Ma et al., 1991; Montgomery et al., 1993).

[0007] Another type of leptospirosis is Miyamoto's leptospirosis ( Borrelia miyamotoiLeptospirosis, with an incubation period of several days to several weeks, presents with signs and symptoms including fever, chills, fatigue, severe headache, arthralgia / myalgia, dizziness, confusion, vertigo, rash, difficulty breathing, nausea, abdominal pain, diarrhea, and loss of appetite. Routine laboratory findings for Leptospirosis include leukopenia, thrombocytopenia, and elevated liver transaminase levels. There is currently no universally accepted treatment for Leptospirosis, but antibiotics used to treat Lyme disease (at the same doses) have been reported to be effective.

[0008] Tulamycosis Tularemia is caused by *Tularemia flavus* (… Fancisella tularemia Tularemia is a highly contagious disease caused by streptomycin, with a mortality rate as high as 30%. The incubation period is 3-5 days, but can be as long as 21 days. Signs and symptoms include fever, chills, headache, malaise, fatigue, loss of appetite, myalgia, chest discomfort, cough, sore throat, vomiting, diarrhea, and abdominal pain. Routine laboratory results include normal or elevated white blood cell count and sedimentation rate, thrombocytopenia, hyponatremia, elevated liver transaminases, elevated creatine phosphokinase, and the possible or absent presence of myoglobinuria and sterile pyuria. Routine treatment for tularemia includes the use of streptomycin, gentamicin, ciprofloxacin, and doxycycline.

[0009] Other tick-borne rickettsial diseases (TBRD) TBRD is caused by various obligate intracellular rickettsiae, among which Rickettsia rickettsiae is the most important in the United States. Rickettsia rickettsii ), Chafi Ehrlich ( Ehrlichia chaffeensis ) and phagocytic cells without plasma bodies ( Anaplasma phagocytophilum (Chapman et al., 2006). The following is a brief overview of some of the more significant TBRDs. The general trend for all TBRDs is that management may require hospitalization in up to 50% of cases, with a high rate of hospitalization complications. The standard of care is tetracycline antibiotics, but they are the most effective early infections when TBRDs are difficult to distinguish from other infectious diseases (Chapman et al., 2006). Although tetracycline is considered the standard of care, mortality rates in the treated population can be as high as 5% in the case of Rocky Mountain spotted fever, and 1%–3% in the absence of plasmacytosis and erythrozoonosis. Given that the mortality rate for diseases such as malaria is as low as 0.35% (Mace et al., 2021), and can be treated with three days of oral or intravenous medication, it is clear that the standard of care for TBRDs is inadequate, and patients are generally undertreated.

[0010] For aserine disease, the incubation period is typically 5–14 days. Signs and symptoms include fever, chills, rigors, severe headache, malaise, myalgia, gastrointestinal symptoms (such as nausea, vomiting, diarrhea, and loss of appetite), and rash. Routine laboratory findings for aserine disease (usually observed in the first week of clinical onset) include mild anemia, thrombocytopenia, leukopenia (characterized by relative and absolute lymphopenia and a left shift), and mild to moderate elevation of liver transaminases. The observation of morulae in the cytoplasm of granulocytes during blood smear examination is highly suggestive of the diagnosis.

[0011] The incubation period for ehrlichiosis is 5–14 days. Signs and symptoms include fever, chills, headache, malaise, myalgia, gastrointestinal symptoms (such as nausea, vomiting, diarrhea, and loss of appetite), altered mental status, and rash. Routine laboratory findings for ehrlichiosis include thrombocytopenia, absolute leukopenia, anemia (usually occurring later than thrombocytopenia or leukopenia), and mild to moderate elevation of liver transaminases.

[0012] For Pakaryrickettsial disease, the incubation period is 2-10 days. Signs and symptoms include fever, headache, rash (sparse maculopapular or papular rash on the trunk and extremities), and myalgia. Routine laboratory results include mild elevation of liver transaminases, mild leukopenia, and mild thrombocytopenia.

[0013] For Rocky Mountain spotted fever, the incubation period is 3-12 days. Signs and symptoms include: in the first 1-4 days, high fever, severe headache, malaise, myalgia, periorbital and dorsum of hand edema, and gastrointestinal symptoms (including nausea, vomiting, and loss of appetite); from day 5 onwards, altered mental status, coma, cerebral edema, respiratory damage (pulmonary edema, ARDS), organ or tissue cell necrosis, and multi-organ system damage (CNS, renal failure). The rash usually appears 2-5 days after the onset of symptoms. Routine laboratory tests include thrombocytopenia, elevated liver transaminases, and hyponatremia.

[0014] For tick-borne relapsing fever, the incubation period is approximately 7 days, followed by recurrent episodes of fever lasting about 3 days, intermittently followed by a 7-day afebrile period. Signs and symptoms include headache, myalgia, chills, nausea, vomiting, joint pain, and facial paralysis. Routine laboratory results include: normal to elevated white blood cell count (with a left shift), slightly elevated serum bilirubin, mild to moderate thrombocytopenia, elevated erythrocyte sedimentation rate, and slightly prolonged prothrombin time and partial thromboplastin time. Routine treatment for tick-borne relapsing fever involves tetracycline, erythromycin, and ceftriaxone.

[0015] There is an urgent need for new methods to treat and prevent non-viral tick-borne diseases such as babesiosis and their symptoms. Summary of the Invention

[0016] This invention relates to a method for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, the method comprising administering an effective amount of long-half-life 8-aminoquinoline to the subject in need. In some embodiments, the tick-borne organism is caused by *Babesia*, *Rickettsia*, *Francis*, *Apocytoplasmosis*, *Ehrlichia*, or *Breospira*, and the induced disease can be one or more of the following, but is not limited to: African tick-borne fever, *Apocytoplasmosis*, babesiosis, breech disease, erythrozoonosis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsial disease, rickettsial disease, Rocky Mountain spotted fever, southern tick-associated rash, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In some embodiments, the long-half-life 8-aminoquinoline is capable of treating or preventing the tick-borne disease at the minimum single dose or initial dose in a 50 mg regimen. In some embodiments, the long half-life 8-aminoquinoline is tafenoxanone or a pharmaceutically acceptable salt thereof. In some implementations, administration is performed according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days via the following administration methods: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) administration of 600 mg over 1-5 days via the following administration methods. Loading dose of mg: (i) 6 100 mg doses, or (ii) 4 150 mg doses, or (iii) 3 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, then 200 mg once a week for up to 52 weeks.In some implementations, the required subjects are: symptomatic outpatients, symptomatic outpatients with risk factors for disease progression, symptomatic outpatients with immunodeficiency, symptomatic inpatients, symptomatic inpatients with risk factors for disease progression, symptomatic inpatients with immunodeficiency, asymptomatic patients, asymptomatic patients without risk factors, asymptomatic patients with risk factors, asymptomatic patients at risk of tick bites, asymptomatic patients without risk factors but at risk of tick bites, asymptomatic patients with risk factors but at risk of tick bites, patients without risk factors but bitten by ticks and at risk of tick-borne disease infection, and patients with risk factors but bitten by ticks and at risk of tick-borne disease infection.

[0017] In some embodiments, the present invention relates to a method for treating or preventing non-viral tick-borne diseases or their symptoms in human subjects, the method comprising: (a) administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I),

[0018] Formula (I) Wherein R is any halogenated substituent with a molecular weight ≤205. In some embodiments, the tick-borne organism is caused by Babesia, Rickettsia, Francisella, Aplasticis, Ehrlichia, or Borrelia, and the disease caused can be one or more of the following, but is not limited to: African tick-borne fever, Aplasticis disease, Babesia infection, Borrelia infection, Ehrlichiosis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsial disease, Rickettsia, Rocky Mountain spotted fever, Southern tick-associated rash, tick-borne relapsing fever, Tularemia, and 364D Rickettsia. In some embodiments, the long half-life 8-aminoquinoline is capable of treating or preventing the tick-borne disease with the minimum single dose or initial dose in a 50 mg regimen. In some embodiments, the long half-life 8-aminoquinoline is tafenoxanone or a pharmaceutically acceptable salt thereof. In some implementations, administration is carried out according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days by: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by 200 mg doses within 12 days of the initial loading dose. The maintenance dose of mg; and (h) a loading dose of 600 mg administered over 1–5 days by the following administration methods: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.In some implementations, the required subjects are: symptomatic outpatients, symptomatic outpatients with risk factors for disease progression, symptomatic outpatients with immunodeficiency, symptomatic inpatients, symptomatic inpatients with risk factors for disease progression, symptomatic inpatients with immunodeficiency, asymptomatic patients, asymptomatic patients without risk factors, asymptomatic patients with risk factors, asymptomatic patients at risk of tick bites, asymptomatic patients without risk factors but at risk of tick bites, asymptomatic patients with risk factors but at risk of tick bites, patients without risk factors but bitten by ticks and at risk of tick-borne disease infection, and patients with risk factors but bitten by ticks and at risk of tick-borne disease infection.

