WO2017201030A1 - Procédés de traitement d'une infection virale - Google Patents

Procédés de traitement d'une infection virale Download PDF

Info

Publication number
WO2017201030A1
WO2017201030A1 PCT/US2017/032875 US2017032875W WO2017201030A1 WO 2017201030 A1 WO2017201030 A1 WO 2017201030A1 US 2017032875 W US2017032875 W US 2017032875W WO 2017201030 A1 WO2017201030 A1 WO 2017201030A1
Authority
WO
WIPO (PCT)
Prior art keywords
hours
virus
grams
single administration
influenza
Prior art date
Application number
PCT/US2017/032875
Other languages
English (en)
Inventor
Anthony Michael TRESTON
Kelly Lyn Warfield
Original Assignee
Emergent Virology Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Emergent Virology Llc filed Critical Emergent Virology Llc
Publication of WO2017201030A1 publication Critical patent/WO2017201030A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention generally relates to methods of treating or preventing viral infection such as Influenza virus infection or Dengue virus infection.
  • Pandemic, zoonotic and seasonal Influenza viruses remain a significant global threat to human health. Continuous evolution of Influenza viruses via both drift and shift in the viral genome results in generation of new Influenza virus strains each year and the potential for dangerous pandemics due to lack of immunity to these emerging, divergent viruses.
  • Dengue virus belongs to the genus Flavivirus of the Flaviviridae family and causes dengue hemorrhagic fever (DHF).
  • Dengue virus includes four closely related serotypes, usually referred to as Dengue 1, Dengue 2, Dengue 3, and Dengue 4. Recovery from infection by one provides lifelong immunity against that serotype but confers only partial and transient protection against infection by the other three. Current evidence suggests that sequential infection with different serotypes of Dengue increases the risk of more serious disease including DHF.
  • Dengue is transmitted primarily by the Aedes aegypti mosquito and is the most common mosquito-borne viral disease of humans. Globally, 2.5 billion people— 40% of the world's population— live in the warm areas where Aedes aegypti is common and dengue can be transmitted. The rapid growth of tropical cities and their human and mosquito populations is bringing ever greater numbers of people into contact with this vector. The geographical spread of both the mosquito vectors and the virus has led to a global increase in epidemic dengue fever and the emergence of dengue hemorrhagic fever (DHF). Thus, novel antiviral treatments for Dengue infection are also needed.
  • DHF dengue hemorrhagic fever
  • the present invention provides a method for treating or preventing Influenza virus infection.
  • the method is for treating or preventing a disease or condition caused by or associated with an Influenza virus in a subject such as a human subject in need thereof.
  • the method comprises administering to the human subject an amount of N-(9- methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof over a period of time not exceeding 48 hours.
  • the amount ranges from at least 1.1 grams to about 30 grams over the 48 hours.
  • the method comprises administering to the subject in a first single administration step a first dose of N-(9-methoxynonyl)deoxynojirimycin (UV-4) or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • UV-4 N-(9-methoxynonyl)deoxynojirimycin
  • the first dose ranges from at least 1.1 grams to about 10 grams such as about 2 grams to about 5 grams.
  • the first single administration is the only administration of N-(9-methoxynonyl)deoxynojirimycin to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • this disclosure provides a method of treating or preventing a disease or condition caused by or associated with an Influenza virus in a human subject in need thereof, the method comprising administering to the human subject in a first single administration step a first dose of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the first dose ranges from at least 1.1 grams to about 10 grams; and wherein the first single
  • the Influenza virus is an Influenza A virus, Influenza B virus, or Influenza C virus.
  • the Influenza virus is Influenza A virus.
  • the Influenza A virus is an HI, H2, H3, H5, H7, H9, or H10 subtype.
  • the Influenza virus can be an H1N1 subtype of the Influenza A virus.
  • the Influenza virus is an H3N2 subtype of the Influenza A virus.
  • the Influenza virus is an Influenza B virus.
  • UV-4 or a pharmaceutically acceptable salt thereof can be administered in the methods of this disclosure according to various dosing regimens which vary parameters such as dosing frequencies, amounts, and time points of administration relative to infection.
  • the first dose of N-(9-methoxynonyl)deoxynojirimycin or equivalent amount of a pharmaceutically acceptable salt thereof ranges from about 2 grams to about 5 grams.
  • the first single administration step takes place up to about 24 hours before or up to about 72 hours after exposure to the Influenza virus. In some embodiments, the first single administration step takes place about 4 hours to about 24 hours after the subject is infected with or exposed to the Influenza virus.