[0019] In some embodiments, a method is provided for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, the method comprising administering tafenoxane to the subject in need. In some embodiments, the tick-borne organism is caused by *Babesia*, *Rickettsia*, *Francis*, *Apocytoplasmosis*, *Ehrlichia*, or *Breospira*, and the disease caused can be one or more of the following, but is not limited to: African tick-borne fever, *Apocytoplasmosis*, babesiosis, borreospirosis, erythropathiasis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsial disease, rickettsial disease, Rocky Mountain spotted fever, southern tick-associated rash, tick-borne relapsing fever, tularemia, and 364D rickettsial disease. In some embodiments, the long-half-life 8-aminoquinoline is capable of treating or preventing the tick-borne disease at the minimum single dose or initial dose in a 50 mg regimen. In some embodiments, the long half-life 8-aminoquinoline is tafenoxanone or a pharmaceutically acceptable salt thereof. In some implementations, administration is carried out according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and up to three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days by: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by 200 mg doses within 12 days of the initial loading dose. The maintenance dose of mg; and (h) a loading dose of 600 mg administered over 1–5 days by the following administration methods: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.In some implementations, the required subjects are: symptomatic outpatients, symptomatic outpatients with risk factors for disease progression, symptomatic outpatients with immunodeficiency, symptomatic inpatients, symptomatic inpatients with risk factors for disease progression, symptomatic inpatients with immunodeficiency, asymptomatic patients, asymptomatic patients without risk factors, asymptomatic patients with risk factors, asymptomatic patients at risk of tick bites, asymptomatic patients without risk factors but at risk of tick bites, asymptomatic patients with risk factors but at risk of tick bites, patients without risk factors but bitten by ticks and at risk of tick-borne disease infection, and patients with risk factors but bitten by ticks and at risk of tick-borne disease infection.

[0020] In some embodiments, the method of the present invention further includes administering a second and / or third agent, such as doxycycline, azithromycin-atorvaquinone, clindamycin-quinine, artesunate, artemether-fluorenol, or any other agent recommended by IDSA or CDC for the treatment or prevention of nonviral tick-borne diseases.

[0021] In some embodiments of the method of the present invention, the risk factors for disease progression are selected from: age > 55 years, fatigue, nausea, diarrhea, symptom duration > 7 days, abnormal laboratory test results (such as decreased / increased white blood cell count, increased bilirubin and increased creatinine) or pre-existing diseases that cause immunodeficiency or treatments for such diseases, and combinations thereof.

[0022] In some embodiments of the method of the present invention, the immunodeficiency state is caused by a disease selected from the following: asplenia, hyposplenism, prior treatment with immunosuppressive drugs, pre-existing autoimmune diseases or other diseases known to suppress the immune system, and combinations thereof.

[0023] In some embodiments, the pathogen is a type of Babesia, or the disease is Babesia disease.

[0024] In some embodiments, the pathogen is a type of borborygmus, or the disease is borborygia or Lyme disease.

[0025] In some embodiments, the pathogen is a type of rickettsia, or the disease is a rickettsial disease.

[0026] In some embodiments, the pathogen is a plasmaless or erechinococcosis, and the disease is a plasmaless disease or erechinococcosis.

[0027] In some embodiments, the pathogen is a type of Francisella, and the disease is tularemia.

[0028] In some implementations, administration is carried out via one or more routes, including sublingual and / or oral and / or intravenous routes.

[0029] In some implementations, administration is performed according to the administration regimen in Table 1 and / or according to any of the embodiments.

[0030] In some embodiments, the long half-life 8-aminoquinoline administered to the subject over a twelve-month period does not exceed 11,000 mg.

[0031] In some embodiments, the amount of compound (I), its pharmaceutically acceptable salt, or pharmaceutical composition containing compound (I) administered to the subject within twelve months does not exceed 11,000 mg, wherein R is any halogenated substituent with a molecular weight ≤205.

[0032] In some embodiments, the kit comprises: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-phosphate dehydrogenase (G6PD) deficiency; (b) a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I); and (c) instructions for use; wherein R in formula (I) is any halogenated substituent with a molecular weight ≤205.

[0033] In some embodiments, the kit comprises: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-phosphate dehydrogenase (G6PD) deficiency; (b) a long half-life 8-aminoquinoline; and (c) instructions for use.

[0034] In some embodiments, the kit comprises: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-phosphate dehydrogenase (G6PD) deficiency; (b) tafenoxine; and (c) instructions for use.

[0035] In some embodiments, a method is provided for pretreatment of a human subject with a nonviral tick-borne disease and / or its symptoms, the method comprising administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0036] Formula (I), Wherein R is any halogenated substituent with a molecular weight ≤205. In some embodiments, the compound of formula (I) is tafenoxane or a salt thereof.

[0037] Implementation Overview This invention relates to methods for treating and / or preventing tick-borne diseases or their symptoms in human subjects. The method includes administering an effective amount of long-half-life 8-aminoquinoline to a subject requiring treatment or prevention of tick-borne diseases. In another aspect, this invention relates to the use of long-half-life 8-aminoquinoline for treating or preventing tick-borne diseases or their symptoms in human subjects, comprising administering an effective amount of long-half-life 8-aminoquinoline to said human subject.

[0038] Babesia In some embodiments of the invention, the tick-borne disease is caused by a parasite of Babesia. In these embodiments, the tick-borne disease may be babesiosis. In some embodiments, the invention relates to treating human subjects with tick-borne diseases caused by parasites of Babesia, wherein the subject has been diagnosed with infection with a Babesia parasite prior to administration of long-half-life 8-aminoquinoline. In some embodiments, for example, in cases where the subject is infected with the Babesia parasite, the subject may also be co-infected with a spirochetal or borborygian spirochete.

[0039] In some embodiments, the present invention relates to treating human subjects with tick-borne diseases caused by parasites of Babesia, wherein the subjects have been diagnosed with at least one of Babesia infection and Babesia disease. In some embodiments, the diagnosis includes laboratory tests confirming Babesia infection and / or Babesia disease.

[0040] In some embodiments, the subjects receiving treatment according to the present invention are symptomatic outpatients or symptomatic inpatients. In some embodiments, the subjects are symptomatic inpatients.

[0041] In some embodiments, the present invention relates to the prevention of tick-borne diseases in human subjects who are at increased risk of exposure to or potential exposure to tick-borne pathogens containing Babesia parasites.

[0042] non-Babesia In some embodiments of the invention, the tick-borne disease is caused by a non-Babesia parasite. In these embodiments, the disease may be caused by parasites such as *Breospirochetes*, *Rickettia*, *Francis*, *Aplasticis*, or *Ehrlichia*. In some embodiments, the tick-borne disease may be selected from one or more of the following: Lyme disease, borborygia, African tick-bite fever, *Aplasticis*, *Ehrlichia*, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsia, rickettsia, Rocky Mountain spotted fever, southern tick-associated rash, tick-borne relapsing fever, tularemia, and 364D rickettsia. In other embodiments, the tick-borne disease is caused by a *Breospirochetes* parasite, and the long-half-life 8-aminoquinoline is administered to the subject to prevent or reduce the severity of borborygia and / or Lyme disease.

[0043] In some embodiments, for example, a treatment method or use includes the use of long-half-life 8-aminoquinoline to treat a subject who has been diagnosed with infection with a parasite such as *Brephaeroidetes*, *Rickettella*, *Francisella*, *Aplasticis*, or *Ehrlich* prior to administration of the long-half-life 8-aminoquinoline. In other embodiments, the present invention relates to the prevention of tick-borne diseases in human subjects who are at increased risk of exposure to or potential exposure to tick-borne pathogens including *Babesia* parasites.

[0044] Pre-exposure prophylaxis and post-exposure protection against tick-borne diseases In embodiments of the invention intended to prevent tick-borne diseases (e.g., diseases caused by Babesia or non-Babesia parasites), a human subject may be identified as requiring prevention when they are identified as having an increased risk of exposure to tick-borne pathogens. For example, in some embodiments, subjects with increased exposure risk include those traveling to and / or engaging in recreational or professional activities in areas or environments associated with an increased risk of tick bites. In some embodiments, the invention aims to identify human subjects requiring prevention. In some embodiments, the increased risk of tick bites includes an increased risk of bites from black-legged ticks.

[0045] In embodiments of the present invention relating to the prevention of tick-borne diseases, a human subject may be identified as requiring prevention when they are identified as having been potentially exposed to a tick-borne pathogen, for example, in some embodiments, the tick-borne disease is caused by a non-Babesia parasite, or in other embodiments by a Babesia parasite. In some embodiments, the potential exposure may be a known or suspected tick bite from a known tick or suspected black-legged tick. In some embodiments, the potential exposure is a known or suspected tick bite. In other embodiments, the potential exposure is a known tick bite from a black-legged tick.

[0046] Composition, use and administration In each embodiment of the invention, the long-half-life 8-aminoquinoline can be a compound capable of treating or preventing tick-borne diseases with a minimum single dose or initial dose of 50 mg. In some embodiments, the long-half-life 8-aminoquinoline is a compound of formula (I) and a pharmaceutically acceptable salt thereof.

[0047] Formula (I) Wherein R is any halogenated substituent with a molecular weight ≤205. In other embodiments, the long-half-life 8-aminoquinoline can be a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. In other embodiments, the long-half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof. In other embodiments, the long-half-life 8-aminoquinoline can be a pharmaceutical composition comprising tafenoxane and a pharmaceutically acceptable carrier.

[0048] In each aspect of the invention, the long-half-life 8-aminoquinoline can be administered to the subject (e.g., a subject requiring treatment or prevention of tick-borne diseases) according to one of the following schemes: (a) The initial dose is 50 mg, followed by an additional 50 mg dose within one week after the initial dose; (b) The initial dose is 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) The initial dose is 150 mg, followed by at least one and up to four additional doses within one week of the initial dose; (d) The initial dose is 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) The initial dose is 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) One dose of 400 mg; (g) A loading dose of 600 mg is administered over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) Administer a loading dose of 600 mg over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

[0049] In other embodiments, a subject requiring treatment or prevention may be administered approximately 200 mg of long-half-life 8-aminoquinoline daily for four days, wherein the daily dose may be a single dose or divided doses. In some embodiments, for example when a subject is being treated for a non-babesiosis infection (such as spirochetosis and / or Lyme disease), the subject may be further administered approximately 200 mg / week of long-half-life 8-aminoquinoline for up to 52 weeks, wherein the weekly dose may be a single dose or divided doses. In each embodiment, the long-half-life 8-aminoquinoline may be administered via sublingual, oral, and / or intravenous routes or a combination of these routes of administration. In some embodiments, the amount of long-half-life 8-aminoquinoline administered to the subject over a twelve-month period does not exceed 11,000 mg.

[0050] In some embodiments, additional pharmaceutical agents may be administered to the subject over one or more days of the treatment or prevention regimen. For example, in some embodiments, the additional pharmaceutical agents include one or more of azithromycin, atovaquinone, and / or doxycycline administered to the subject. In other embodiments, the method and / or use of long-half-life 8-aminoquinoline for treatment or prevention may further include administering a second or third agent to the human subject, the second or third agent being selected from one or more of doxycycline, azithromycin-atovaquinone, clindamycin-quinine, artesunate, artemether-fluoreneol, and any other agents recommended by the IDSA or CDC for the treatment of nonviral tick-borne diseases.

[0051] It should be understood that the terms "dosages" or "dose" as used herein should be interpreted according to their common usage, such as referring to the amount of active ingredient administered to a subject (e.g., a dose of long-half-life 8-aminoquinoline or a pharmaceutically acceptable salt thereof). It should also be understood that the specific embodiments described herein are exemplary in nature and are not intended to limit the full scope of the applicant's invention, as will be understood by those skilled in the art from the applicant's disclosure. Attached Figure Description

[0052] The foregoing will become apparent from the following more detailed description of exemplary embodiments of the present invention, as illustrated in the accompanying drawings.

[0053] Figure 1A and Figure 1B This article describes the molecular structures of primaquine and tafenoxane, along with a summary of cited biological data. Tafenoxane has a longer half-life in vivo, making it more potent and exhibiting a broader spectrum of action in a variety of organisms. Detailed Implementation

[0054] definition All definitions of substituents described below also apply to the use of the term in conjunction with another substituent. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0055] As used herein, the singular forms “a,” “and,” and “the” include plural references unless the context clearly indicates otherwise. Furthermore, the term “comprising” is intended to cover embodiments of methods, apparatuses, compositions, etc., that are substantially composed of and / or comprised of the listed steps, components, etc. Similarly, the term “substantially composed of” is intended to cover embodiments of methods, apparatuses, compositions, etc., that are comprised of the listed steps, components, etc.

[0056] As used herein, the term "about" refers to a value that differs from a given value by less than 15%. In other embodiments, the term "about" means that the value differs from a given value by less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0057] As used in this article, "asymptomatic" refers to a human subject who does not exhibit symptoms of tick-borne diseases and may or may not have been bitten by a tick and may or may not be at risk of being bitten by a tick. For example, an asymptomatic person may have been bitten by a tick but has not developed symptoms of a tick-borne disease, or may be a healthy person planning to engage in travel or recreational activities that may increase the risk of tick bites.

[0058] As used herein, “G6PD” refers to glucose-6-phosphate dehydrogenase, and “G6PD deficiency” refers to a subject’s deficiency of this enzyme. In humans, treatment with 8-aminoquinoline in subjects with G6PD deficiency may result in hemolysis, a condition that may be clinically significant in some cases. Typically, the methods described herein are used in subjects without G6PD deficiency.

[0059] As used herein, “G6PD normal” refers to human subjects with normal levels of glucose-6-phosphate dehydrogenase. Normal G6PD levels can be determined by approved laboratory testing using validation methods known to those skilled in the art.

[0060] Human subjects may be adults or children. As used herein, “child” refers to a human subject aged between 1 day and 17 years. The term “adult” refers to a human subject aged 18 years or older.

[0061] As used herein, “loading phase,” “loading dose,” or “initial dose” refers to the initial administration of the substance, and is at least a single dose. For example, a loading phase may be once daily for three consecutive days or less prior to a dose administered at a lower frequency.

[0062] As used herein, "subsequent dose" refers to a dose administered after one or more initial doses, and at least one dose. The one or more subsequent doses may be the same as or different from the one or more initial doses. The one or more subsequent doses may be administered within the same time frame or within a different time frame than the one or more initial doses.

[0063] As used in this article, "maintenance dose" refers to the dose administered after one or more initial doses and subsequent doses.

[0064] As used in this article, "every day" refers to a given 24-hour period.

[0065] As used in this article, “weekly” refers to a given seven-day period.

[0066] As used herein, “three times a day” or “three times daily” means administering the composition three times every 24 hours.

[0067] As used herein, “four times a day” (QDS) or “four times a day” means administering the composition four times every 24 hours.

[0068] In particular, the methods and compositions described herein may be implemented using pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The disclosed compound of formula (I) or a pharmaceutically available salt thereof may be administered to a subject as part of a pharmaceutical composition of the methods described herein, together with an accepted drug carrier or diluent, according to any dosage regimen described herein. The formulation of the compound to be administered will vary depending on the chosen route of administration (e.g., solution, emulsion, capsule). A suitable drug carrier may contain an inert component that does not interact with the compound. Standard pharmaceutical formulation techniques may be employed, such as those described in Remington's spharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Drug carriers suitable for parenteral administration include, for example, sterile water, physiological saline, antibacterial saline (saline containing approximately 0.9 mg / ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's lactate, and the like. Methods of encapsulating compositions (e.g., in the coating of hard gelatin or cyclodextrin) are known in the art (Baker et al., “Controlled Release of Biological Active Agents”, John Wiley and Sons, 1986).

[0069] "Pharmaceutical acceptable carrier" refers to a non-therapeutic ingredient of sufficient purity and quality for the formulation of the compositions of the present invention, which, when administered appropriately, generally does not produce adverse reactions and serves as a carrier for an active pharmaceutical ingredient (e.g., a compound of formula (I), such as tafenoxane).

[0070] The phrase “pharmaceutically acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other ingredients containing the formulation and / or the mammals treated with it.

[0071] Pharmaceutical formulations contain pharmaceutically acceptable and physiologically acceptable carriers, diluents, or excipients. In this document, the terms "pharmaceutically acceptable" and "physiologically acceptable" include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic agents, and absorption enhancers or delayers compatible with drug administration. Such formulations may be contained in liquids (emulsions, suspensions, syrups, or elixirs) or may be in solid form (coated or uncoated tablets, hard or soft capsules, powders, granules, crystals, or microbeads). Complementary compounds (e.g., preservatives, antimicrobial agents, antiviral agents, and antifungal agents) may also be incorporated into the compositions.

[0072] The compounds of this invention can be formulated into pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts of the compounds of this invention can be prepared using conventional techniques. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. The pharmaceutically acceptable salts of any compound described herein are intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0073] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. It also includes salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. It also encompasses salts of amino acids, such as arginine salts, gluconates, galacturons (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds can be prepared by contacting a free base with a sufficient amount of the desired acid to generate the salt using methods and techniques well known to those skilled in the art.

[0074] "Pharmaceutically acceptable base addition salts" refer to salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can form with metals or amines, such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, salts of substituted amines (including naturally occurring substituted amines), salts of cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrazine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., ibid.

[0075] The phrase “effective amount” refers to an amount of a medicine that (i) treats or prevents a particular disease, condition or disorder, (ii) alleviates, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the occurrence of one or more symptoms of a particular disease, condition or disorder described herein.

[0076] As used herein, the term “immunodeficiency” refers to any person who has one or more of the following conditions: asplenia, hyposplenism, autoimmune disease, has received immunosuppressive therapy (e.g., drugs in this non-exclusive list: rituximab, cyclophosphamide, vincristine, prednisone, cortisol, and doxorubicin), or has any pre-existing condition that suppresses the immune system (e.g., diseases in this non-exhaustive list: organ transplantation, AIDS, B-cell lymphoma, multiple myeloma, diseases associated with decreased B-cell count, hereditary spherocytosis, Evan syndrome, brain tumor, carcinoma, gastric cancer, and X-linked agammaglobulinemia).

[0077] As used in this article, the term "normal immune function" refers to anyone who is not immune-deficient as described above.

[0078] As used in this article, "semi-immune" refers to residents of malaria-endemic countries who have developed partial immunity due to repeated exposures to symptomatic malaria. They typically do not exhibit clinical signs and symptoms of malaria when the presence of malaria parasites in their blood is confirmed microscopically. Antimalarial drugs work at different doses in both semi-immune and non-immune populations.

[0079] As used in this article, "non-immune" refers to a group that has not been adequately exposed to malaria before, such that when the presence of the malaria parasite is confirmed under a microscope, they are unable to develop immunity to the signs and symptoms of malaria. Groups without immunity who have never been exposed to malaria may also be malaria-naïve.

[0080] As used herein, a subject "needs" treatment if they or a non-human animal subject (preferably human) will derive a biological, medical, or quality-of-life benefit from the treatment. In some embodiments, the subject has typical symptoms of babesiosis or other non-viral tick-borne diseases and requires treatment. In other embodiments, the subject is suspected or known to have been bitten by a tick and requires post-exposure prophylaxis to prevent symptomatic infection. In some embodiments, the subject is expected to travel or engage in recreational activities (e.g., hiking or camping) that may be associated with a higher risk of tick bites and therefore requires prophylaxis. In some embodiments, the subject has a higher occupational risk of tick bites compared to others in the group (e.g., forestry workers or wilderness guides).

[0081] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to a significant reduction or inhibition of a particular disease, symptom, disorder, or illness, or a baseline reduction in the activity of a biological activity or process.

[0082] As used in this article, the terms “subject,” “patient,” and “group” are used interchangeably and refer to humans of any age and sex.

[0083] As used herein, the terms “treat,” “teating,” or “treatment” refer to any disease or disorder. In one embodiment, it means improving a disease or disorder (i.e., delaying, halting, or alleviating the development of a disease or at least one of its clinical symptoms). In another embodiment, “treat,” “teating,” or “treatment” means alleviating or improving at least one physical indicator, including those that the subject may not be aware of. In yet another embodiment, “treat,” “teating,” or “treatment” means regulating a disease or disorder, including regulation at the physical level (e.g., stabilization of noticeable symptoms), regulation at the physiological level (e.g., stabilization of physical indicators), or regulation at both levels simultaneously. In yet another embodiment, “treat,” “teating,” or “treatment” means prevention (i.e., preventing or delaying the onset, development, or progression of a disease or disorder).