  • the first single administration step takes place about 4 hours to about 12 hours after the subject is infected with or exposed to the Influenza virus. In some embodiments, the first single administration step takes place about 1 hour to about 8 hours before the subject is exposed to the Influenza virus. In some embodiments, the first single administration step takes place (a) within 48 hours of the human subject showing symptoms of Influenza virus infection; (b) within 48 hours of the human subject being diagnosed as infected with the Influenza virus; c) within 48 hours of the human subject being exposed or expected to be exposed to Influenza virus; or (d) within 24 or 48 hours before the human subject is exposed or expected to be exposed to the Influenza virus.
  • the first single administration step takes place (a) within 48 hours of the human subject showing symptoms of Influenza virus infection; (b) within 48 hours of the human subject being diagnosed as infected with the Influenza virus; (c) within 48 hours of the human subject being exposed to Influenza virus; or (d) within 12 or 48 hours before the human subject is exposed or expected to be exposed to the Influenza virus.
  • the first single administration step takes place (a) within 24 hours of the human subject showing symptoms of Influenza virus infection; (b) within 24 hours of the human subject being diagnosed as infected with the Influenza virus; (c) within 24 hours of the human subject being exposed to Influenza virus; or (d) within 12 or 24 hours before the human subject is exposed or expected to be exposed to the Influenza virus. In some embodiments, the first single administration step takes place within about 4 hours to about 12 hours of the human subject showing symptoms of Influenza virus infection or within about 4 hours to about 12 hours of the human subject being exposed to or diagnosed as infected with the Influenza virus.
  • the first single administration is the only administration of N-(9-methoxynonyl)deoxynojirimycin to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the method further comprises administering from 1.1 grams to 10 grams, or from about 2 grams to 5 grams of a second dose of N-(9- methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof about 8 to about 24 hours after the first single administration step, wherein the second dose is administered in a second single administration step.
  • the method further comprises administering from 1.1 grams to about 10 grams, or from about 2 grams to about 5 grams of a third dose of N-(9- methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof about 8 to about 24 hours after the second single administration step, wherein the third dose is administered in a third single administration step. In some embodiments, no more than 1, 2 or 3 doses or administrations are given.
  • UV-4 can be administered in the methods of this disclosure in various salt forms and formulations.
  • N-(9-methoxynonyl)deoxynojirimycin is administered as N-(9-methoxynonyl)deoxynojirimycin hydrochloride.
  • the N-(9-methoxynonyl)deoxynojirimycin hydrochloride is administered in an amount equivalent to an amount from at least 1.1 grams to about 10 grams of N-(9- methoxynonyl)deoxynojirimycin.
  • the N-(9- methoxynonyl)deoxynojirimycin or the pharmaceutically acceptable salt thereof is formulated in a dosage form including but not limited to an aqueous oral solution, tablet, or capsule.
  • the present invention also provides a method for treating or preventing Dengue virus infection.
  • the method is for treating or preventing a disease or condition caused by or associated with a Dengue virus in a subject such as a human subject in need thereof.
  • the method comprises administering to the human subject an amount of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof over a period of time not exceeding 48 hours. In some embodiments, the amount ranges from at least 1.1 grams to about 30 grams over the 48 hours.
  • the method comprises administering to the subject in a first single administration step a first dose of N-(9- methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first dose ranges from about 20 mg/kg body weight to about 100 mg/kg body weight.
  • the first dose ranges from at least 1.1 grams to about 10 grams (e.g., about 2 grams to about 5 grams).
  • the first single administration is the only administration of N-(9- methoxynonyl)deoxynojirimycin to treat or prevent the disease or condition caused by or associated with the Dengue virus.
  • this disclosure provides a method of treating or preventing a disease or condition caused by or associated with a Dengue virus in a human subject in need thereof, the method comprising administering to the human subject in a first single administration step a first dose of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the first dose ranges from about 20 mg/kg body weight to about 100 mg/kg body weight.
  • a first dose of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof wherein the first dose ranges from about 20 mg/kg body weight to about 100 mg/kg body weight.
  • one way to calculate human doses can be based on body surface area. See e.g., Guidance for Industry issued by the United States Food and Drug
  • the first dose can range from about 740 mg/m 2 to about 3700 mg/m 2 body surface area.
  • the first dose of drug administered to a human can be at least 1.1 grams to about 10 grams. In other embodiments, the first dose of drug administered to a human can range from about 2 grams to about 5 grams.
  • the Dengue virus is a Dengue 1 virus. In some embodiments, the Dengue virus is a Dengue 2 virus. In some embodiments, the Dengue virus is a Dengue 3 virus. In some embodiments, the Dengue virus is a Dengue 4 virus.