[0084] As used herein, the terms “pre-treat,” “pre-treating,” or “pre-treatment,” with respect to any disease or disorder, refer to an implementation described by “treat,” “treating,” or “treatment,” wherein the first administration is given prior to exposure to (or potential exposure to) the disease or disorder. In a particular implementation, “pre-treat,” “pre-treating,” or “pre-treatment” for any disease or disorder means reducing the severity of the disease or disorder or accelerating its recovery, wherein the first administration is given prior to exposure to (or potential exposure to) the disease or disorder.

[0085] As used herein, the term "administration" refers to, but is not limited to, the following routes of administration: local, oral, sublingual, oral, parenteral, subcutaneous, transdermal, oral, intravascular (e.g., intravenous or intra-arterial), intramuscular, subcutaneous, intranasal, and intraocular. Administration may be performed locally at specific anatomical sites, such as sites of infection, or systemically.

[0086] As used herein, the term “prevent” or “prevention” means partially, substantially, or completely achieving one or more of the following outcomes: avoiding illness, disorder, or syndrome caused by infection with a nonviral tick-borne pathogen; avoiding clinical symptoms or indicators associated with illness, disorder, or syndrome caused by infection with a nonviral tick-borne pathogen; reducing the severity of illness, medical complications, disorder, or syndrome caused by infection with a nonviral tick-borne pathogen; or avoiding death.

[0087] As used in this article, the term "symptomatic" refers to subjects who exhibit symptoms of one or more nonviral tick-borne diseases during clinical evaluation.

[0088] As used herein, the term "tafenoxine" refers to compounds of formula (I) having the following structure:

[0089] The compound is also known as N(4)-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine, or a pharmaceutically acceptable salt thereof. Tafenoxane may also be called tafenoxane [INN:BAN], etaquine, UNII-262P8GS9L9, C 24 H 28 F3N3O3, CHEBI:172505, AIDS006901, 106635-81-8 (maleate), AIDS-006901, CID115358, SB-252263, WR238605, WR-238605, WR238605, LS-172012, 1,4-pentanediamine, N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-8-quinolinyl)-, 106635-80-7, N(4)-(2,6-dimethyl) oxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine, N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]diamine, (4-amino-1-methylbutyl){2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy](8-quinolinyl)}amine, (R)-N3-(2,6-dimethoxy-4-methyl-5-(3-trifluoromethyl)phenoxy)quinolin-8-yl)pentane-1,4-diamine, (RS)-N 3 -(2,6-Dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinolin-8-yl)pentane-1,4-diamine. Its pharmaceutically acceptable salts include:

[0090] The succinate with the above structure has the CAS number 106635-81-8.

[0091] The compounds of the present invention, which can be used to carry out the methods described herein, may have one or more chiral centers and thus exist in a variety of stereoisomers. All stereoisomers and mixtures thereof are included within the scope of protection of the present invention. Racemic compounds can be separated using preparative HPLC and chromatographic columns with chiral stationary phases, or resolved using methods known to those skilled in the art to produce single enantiomers. Furthermore, chiral intermediate compounds can be resolved and used to prepare the chiral compounds of the present invention.

[0092] The compounds described herein may exist in the form of one or more tautomers. All tautomers and mixtures thereof are included within the scope of this invention.

[0093] The compounds of this invention can be administered in the form of a free base or in the form of a pharmaceutically acceptable salt. For example, acidic salts of the compounds of this invention containing an amino group or other basic groups can be obtained by reacting the compound with a suitable organic or inorganic acid to obtain a pharmaceutically acceptable anionic salt form. Examples of anionic salts include acetates, benzenesulfonates, benzoates, bicarbonates, tartrates, bromides, calcium ethylenediaminetetraacetate, camphorsulfonates, carbonates, chlorides, citrates, dihydrochlorides, ethylenediaminetetraacetate, edisylate, estotate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolylarsanilate, and hexylresorcinol. Salts, hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, iodide, hydroxyethyl sulfonate, lactate, lacturonate, malate, maleate, mandelate, methanesulfonate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, papoate, pantothenate, phosphate / bisphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theophylline, p-toluenesulfonate, and triethyl iodide salts. In one embodiment, the compound of formula (I) is a hydrochloride salt.

[0094] When used in this document, a dose range reflected as two numbers refers to these doses and all doses within that range. For example, a dose range of 10 mg - 11 mg refers to 10.0 mg, 10.05 mg, 10.10 mg, 10.15 mg, 10.20 mg, 10.25 mg, 10.30 mg, 10.35 mg, 10.40 mg, 10.45 mg, 10.50 mg, 10.55 mg, 10.60 mg, 10.65 mg, 10.70 mg, 10.75 mg, 10.750 mg, 10.80 mg, 10.90 mg, 10.90 mg, 10.95 mg, 11.00 mg, and any and all of these doses, such as 10.34 mg, 10.78 mg, etc.

[0095] As used in this article, “suspected nonviral tick-borne disease” refers to a subject whose known symptoms are consistent with those of a nonviral tick-borne disease. This does not need to be associated with evidence of a tick bite, as in many cases, ticks are not observed attaching to a person, and / or the timing of the tick bite may be unknown. The type of suspected nonviral tick-borne disease depends on the possible infecting pathogen. For example, observed migratory erythema may be Lyme disease caused by Borrelia burgdorferi; while in the absence of other diagnoses, the presence of fever, fatigue, loss of appetite, and anemia may suggest babesiosis.

[0096] Long half-life 8-aminoquinolines Substituents at positions 2, 4, and 5 of the 8-aminoquinoline ring are known to affect long half-lives and produce a broader spectrum of action against pathogens such as Pneumocystis and Plasmodium. This also appears to be the case for some tick-borne diseases, as 4-methyl-substituted primary aminoquina is more effective against Babesia microsporum than primary aminoquina (Reubush et al., 1980). Furthermore, one and three doses of tafenoxanone were sufficient to clear and cure babesiosis in immunocompromised mice and dogs (Liu et al., 2020), while daily administration of primary aminoquina only inhibited Babesia microsporum in Mongolian jirds, although these animals were reported to be immunocompromised (Reubush et al., 1980).

[0097] Compared to primary aminoquinoline, which has a shorter half-life, 8-aminoquinoline can have its half-life extended by substitution at positions 2, 4, and 5 of the quinoline ring, thereby improving potency and broadening its action spectrum. See also Figure 1A and Figure 1BFor example, primaquine has only weak activity against the hematogenous phase of Plasmodium falciparum, while tafenoxanil is very effective (Baird et al., 2002. Am J TropMed Hyg. 2002 Jun; 66(6):659-60; McCarthy et al., 2019. Clin Infect Dis. 2019 Jul18; 69(3):480-486). Similarly, while tafenoxanil can be used as a monotherapy to treat Pneumocystis pneumonia in mice, primaquine must be combined with clindamycin to achieve the same results (Bartlett et al., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1991, Vol 35(2): 277-282). In addition, a single dose of 20 mg / kg of tafenoxanil cleared Babesia parasitemia in mice (Mordue and Wormser 2019. 442 jid 2019:220, 1 August), while primamiquine required a higher dose (100 mg / kg) (Yao et al., 2015. J Infect Dev Ctries. 2015 Sep 27;9(9):1004-10).

[0098] This study, conducted in a comprehensive QTC (Quick Time Tolerance) study, found that administration of up to 1200 mg of tafenoxane over three days did not increase the upper limit of the 90% confidence interval for the QTC interval, thus meeting generally accepted regulatory criteria that the drug does not exhibit cardiotoxicity (Green's Law). et al 2014. J Clin Pharmacol 54:995-1005. Importantly, when the two drugs are used in combination, tafenoxane does not increase the known QTC prolongation associated with chloroquine (Green et al., 2014). Tafenoxane can also be safely administered over three days at a loading dose of 600 mg, followed by weekly doses of 200 mg for up to one year without increasing the overall incidence of adverse events experienced by patients relative to placebo. Only gastrointestinal reactions (mild to moderate) and corneal vortex opacities were the only specific adverse events with increased risk—these reactions were reversible and not clinically significant (Moreno et al., 2021).

[0099] Patient population Subjects requiring prevention or treatment of nonviral tick-borne diseases include, but are not limited to, the following patient groups: symptomatic outpatients, symptomatic inpatients, and symptomatic outpatients or inpatients with risk factors for disease progression (different from immunosuppressive status) (for babesiosis, this includes age >55 years, fatigue, nausea, diarrhea, symptom duration >7 days, decreased / increased white blood cell count, increased bilirubin, increased creatinine, parasitemia >10%, or any pre-existing disease leading to immunodeficiency or treatment for such diseases, or combinations thereof). Outpatients or inpatients with symptomatic immunocompromised individuals (in the case of babesiosis, those with asplenia, hyposplenism, autoimmune diseases, those who have received immunosuppressive therapy, or those with any pre-existing immune system-suppressing disease); asymptomatic individuals who may be at risk of tick bites (regardless of the presence of risk factors); and tick-bitten individuals who may be infected with babesiosis or other non-viral tick-borne diseases caused by Babesia and / or Borrelia and / or Aplasticis and / or Rickettsia and / or Ehrlich and / or Francisella spp. (regardless of the presence of risk factors).

[0100] Diagnostic criteria For the therapeutic indications claimed in this invention, the diagnostic criteria include, but are not limited to: tick-borne diseases (such as babesiosis) confirmed by laboratory testing such as blood smears and / or polymerase chain reaction (PCR); parasite load (such as parasitemia in blood smears); and suspected infection determined based on diagnostic criteria.

[0101] Dosing regimen The dosing regimens according to the invention are effective in preventing and / or treating non-viral tick-borne diseases in a given subject. Oral administration and / or formulations are intended to minimize gastrointestinal (GI) discomfort in the subject, particularly when the dose provided is ≥400 mg / day. Adult subjects generally tolerate doses of tafenoxane above 400 mg poorly (e.g., this dose may cause gastrointestinal problems or toxicity), regardless of the subject's G6PD status. In G6PD-normal adult subjects, doses of up to 400 mg of tafenoxane may be well tolerated, while in G6PD-deficient subjects, doses of 300 mg or higher may be poorly tolerated. Administration via oral, sublingual, intravascular (e.g., intravenous or intra-arterial) routes, and / or delivery designs (tablets, films, etc.) that minimize GI discomfort, can minimize and / or avoid and / or alleviate GI discomfort. Maintenance dosing may be continued for 6 months to 1 year if necessary, provided that the total dose administered over 12 months does not exceed 11,000 mg.

[0102] In a particular embodiment, the long-half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof. The long-half-life 8-aminoquinoline may be administered to a human subject as at least one initial (loading) dose. In a particular embodiment, a dose of 50 mg to 400 mg is administered.

[0103] In a further embodiment, the method for treating and / or preventing non-viral tick-borne diseases further includes administering a second agent (such as a drug) to a human subject. In other embodiments, the method includes administering an effective amount of the second agent to the subject. In a further embodiment, administration of tafenoxane or the compound of formula (I) is simultaneous with administration of the second agent. In other embodiments, administration of tafenoxane or the compound of formula (I) is not simultaneous with administration of the second agent. In a further embodiment, the second agent is not administered.

[0104] In other embodiments, the second agent is selected from one or more of the following: artemether, artesunate, atovaquinone, atovadone-chloroguanidine, azithromycin, clindamycin, doxycycline, phenfluorene, quinine, and tetracycline.

[0105] One embodiment of the invention is a dosing regimen according to Table 1, with or without a second agent. Specifically, in both methods for treating and preventing non-viral tick-borne diseases, the methods include administering to the subject an effective amount of tafenoxane or a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoxane or a compound of formula (I).

[0106] Formula (I) Where R is any halogenated substituent with a molecular weight ≤205, and administration is performed according to the dosing regimen in Table 1.

[0107] Table 1

[0108] Exemplary implementation Implementation Method 1 – A method for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, the method comprising administering an effective amount of long-half-life 8-aminoquinoline to the subject in need.

[0109] Implementation Method 2 – According to the method of Implementation Method 1, wherein the organism transmitted by ticks is caused by Babesia, Rickettsia, Francisella, Aplasticis, Ehrlich, or Borrelia, and the disease caused may be, but is not limited to, one or more of the following: African tick-borne fever, Aplasticis disease, Babesia disease, Borrelia disease, Ehrlich disease, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsial disease, Rickettsia, Rocky Mountain spotted fever, Southern tick-associated rash, tick-borne relapsing fever, Turafenosis, and 364D Rickettsia.

[0110] Implementation Method 3 – The method of Implementation Method 1 or 2, wherein the long half-life 8-aminoquinoline is capable of treating or preventing non-viral tick-borne diseases at the minimum single dose or initial dose in a 50 mg dosing regimen.

[0111] Implementation Method 4 – The method according to any one of Implementation Methods 1-3, wherein the long half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof.

[0112] Implementation Method 5 – The method according to any one of Implementation Methods 1-4, wherein the administration is performed according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and at most five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days by: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by 200 mg doses within 12 days of the initial loading dose. The maintenance dose of 600 mg; and (h) a loading dose of 600 mg administered over 1–5 days by the following administration routes: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

[0113] Implementation Method 6 – The method according to any one of Implementation Methods 1-5, wherein the subject in need is: a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with immunodeficiency, a symptomatic hospitalization, a symptomatic hospitalization with risk factors for disease progression, a symptomatic hospitalization with immunodeficiency, an asymptomatic person, an asymptomatic person without risk factors, an asymptomatic person with risk factors, an asymptomatic person facing tick bite risk, an asymptomatic person without risk factors and facing tick bite risk, an asymptomatic person with risk factors and facing tick bite risk, a person without risk factors who has been bitten by a tick and is at risk of contracting the tick-borne disease, and a person with risk factors who has been bitten by a tick and is at risk of contracting the non-viral tick-borne disease.

[0114] Implementation Method 7 – A method for treating or preventing non-viral tick-borne diseases or their symptoms in human subjects, the method comprising: (a) administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I),

[0115] Formula (I) Where R is any halogenated substituent with a molecular weight ≤ 205.

[0116] Implementation Method 8 – The method according to Implementation Method 7, wherein the organism transmitted by ticks is caused by Babesia, Rickettsia, Francisella, Aplasticis, Ehrlichia, or Borrelia, and the disease caused may be, but is not limited to, one or more of the following: African tick-bite fever, Aplasticis disease, Babesia disease, Borrelia disease, Ehrlichiosis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkley Rickettsia, Rickettsia, Rocky Mountain spotted fever, Southern tick-associated rash, tick-borne relapsing fever, Turafenosis, and 364D Rickettsia.

[0117] Implementation Method 9 – The method according to Implementation Method 7 or 8, wherein the long half-life 8-aminoquinoline is capable of treating or preventing non-viral tick-borne diseases at the minimum single dose or initial dose in a 50 mg dosing regimen.

[0118] Implementation Method 10 – The method according to any one of Implementation Methods 7-9, wherein the long half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof.

[0119] Implementation Method 11 – The method according to any one of Implementation Methods 7-10, wherein the administration is carried out according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and at most five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days by: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by 200 mg doses within 12 days of the initial loading dose. The maintenance dose of 600 mg; and (h) a loading dose of 600 mg administered over 1–5 days by the following administration routes: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

[0120] Implementation Method 12 – The method according to any one of Implementation Methods 7-11, wherein the subject in need is: a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with immunodeficiency, a symptomatic hospitalization, a symptomatic hospitalization with risk factors for disease progression, a symptomatic hospitalization with immunodeficiency, an asymptomatic person, an asymptomatic person without risk factors, an asymptomatic person with risk factors, an asymptomatic person at risk of tick bites, an asymptomatic person without risk factors but at risk of tick bites, an asymptomatic person with risk factors but at risk of tick bites, a person without risk factors who has been bitten by a tick and is at risk of contracting the non-viral tick-borne disease, and a person with risk factors who has been bitten by a tick and is at risk of contracting the non-viral tick-borne disease.

[0121] Implementation Method 13 – A method for treating or preventing nonviral tick-borne diseases or their symptoms in human subjects, the method comprising administering tafenoxane to the subject in need.

[0122] Implementation Method 14 – The method according to Implementation Method 13, wherein the organism transmitted by ticks is caused by Babesia, Rickettsia, Francisella, Aplasticis, Ehrlichia, or Borrelia, and the disease caused may be, but is not limited to, one or more of the following: African tick-bite fever, Aplasticis disease, Babesia disease, Borrelia disease, Ehrlichiosis, Lyme disease, Mediterranean spotted fever, relapsing tick-fever, Parkinsonian rickettsial disease, Rickettsia, Rocky Mountain spotted fever, Southern tick-associated rash, tick-borne relapsing fever, Turafenosis, and 364D Rickettsia.

[0123] Implementation Method 15 – The method according to Implementation Method 13 or 14, wherein the long half-life 8-aminoquinoline is capable of treating or preventing non-viral tick-borne diseases at the minimum single dose or initial dose in a 50 mg dosing regimen.

[0124] Embodiment 16 – The method according to any one of Embodiments 13-15, wherein the long half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof.

[0125] Implementation Method 17 – The method according to any one of Implementation Methods 13-16, wherein the administration is performed according to one of the following regimens: (a) an initial dose of 50 mg, followed by an additional 50 mg dose within one week of the initial dose; (b) an initial dose of 100 mg, followed by at least one and at most five additional doses within one week of the initial dose; (c) an initial dose of 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) an initial dose of 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) an initial dose of 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) a single dose of 400 mg; (g) a loading dose of 600 mg administered over 1-5 days by: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by 200 mg doses within 12 days of the initial loading dose. The maintenance dose of 600 mg; and (h) a loading dose of 600 mg administered over 1–5 days by the following administration routes: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

[0126] Implementation Method 18 – The method according to any one of Implementation Methods 13-17, wherein the subject in need is: a symptomatic outpatient, a symptomatic outpatient with risk factors for disease progression, a symptomatic outpatient with immunodeficiency, a symptomatic hospitalization, a symptomatic hospitalization with risk factors for disease progression, a symptomatic hospitalization with immunodeficiency, an asymptomatic person, an asymptomatic person without risk factors, an asymptomatic person with risk factors, an asymptomatic person at risk of tick bites, an asymptomatic person without risk factors but at risk of tick bites, an asymptomatic person with risk factors but at risk of tick bites, a person without risk factors who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease, and a person with risk factors who has been bitten by a tick and is at risk of contracting the nonviral tick-borne disease.

[0127] Implementation Method 19 – The method according to any one of Implementation Methods 1-18 further includes administering a second and / or third agent, such as doxycycline, azithromycin-atorvaquinone, clindamycin-quinine, artesunate, artemether-phenfluorene, or any other agent recommended by IDSA or CDC for the treatment or prevention of nonviral tick-borne diseases.

[0128] Implementation Method 20 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the risk factors for disease progression are selected from: age > 55 years, fatigue, nausea, diarrhea, symptom duration > 7 days, abnormal laboratory test results such as decreased / increased white blood cell count, increased bilirubin, and increased creatinine, or any pre-existing disease that leads to a state of immunodeficiency or treatment for such diseases, and combinations thereof.

[0129] Implementation Method 21 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the immunodeficiency state is caused by a disease selected from the following: asplenia, hyposplenism, prior treatment with immunosuppressive drugs, pre-existing autoimmune diseases or other diseases known to suppress the immune system, and combinations thereof.