  • UV-4 or a pharmaceutically acceptable salt thereof can be administered in the methods of this disclosure according to various dosing regimens which vary parameters such as dosing frequencies, amounts, and time points of administration relative to infection.
  • the first single administration step takes place up to about 24 hours before or up to about 72 hours after exposure to the Dengue virus. In some embodiments, the first single administration step takes place about 4 hours to about 24 hours after the human subject is infected with or exposed to the Dengue virus. In some embodiments, the first single administration step takes place about 4 hours to about 12 hours after the human subject is infected with or exposed to the Dengue virus. In some embodiments, the first single administration step takes place about 1 hour to about 8 hours before the human subject is exposed to the Dengue virus.
  • the first single administration step takes place (a) within 48 hours of the human subject showing symptoms of Dengue virus infection; or (b) within 48 hours of the human subject being diagnosed as infected with the Dengue virus; (c) within 48 hours of the human subject being exposed to the Dengue virus; or (d) within 24 hours before the human subject is exposed or expected to be exposed to the Dengue virus.
  • the first single administration step takes place (a) within 24 hours of the human subject showing symptoms of Dengue virus infection; (b) within 24 hours of the human subject being diagnosed as infected with the Dengue virus; (c) within 24 hours of the human subject being exposed to the Dengue virus; or (d) within 12 or 24 hours before the human subject is exposed or expected to be exposed to the Dengue virus.
  • the first single administration step takes place within about 4 hours to about 24 hours of the human subject showing symptoms of Dengue virus infection or within about 4 hours to about 24 hours of the subject being diagnosed as infected with the Dengue virus.
  • the first single administration step takes place within about 4 hours to about 12 hours of the human subject showing symptoms of Dengue virus infection or within about 4 hours to about 12 hours of the subject being diagnosed as infected with the Dengue virus.
  • the first single administration is the only administration of
  • the method further comprises administering from about 20 mg/kg body weight to about 100 mg/kg, body weight, or from about 740 mg/m 2 to about 3700 mg/m 2 body surface area, or from 1.1 grams to about 10 grams, or from about 2 grams to 5 grams of a second dose of N-(9- methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof about 8 to about 24 hours after the first single administration step, wherein the second dose is administered in a second single administration step.
  • the method further comprises administering from about 20 mg/kg body weight to about 100 mg/kg, body weight, or from about 740 mg/m 2 to about 3700 mg/m 2 body surface area, or from 1.1 grams to 10 grams, or from about 2 grams to 5 grams of a third dose of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof about 8 to about 24 hours after the second single administration step, wherein the third dose is administered in a third single administration step.
  • N-(9-methoxynonyl)deoxynojirimycin can be administered in the methods of this disclosure in various salt forms and formulations.
  • the N-(9- methoxynonyl)deoxynojirimycin in the first single administration step is administered as N-(9-methoxynonyl)deoxynojirimycin hydrochloride.
  • the N-(9- methoxynonyl)deoxynojirimycin in the second and/or third single administration step is administered as N-(9-methoxynonyl)deoxynojirimycin hydrochloride.
  • the N-(9-methoxynonyl)deoxynojirimycin or the pharmaceutically acceptable salt thereof is formulated in a dosage form including but not limited to an aqueous oral solution, tablet, and capsule.
  • Doses for administration to other species based on doses for mice can be calculated using metrics known to those skilled in the art, including metrics based on body weight, body surface area, or exposure.
  • metrics based on body weight, body surface area, or exposure For example, one way to convert mouse doses to human equivalent dose is based on body surface area. See e.g., Guidance for Industry issued by the Food and Drug Administration, "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers" (July 2005).
  • a mouse dose in mg/kg may be converted into a human equivalent dose in mg/kg by dividing the mouse dose by 12.3. See Table 1, page 7.
  • FIGs. 1A-1C show results of an in vivo study against Influenza A (H1N1)
  • FIG. 1A shows the survival data over the course of the study.
  • FIGs. IB and 1C show weight loss data and health scores over the course of the study, respectively.
  • FIG. 2 shows survival data of an in vivo study against Influenza A (H1N1)
  • FIG. 3 shows survival data of an in vivo study against Influenza A (H1N1) infection in which mice were administered a single dose of 500 mg/kg - 1,000 mg/kg UV- 4B at various time points relative to infection compared to 100 mg/kg TID for 5 days.
  • FIGs. 4A and 4B show survival data of an in vivo study against Influenza A
  • H1N1 infection in which mice were administered multiple (two (FIG. 4A) or three (FIG. 4B)) doses of 250 mg/kg - 750 mg/kg UV-4B at various time points relative to infection compared to 100 mg/kg TID for 5 days.