[0130] Implementation Method 22 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the pathogen is a type of Babesia, or the disease is Babesia disease.

[0131] Implementation Method 23 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the pathogen is a type of borborygmus, or the disease is borborygia or Lyme disease.

[0132] Implementation Method 24 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the pathogen is a type of rickettsia, or the disease is a rickettsial disease.

[0133] Implementation Method 25 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the pathogen is a plasmaless or erythrozoite, and the disease is a plasmaless disease or erythrozoonosis.

[0134] Implementation Method 26 – The method according to Implementation Method 6, Implementation Method 12 or Implementation Method 18, wherein the pathogen is a type of Francisella bacillus and the disease is tularemia.

[0135] Embodiment 27 – The method according to any one of Embodiments 1-26, wherein the administration is carried out via one or more routes, including sublingual and / or oral and / or intravenous routes.

[0136] Implementation Method 28 – The method according to any one of Implementation Methods 1-27, wherein the administration is performed according to the administration regimen in Table 1 and / or according to any embodiment.

[0137] Implementation Method 29 – The method according to any one of Implementation Methods 1-28, wherein the subject is administered no more than 11,000 mg over a twelve-month period.

[0138] Implementation 30—A kit comprising: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-dehydrogenase (G6PD) deficiency; (b) a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I); and

[0139] Formula (I) (c) Instructions for use; where R is any halogenated substituent with a molecular weight ≤205.

[0140] Implementation 31 – A kit comprising: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-dehydrogenase (G6PD) deficiency; (b) a long half-life 8-aminoquinoline; and (c) instructions for use.

[0141] Implementation 32 – A kit comprising: (a) a device for detecting nonviral tick-borne diseases and / or their symptoms and / or glucose-6-dehydrogenase (G6PD) deficiency; (b) tafenoxine; and (c) instructions for use.

[0142] Implementation Method 33 – A method for pretreatment of a nonviral tick-borne disease or its symptoms in a human subject, the method comprising: administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0143] Formula (I) Where R is any halogenated substituent with a molecular weight ≤ 205.

[0144] Implementation Method 34 – The method according to Implementation Method 33, wherein the compound of Formula (I) is tafenoxane or a salt thereof.

[0145] Example Example 1 – Substituted 8-aminoquinoline is more active and has a broader activity spectrum than primary aminequine. Tafenoxane, due to its longer half-life (14 days vs. approximately 6 hours), exhibits greater efficacy and a broader activity spectrum against Plasmodium and other pathogens. This is attributed to the addition of substituents at positions 2, 4, and 5, which increase steric hindrance, lipophilicity, and the blocking sites of metabolic attack. Furthermore, research by Ruebush et al. (1980) showed that the addition of a methyl group at position 4 of primaquine (a substitution also present in tafenoxane) resulted in superior efficacy against Babesia microsporum in animals compared to primaquine. Tafenoxane and similarly substituted 8-aminoquinolines (such as...) Figure 1A (and those shown in Figure 2), exhibiting a more effective and broader spectrum of activity against tick-borne pathogens, and acting in a manner similar to tafenoxine described in this embodiment.

[0146] Example 2 – Tafenoxane can eliminate all blood-borne parasites in active malaria infections. Fukuda et al. assessed vivax malaria ( Plasmodium vivax malaria The efficacy of tafenoxane versus standard treatment in patients with symptomatic vivax malaria was assessed. Patients received either tafenoxane monotherapy (400 mg / day for 3 days) or standard treatment (primaquine + chloroquine). In the tafenoxane group, all patients cleared their blood stage parasites by day 8; for patients with available data, no relapses occurred during follow-up (relapses could be caused by reinduction of the blood or liver stage, which is indistinguishable in vivax malaria infection). This suggests that tafenoxane monotherapy (1200 mg for 3 days) is sufficient to clear all blood stage organisms during treatment of symptomatic infections.

[0147] Example 3 – Administration of 800 mg of tafenoxine prior to the establishment of non-immune herd infection completely inhibited the development of hematogenous parasites. McCarthy et al. evaluated the efficacy of a 200 mg dose following a 600 mg loading dose (followed by an FDA-approved weekly maintenance dose of 200 mg for malaria prophylaxis) in clearing the blood-phase parasite of *Plasmodium falciparum* in non-immunized volunteers in a human challenge trial. Three days after the last 200 mg dose of tafenoxane, subjects contracted the parasite. All subjects in the control group subsequently developed blood-phase parasitemia, while none in the tafenoxane group did. These data suggest that administration of a total dose of 800 mg and / or the first four 200 mg doses of an FDA-approved malaria prophylaxis regimen before the onset of symptoms in non-immunized subjects can prevent the development of symptomatic malaria.

[0148] Example 4 – Low single-dose tafenoxanone can eliminate Plasmodium falciparum gametophytes in semi-immune (i.e., immunocompetent) populations Studies by Stone et al. have shown that in patients with asymptomatic Plasmodium falciparum infection, a single dose of 1.66 mg / kg of tafenoxanil combined with dihydroartemisinin / piperaquine to clear the asexual blood phase can render gametophytes non-infectious to mosquitoes within 7 days. In contrast, dihydroartemisinin / piperaquine alone requires 14 days. Therefore, a dose as low as 1.66 mg / kg of tafenoxanil (83 mg for a 50 kg adult or adolescent) can clear gametophytes from individuals who are partially immune to malaria (i.e., have normal immune function).

[0149] Example 5 – Low single-dose tafenoquine can eliminate Plasmodium falciparum gametophytes in semi-immune (immunely normal) populations. Studies by Stone et al. have shown that in asymptomatic Plasmodium falciparum infected patients, a single dose of primaquine combined with dihydroartemisinin / piperaquine to clear the asexual blood phase resulted in statistically lower levels of gamete infectivity to mosquitoes two days after administration. In contrast, dihydroartemisinin / piperaquine alone required 14 to 21 days. Therefore, a low single dose of primaquine (the 8-aminoquinoline parent compound of tafenoxanone) can clear gametee from populations that are partially immune to malaria (immunely normal).

[0150] Example 6 – The mechanism of action of primaquine on Plasmodium falciparum gametophytes is as follows: site-specific induction of oxidative stress mediated by the production of excess hydrogen peroxide. Studies by Cammarda et al. have shown that when gametophytes of Plasmodium falciparum are exposed to primaquine, they are killed by site-specific (bone marrow) overproduction of hydrogen peroxide and subsequent oxidative damage. The excess hydrogen peroxide is produced through a two-step biochemical reaction: (i) primaquine is sequentially oxidized to hydroxylated metabolites via a cytochrome reductase-cytochrome P-450 2D6 complex; (ii) the hydroxylated metabolites are spontaneously oxidized to quinoneimmine metabolites, which are then reduced back to the hydroxylated substances, producing hydrogen peroxide. The hydrogen peroxide locally kills the parasite at the site of this metabolism (bone marrow, liver, and other sites).

[0151] Example 7 – The mechanism of action of tafenoxanone on Babesia is through the induction of oxidative stress. Studies by Liu et al. have shown that hydrogen peroxide treatment (100 μmol / L) for 2 hours kills Babesia in vitro by inducing the formation of large vacuoles. The authors also confirmed that a single dose of 20 mg / kg in mice effectively killed Babesia rhodesianis (…). B. rodhaini The hematogenous phase of tafenoxanone induces the formation of large vacuoles, which are visually and numerically (i.e., in terms of size) indistinguishable from those produced in vitro by hydrogen peroxide. In mice, a single dose of tafenoxanone upregulated antioxidant enzymes in *Babesia rhodesiana*. Therefore, tafenoxanone kills *Babesia* by inducing oxidative stress, similar to the effects of hydrogen peroxide and primaquine on *Plasmodium falciparum* gametophytes (see Example 6). Wilkinson et al. (2003) also found that *Bruciana brucellosa* (… Trypanosome brucei The hemorrhagic form of *Bruciana bruxii* was killed after 90 minutes of exposure to approximately 140 μmol / L hydrogen peroxide, and the hemorrhagic form of *Bruciana bruxii* was also susceptible to tafenoxane. These observations suggest that if micromolar concentrations of hydrogen peroxide can kill an organism after several hours of exposure, then under suitable conditions, that organism may be susceptible to the effects of tafenoxane in vivo.

[0152] Example 8 – An organism’s sensitivity to tafenoxane is related to its intrinsic sensitivity to the drug, but not to whether the organism induces a specific intracellular life cycle within mammalian cells. Tafenoxane, with similar potency (<4 μmol / L, Yardley et al., 2010; Carvahlo et al., 2015), kills the extracellular blood phase of Trypanosoma brusie and Leishmania. Leishmania majorThe intracellular aflagellated form of tafenoxanil; Dow's U.S. Patent Application Publication No. 2021-0267963 discloses that tafenoxanil has significantly lower activity against independently living Gram-negative bacteria than against independently living Gram-positive bacteria. Therefore, an organism's sensitivity to tafenoxanil does not depend on whether the organism has an obligate intracellular life cycle in mammalian cells. Thus, obligate intracellular bacteria (rickettsiae, apoplastics, erythrozoites, babesiella) and bacteria believed to primarily exhibit an extracellular life cycle (borreliforms) may both be sensitive to tafenoxanil.

[0153] Example 9 – Borrelia and other spirochetes are susceptible to the effects of hydrogen peroxide. Although Borrelia burgdorferi are Gram-negative bacteria, and based on previous research (Dow's U.S. Patent Application Publication No. 2021-0267963), they may be considered resistant to tafenoxanil. However, some (but not all) Borrelia burgdorferi are susceptible to hydrogen peroxide, and this susceptibility may be enhanced under certain physiological conditions. For example, a 2017 study by Ramsey et al. showed that treatment with hydrogen peroxide as low as 62.5 μmol / L for 4 hours inhibited the growth of strain B31 5A18NP1; a 1991 study by Sambri et al. showed that enhanced iron uptake makes Borrelia burgdorferi more susceptible to hydrogen peroxide; and a 2016 study by Showman et al. showed that strains with mutations in oxidation response genes and higher susceptibility to hydrogen peroxide were less infectious to mammalian hosts.