  • FIG. 5 shows survival data of an in vivo study against Influenza A (H3N2sw) infection in which mice were administered a single dose of 100 mg/kg - 1,000 mg/kg UV- 4B at 8 hours post-infection.
  • FIG. 6 shows survival data of an in vivo study against Influenza B/Sichuan
  • mice were administered a single dose of 100 mg/kg - 1,000 mg/kg UV- 4B at 8 hours post-infection.
  • FIGs. 7A and 7B show results of an in vivo study against Dengue virus infection in which mice were administered a single dose of 100 mg/kg - 1,000 mg/kg UV-4B at 8 hours post-infection.
  • FIG. 7A shows the survival data over the course of the study.
  • FIG. 7B shows the weight loss data over the course of the study.
  • FIGs. 8A-8E show results of an in vivo study against Dengue virus infection, in which mice were administered a single dose or multiple doses of 250 mg/kg - 750 mg/kg UV-4B at various time points relative to infection.
  • FIG. 9 shows viral load data of an in vivo study against Dengue 2 infection in which mice were administered a single dose of 750 mg/kg UV-4B at 36 hours postinfection or two doses of 750 mg/kg UV-4B at 36 hours and 52 hours post-infection.
  • FIG. 10 shows Dengue 2 viral load data from an in vivo mouse study described in
  • Example 10 in which mice were administered a single dose of 750 mg/kg UV-4B at 36 hours post-infection or two doses of 750 mg/kg UV-4B at 36 hours and 52 hours postinfection.
  • FIGs. 11A and 11B show levels of IFN- ⁇ and IL- ⁇ in UV-4B treated and water only treated mice from the in vivo study described in Example 10, respectively.
  • FIGs. 12A and 12B show levels of IL-6 and IL- 10 in UV-4B treated and water only treated mice from the in vivo study described in Example 10, respectively.
  • FIGs. 13A and 13B show levels of IL-12/IL-23p40 and IL-17A in UV-4B treated and water only treated mice from the in vivo study described in Example 10, respectively.
  • FIGs. 14A and 14B show levels of IL-22 and KC-GRO in UV-4B treated and water only treated mice from the in vivo study described in Example 10, respectively.
  • FIGs. 15A and 15B show levels of VEGF-A and T F-a in UV-4B treated and water only treated mice from the in vivo study described in Example 10.
  • tolerance in the art and not more than ⁇ 10% of a stated value By way of example only, about 50 means from 45 to 55 including all values in between. As used herein, the phrase "about" a specific value also includes the specific value, for example, about 50 includes 50.
  • a viral "infection” describes a diseased state in which a virus such as Influenza virus or Dengue virus invades a healthy cell and uses the cell's machinery to multiply or replicate, ultimately resulting in release of viral particles. This release results in the infection of other cells by the newly produced particles. Latent infection by certain viruses is also a possible result of viral infection.
  • Influenza refers to an infectious disease caused by an
  • Influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae: Influenzavirus A, Influenzavirus B, and Influenzavirus C.
  • the Influenzavirus A genus includes a single species, Influenza A virus, which can cause influenza in birds and certain mammals, including humans, pigs, felines, canines and equines.
  • the Influenzavirus B genus includes a single species, Influenza B virus, which can cause influenza in humans and seals.
  • the Influenzavirus C genus includes a single species, Influenza C virus, which can cause influenza in humans and pigs.
  • Influenza A viruses are negative sense, single-stranded, segmented RNA viruses.
  • Influenza A virus can cause influenza in birds and certain mammals, including humans, pigs, felines, canines and equines.
  • Serotypes and subtypes of Influenza A include H1N1 Influenza A; H1N2 Influenza A; H2N2 Influenza A; H3N1 Influenza A; H3N2 Influenza A; H3N8 Influenza A; H5N1 Influenza A; H5N2 Influenza A; H5N3 Influenza A; H5N8 Influenza A; H5N9 Influenza A; H5N9 Influenza A; H7N1 Influenza A; H7N2 Influenza A; H7N3 Influenza A; H7N4 Influenza A; H7N7 Influenza A; H9N2 Influenza A; H10N7 Influenza A.
  • Dengue virus refers to a dengue virus.
  • Dengue virus belongs to the genus Flavivirus of the Flaviviridae family and includes four closely related serotypes, usually referred to as Dengue 1, Dengue 2, Dengue 3, and Dengue 4.
  • the term “treating” refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disease or disorder.
  • “treating" a disease or condition caused by or associated with Influenza virus or Dengue virus means inhibiting the replication of the virus, inhibiting viral transmission, and/or ameliorating, alleviating, or otherwise improving the symptoms of a disease or condition caused by or associated with the virus.