[0154] Studies by Steiner et al. (1984) showed that treatment with hydrogen peroxide at concentrations of 50 μmol / L or 100 μmol / L for 2 hours in a 3% oxygen atmosphere significantly inhibited the growth of Treponema pallidum (syphilis). Treponema palludum ) growth.

[0155] Studies by Murgia et al. have shown that exposure to exogenous hydrogen peroxide at a concentration of <180 μmol / L for only 30 minutes can kill Leptospira ( Leptospira (Multiple serotypes)

[0156] These data indicate that although spirochetes are Gram-negative bacteria, they are still susceptible to tafenoxane-like mechanisms of action under certain conditions. It is anticipated that combination therapy with standard treatment regimens such as doxycycline will enhance the susceptibility of tick-borne spirochetes to tafenoxane.

[0157] Example 10 – Tafenoquine is active against Babesia spp. in animal models. Studies by Liu et al. have shown that treatment of Rhodesian Balb / c mice infected with Babesia rubescens (immune-normal mice) with a single dose of 20 mg / kg tafenoxanone cleared parasitemia and achieved 100% survival, while untreated animals were fatal after infection. In immunocompromised SCID mice, a single dose of 20 mg / kg tafenoxanone cleared initial parasitemia but did not prevent relapse—thus delaying death rather than preventing it as in immunocompetent Balb / c mice.

[0158] In splenectomized dogs infected with Babesia gibsoni, parasitemia was cleared and mortality was prevented after single-dose administration of 100 mg ARAKODA tablets (9–11.5 mg / kg) on ​​days 12, 19, and 48. Dogs given tafenoxanone also experienced relief of infection symptoms such as loss of appetite, rapid breathing, and rapid pulse. The equivalent human dosing regimen, adjusted for body surface area, would be approximately 4–6 mg / kg / day for 3 days; for a 70 kg human, the regimen would be 280–420 mg / day for 3 days.

[0159] Example 11 – Babesia was cured in a patient who had failed all other treatments (the patient was considered to have normal immune function at the time) through a prophylactic administration of tafenoxanil. A hospitalized patient with Babesia microsporum infection, suspected to have experienced immunosuppression due to prior rituximab treatment, relapsed twice after receiving azithromycin + atovaquine, and then relapsed a third time after receiving azithromycin + atovaquine + clindamycin. The fourth round of chemotherapy, high-dose malarone + atovaquine + clindamycin + azithromycin, was subsequently discontinued due to adverse events. Following this, a six-week course of malaria prophylaxis with an approved dose of tafenoxanone as monotherapy resulted in a cure. This case example demonstrates the potential utility of FDA-approved tafenoxanone regimens in the treatment of human Babesia disease.

[0160] Example 12 – The effectiveness of antimalarial drugs in non-immune populations cannot be predicted based on their effective dose in semi-immune populations. Given the complexity, cost, and risks of new drug development, it is crucial that, where possible, drug regimens be effective for both immunocompetent and immunocompromised populations.

[0161] In the case of malaria, semi-immune individuals develop resistance to the symptoms of malaria and usually do not develop clinical malaria. However, these semi-immune individuals can still be infected with the parasites that cause malaria, which can be observed under a microscope in blood samples. When the presence of malaria parasites is confirmed microscopically, non-immune malaria individuals have not been adequately exposed to malaria and therefore cannot develop immunity to the signs and symptoms of malaria. Non-immune malaria individuals who have never been exposed to malaria may also be susceptible to malaria.

[0162] For malaria drugs, based on clinical study data involving semi-immune populations, it is impossible to predict whether the drug will have a useful preventive effect in non-immune or malaria-susceptible subjects. Azithromycin showed lower activity in non-immune / malaria-susceptible subjects than in semi-immune subjects, and its efficacy was far below the standard of care for further development of azithromycin (even 20 years after the completion of relevant clinical studies, azithromycin has not been approved by the FDA for malaria prevention). The table below highlights two studies on azithromycin: Andersen et al., Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya 26(1) CUN INFECT Dis (1998) 146-50 and Taylor et al., Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in / rain Jaya, Indonesia 28(1) CUN INFECT Dis (1999) 74-81. These data suggest that for some drugs, even at doses known to be safe and effective for other indications, it is impossible to predict effective prevention of Plasmodium falciparum (a mosquito-borne parasite that causes malaria) in susceptible subjects.

[0163] Table 2: Prophylactic efficacy of azithromycin against Plasmodium falciparum in different immune status populations

[0164] Example 13 – Tafenoxane shows promise for the effective treatment of babesiosis in outpatients and inpatients, regardless of their immune status. Patients with babesiosis are treated with a combination of azithromycin-atorvaquinone or clindamycin-quinine for 7-10 days. In most patients with normal immune function, these regimens can reduce parasitemia to a level that the patient's immune system can clear within 12 months (Krause 2008, Krause 2021). In immunocompromised patients, the immune system cannot clear residual parasitemia, which may lead to relapse, requiring multiple rounds of antimicrobial therapy, and increasing the risk of death and complications (Krause 2008).

[0165] Among hospitalized patients with babesiosis, they may have a range of immune functions from normal to severely immunodeficient. These patients have a low mortality rate (1.6%) but a high risk of complications such as red blood cell transfusion (20%), renal failure (20%), respiratory failure (6.8%), and heart failure (3.5%) (Bloch 2022).

[0166] Administering an 800 mg dose of tafenoxane according to any of the dosage regimens listed in Table 1 is expected to demonstrate the following clinical benefits in these populations: Outpatients Tafenoxane monotherapy is expected to be administered in a manner similar to standard treatment, meaning that in most patients the parasite burden will be largely cleared by day 28 without the need for additional rounds of antibiotic therapy.

[0167] Inpatients Tafenoxane, when used in combination with any standard treatment regimen, is expected to reduce the risk of complications (such as red blood cell transfusion, renal failure, respiratory failure, and heart failure) and shorten the parasite clearance time compared to standard treatment regimens.

[0168] - Immunocompromised patients Tafenoxane, when used in combination with any standard treatment regimen for immunocompromised patients (regardless of the treatment context), is expected to reduce the risk of additional rounds of antimicrobial therapy, as well as the risk of hematologic, pulmonary, and renal complications.

[0169] - When used in combination with artesunate or artemether-fluorenol, a 3-day dosing regimen of tafenoxane (200 mg / day for 3 days) is expected to provide the same benefits as the 800 mg tafenoxane regimen without requiring any combination with standard treatment.

[0170] Example 14 – Tafenoxane shows promise as a post-exposure prophylaxis against tick-borne diseases. Tick ​​bites are a transmission mechanism for many protozoa and rickettsiae that cause a variety of diseases with significant morbidity, including Lyme disease, babesiosis, erythrozoonosis, and aplasmosis. Administering a single dose of doxycycline to asymptomatic individuals within 72 hours of a tick bite as post-exposure prophylaxis to prevent Lyme disease is an acceptable treatment. Currently, there are no post-exposure prophylaxis measures for babesiosis or other tick-borne diseases.

[0171] Due to the combined action of various protozoa, fungi, and bacteria through a mechanism similar to the hydrogen peroxide effect, and the vulnerability of Babesia and spirochetes to hydrogen peroxide, tafenoxanone, with its long half-life and favorable safety profile, is expected to provide the following benefits when administered as a post-exposure prophylaxis following tick bites at single or cumulative doses <800 mg as listed in Table 1: - Monotherapy can reduce the risk of babesiosis infection.

[0172] - Monotherapy can reduce the risk of infection with tick-borne microorganisms that do not cause Lyme disease or babesiosis.

[0173] - Combined treatment with doxycycline can simultaneously prevent Lyme disease, babesiosis, and other tick-borne diseases.

[0174] Example 15 – FDA-approved malaria prophylaxis drugs will prevent babesiosis and other tick-borne diseases in populations at high risk of exposure to infected ticks. The approved dose of tafenoxane for the prevention of malaria (200 mg / day for 3 days, followed by 200 mg once a week) is expected to reduce the risk of babesiosis, and / or Lyme disease, and / or rickettsialosis and / or other tick-borne diseases when administered prophylactically to populations at high risk of tick bite infection.

[0175] Example 16 – Tafenoxine is expected to be active in animal models, either alone or in combination with standard treatment regimens. In suitable tick-borne spirochetal animal models (such as Borrelia, Rickettsia, Ehrlich, and Aplasticis), tafenoxanone administered as monotherapy at doses of 50 mg / kg or less three times, or in combination with standard treatment regimens (doxycycline, azithromycin-atorvaquinone, etc.), is expected to improve survival, reduce microbial burden, decrease persistent infection, and reduce antibiotic resistance. This may occur in specific cases of Lyme disease due to the drug's activity against its usual extracellular form and / or intracellular form in macrophages, endothelial cells (and possibly other cells).

[0176] Example 17 – Human infections caused by tick-borne pathogens are expected to be affected by tafenoxanone at the same dosage as described in Example 13. Standard treatment regimens for human tick-borne diseases such as Lyme disease, Rocky Mountain spotted fever, and aplasmosis (and other diseases) are not perfect because they do not achieve eradication in a minority of patients, or because spirochetes persist naturally or develop resistance to antibiotics. Given tafenoxane's synergistic mechanism of action against multiple pathogenic species, its long half-life, and favorable safety profile, it is anticipated that combining standard treatment regimens with the doses of tafenoxane listed in Example 13 for the treatment of patients with one or more of these infections will, compared to standard treatment, reduce hospitalization complications, and / or shorten microbial clearance time, and / or reduce persistent infection / antimicrobial tolerance, and / or reduce retreatment rates.

[0177] The teachings of all patents, publications and references cited herein are incorporated herein by reference in their entirety for all purposes.

[0178] Although the invention has been shown and described in particular in conjunction with its exemplary embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of protection of the invention as defined by the appended claims.

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Claims

1. A method for treating tick-borne diseases or symptoms thereof in human subjects, the method comprising administering to a subject in need an effective amount of long half-life 8-aminoquinoline, wherein the tick-borne disease is caused by a parasite of the babesiidae family.

2. The method according to claim 1, wherein the tick-borne disease is babesiosis.

3. The method according to claim 1 or 2, wherein the subject has been diagnosed with a babesi parasite prior to the administration of the drug.

4. The method according to claim 1, 2 or 3, wherein the subject is co-infected with a spirochetal spirochete.

5. The method according to any one of claims 1 to 4, wherein the long half-life 8-aminoquinoline is capable of treating the tick-borne disease with the minimum single dose or initial dose in a regimen of 50 mg.

6. The method according to any one of claims 1 to 4, wherein the long half-life 8-aminoquinoline is tafenoxane or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the effective amount of the long half-life 8-aminoquinoline is selected from one of the following: (a) The initial dose is 50 mg, followed by an additional 50 mg dose within one week after the initial dose; (b) The initial dose is 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) The initial dose is 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) The initial dose is 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) The initial dose is 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) One dose of 400mg; (g) A loading dose of 600 mg is administered over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) Administer a loading dose of 600 mg over 1–5 days via the following routes of administration: (i) 6 x 100 mg doses, or (ii) 4 x 150 mg doses, or (iii) 3 x 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

8. The method according to any one of claims 1 to 6, wherein the effective amount of the long half-life 8-aminoquinoline is about 200 mg daily for four days, wherein the daily dose may be a single dose or divided doses.

9. The method according to any one of claims 1 to 8, comprising administering the long half-life 8-aminoquinoline via one or more of the sublingual, oral, and intravenous routes.

10. The method according to any one of claims 1 to 9, wherein the long half-life 8-aminoquinoline administered to the subject within twelve months does not exceed 11,000 mg.

11. The method according to any one of claims 1 to 10, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

12. The method of claim 11, wherein the subject is a symptomatic hospitalized patient.

13. The method according to any one of claims 1 to 12, wherein the subject has been diagnosed with at least one of Babesia infection and Babesia disease, wherein the diagnosis includes laboratory tests confirming at least one of Babesia infection and Babesia disease.

14. A method for treating a tick-borne disease or its symptoms in a human subject, the method comprising administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), Where R is any halogenated substituent with a molecular weight ≤205; The tick-borne diseases mentioned above are caused by parasites of the Babesia genus.

15. The method of claim 14, wherein the tick-borne disease is babesiosis.

16. The method of claim 14 or 15, wherein the subject has been diagnosed with a Babesia parasite prior to the administration of the drug.

17. The method according to claim 14, 15 or 16, wherein the subject is co-infected with a spirochetal parasite.

18. The method according to any one of claims 14 to 17, wherein the effective amount of the compound of formula (I), its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the compound of formula (I) is selected from one of the following: (a) The initial dose is 50 mg, followed by an additional 50 mg dose within one week after the initial dose; (b) The initial dose is 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) The initial dose is 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) The initial dose is 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) The initial dose is 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) One dose of 400mg; (g) A loading dose of 600 mg is administered over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) Administer a loading dose of 600 mg over 1–5 days via the following routes of administration: (i) 6 x 100 mg doses, or (ii) 4 x 150 mg doses, or (iii) 3 x 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

19. The method according to any one of claims 14 to 17, wherein the effective amount of the compound of formula (I), its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the compound of formula (I) is about 200 mg daily for four days, wherein the daily dose may be a single dose or divided doses.

20. The method according to any one of claims 14 to 19, wherein the subject is administered the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) via one or more of the sublingual, oral, and intravenous routes.

21. The method according to any one of claims 14 to 20, wherein the amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) administered to the subject within twelve months does not exceed 11,000 mg.

22. The method according to any one of claims 14 to 21, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

23. The method of claim 22, wherein the subject is a symptomatic hospitalized patient.

24. The method according to any one of claims 14 to 23, wherein the subject has been diagnosed with at least one of Babesia infection and Babesia disease, wherein the diagnosis includes laboratory tests confirming at least one of Babesia infection and Babesia disease.

25. A method for treating a tick-borne disease or symptoms thereof in a human subject, the method comprising administering tafenoxane to the subject in need, wherein the tick-borne disease is caused by a parasite of the babesiidae species.

26. The method of claim 25, wherein the tick-borne disease is babesiosis.

27. The method of claim 25 or 26, wherein the subject has been diagnosed with a Babesia parasite prior to the administration of the drug.

28. The method according to claim 25, 26 or 27, wherein the subject is co-infected with a spirochetal parasite.

29. The method according to any one of claims 25 to 28, wherein the tafenoxine is administered to the subject according to one of the following regimens: (a) The initial dose is 50 mg, followed by an additional 50 mg dose within one week after the initial dose; (b) The initial dose is 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) The initial dose is 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) The initial dose is 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) The initial dose is 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) One dose of 400mg; (g) A loading dose of 600 mg is administered over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) Administer a loading dose of 600 mg over 1–5 days via the following routes of administration: (i) 6 x 100 mg doses, or (ii) 4 x 150 mg doses, or (iii) 3 x 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

30. The method according to any one of claims 25 to 28, comprising administering tafenoxane to the subject at about 200 mg daily for four days, wherein the daily dose may be a single dose or divided doses.

31. The method according to any one of claims 25 to 30, wherein the administration of tafenoxine is selected from one or more routes including sublingual, oral, and intravenous.

32. The method according to any one of claims 35 to 31, wherein the amount of tafenoxane administered to the subject within twelve months does not exceed 11,000 mg.

33. The method according to any one of claims 25 to 32, further comprising administering a second or third agent to the subject, the second or third agent being selected from one or more of doxycycline, azithromycin-atorvaquinone, clindamycin-quinine, artesunate, artemether-phenfluoreneol, and any other agents recommended by IDSA or CDC for the treatment of nonviral tick-borne diseases.

34. The method according to any one of claims 25 to 33, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

35. The method of claim 34, wherein the subject is a symptomatic hospitalized patient.

36. The method according to any one of claims 25 to 35, wherein the subject has been diagnosed with at least one of Babesia infection and Babesia disease, wherein the diagnosis includes laboratory tests confirming at least one of Babesia infection and Babesia disease.

37. Use of an effective amount of long-half-life 8-aminoquinoline for the treatment of tick-borne diseases or symptoms caused by parasites of Babesia in human subjects.

38. The use according to claim 37, wherein the long half-life 8-aminoquinoline is a compound of formula (I), Where R is any halogenated substituent with a molecular weight ≤205; or a pharmaceutically acceptable salt thereof.

39. The use according to claim 37, wherein the long half-life 8-aminoquinoline is tafenquin or a pharmaceutically acceptable salt thereof.

40. The use according to any one of claims 37 to 39, wherein the tick-borne disease is babesiosis.

41. The use according to any one of claims 37 to 40, wherein the subject has been diagnosed with infection with a Babesia parasite prior to the administration of the drug.

42. The use according to any one of claims 37 to 41, wherein the subject is co-infected with a spirochetal parasite.

43. The use according to any one of claims 37 to 42, wherein the long-half-life 8-aminoquinoline is administered to the subject according to one of the following regimens: (a) The initial dose is 50 mg, followed by an additional 50 mg dose within one week after the initial dose; (b) The initial dose is 100 mg, followed by at least one and up to five additional doses within one week of the initial dose; (c) The initial dose is 150 mg, followed by at least one and at most four additional doses within one week of the initial dose; (d) The initial dose is 200 mg, followed by at least one and at most three additional doses within 15 days of the initial dose; (e) The initial dose is 300 mg, followed by an additional 300 mg dose within one week of the initial dose; (f) One dose of 400mg; (g) A loading dose of 600 mg is administered over 1–5 days via the following routes of administration: (i) six 100 mg doses, or (ii) four 150 mg doses, or (iii) three 200 mg doses; followed by a maintenance dose of 200 mg over 12 days of the initial loading dose; and (h) Administer a loading dose of 600 mg over 1–5 days via the following routes of administration: (i) 6 x 100 mg doses, or (ii) 4 x 150 mg doses, or (iii) 3 x 200 mg doses; followed by a maintenance dose of 200 mg for one week after the loading dose is completed, and then 200 mg once weekly for up to 52 weeks.

44. The use according to any one of claims 37 to 42, comprising administering to the subject about 200 mg of long half-life 8-aminoquinoline daily for four days, wherein the daily dose may be a single dose or divided doses.

45. The use according to any one of claims 37 to 44, comprising administering the long half-life 8-aminoquinoline to the subject via one or more of the sublingual, oral, and intravenous routes.

46. ​​The use according to any one of claims 37 to 45, wherein the long half-life 8-aminoquinoline administered to the subject within twelve months does not exceed 11,000 mg.

47. The use according to any one of claims 37 to 46 further comprises administering one or more additional agents to the subject, said additional agents being selected from doxycycline, azithromycin-atorvaquinone, clindamycin-quinine, artesunate, artemether-phenfluorene, and any other agents recommended by IDSA or CDC for the treatment of nonviral tick-borne diseases.

48. The use according to any one of claims 37 to 47, wherein the subject is a symptomatic outpatient or a symptomatic inpatient.

49. The use according to any one of claims 37 to 48, wherein the subject has been diagnosed with at least one of Babesia infection and Babesia disease, the diagnosis being confirmed by laboratory testing confirming at least one of Babesia infection and Babesia disease.

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