  • the treatment can be considered therapeutic if there is a reduction in viral load, and/or a decrease in mortality and/or morbidity.
  • preventing refers to precluding a patient from getting a disorder and/or related symptoms, causing a patient to remain free of a disorder and/or related symptoms for a longer period of time, or halting the progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • preventing a disease or condition caused by or associated with Influenza virus or Dengue virus means inhibiting replication of the virus, inhibiting viral transmission, preventing the virus from establishing itself in its host, and/or preventing symptoms related to the particular viral infection.
  • subject(s) refers to any animal that is susceptible to infection with Influenza virus or Dengue virus, e.g., mammals. In some embodiments, the subjects are humans at least two weeks of age or older. Unless otherwise specified, the dosing amounts described herein are for adult subjects, e.g., adult humans. As understood by those skilled in the art, the dosing amounts described herein may be adjusted for a pediatric patient.
  • UV-4" refers to the chemical compound having the structure:
  • UV-4 is known as (2R,3R,4R,5,S)-2-(hydroxymethyl)-l-(9-methoxynonyl)- piperidine-3,4,5-triol or N-(9-methoxynonyl)-deoxynojirimycin or N-(9-methoxynonyl)- l,5-dideoxy-l,5-imino-D-glucitol.
  • UV-4 has been previously described, for example, in U.S. Application Publication No. 2011/0065752, as useful for treating Influenza virus infections. It was likewise described as useful for treating Dengue viral infections in U.S. Patent No. 8,450,345.
  • UV-4 is a basic molecule and acid addition salts of UV-4 can be prepared according to known methods using any known pharmaceutically acceptable acid. That said, and as used herein, all doses or amounts of UV-4 are expressed as the quantity of free base used.
  • UV-4B refers to the hydrochloride salt of UV-4.
  • the phrase "equivalent amount” refers to the amount of a given acid addition salt of UV-4 equivalent to the desired amount of UV-4 free base.
  • the equivalent amount of the hydrochloride salt of lg of UV-4 is about 1.1 lg UV-4B.
  • Various embodiments are directed to a method for treating or preventing Influenza virus infection.
  • this disclosure provides a method of treating or preventing a disease or condition caused by or associated with an Influenza virus in a subject in need thereof.
  • the method comprises administering to the human subject an amount of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof over a period of time not exceeding 48 hours. In certain embodiments, the period of time does not exceed 42 hours, 36 hours, 30 hours, 24 hours, 18 hours, 12 hours, or 6 hours.
  • the amount ranges from at least 1.1 grams to about 30 grams over the 48 hours, provided that at least 1.1 g of N-(9-methoxynonyl)deoxynojirimycin is given within a 24 hour period. In certain embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 grams of N-(9-methoxynonyl)deoxynojirimycin is given within the 24 hour period, e.g., to a human subject.
  • the method comprises administering to the subject in a first single administration step a first dose of UV-4 or an equivalent amount of a
  • the subject is a human subject.
  • the first single administration step is the only administration of UV-4 or the pharmaceutically acceptable salt thereof given to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the first dose of UV-4 or the equivalent amount of the pharmaceutically acceptable salt thereof ranges from at least 1.1 grams to about 10 grams.
  • the first single administration step is followed by a second and/or third administration step.
  • the UV-4 or the pharmaceutically acceptable salt thereof can be formulated for oral administration.
  • the UV-4 or the pharmaceutically acceptable salt thereof is formulated in a dosage form including but not limited to an aqueous oral solution, tablet, or capsule.
  • the UV-4 or pharmaceutically acceptable salt thereof is formulated as an aqueous oral solution in water or other pharmaceutically acceptable vehicle.
  • the UV-4 or pharmaceutically acceptable salt thereof can be formulated in a solid dosage form, such as one or more pills including tablets or capsules.
  • the UV-4 or pharmaceutically acceptable salt thereof can be formulated for parenteral administration, such as for intravenous injection.
  • the administration of UV-4 or the pharmaceutically acceptable salt thereof can be oral administration.
  • the UV-4 is administered as UV-4B in the first single administration step.
  • the methods described in this disclosure can treat or prevent a disease or
  • the Influenza virus is an Influenza A virus, Influenza B virus, Influenza C virus, or a combination thereof. In some embodiments, the Influenza virus is an Influenza A virus. In some embodiments, the Influenza A virus is an HI, H2, H3, H5, H7, H9, or H10 subtype. In some embodiments, the Influenza A virus is an H1N1 subtype of the
  • Other Influenza A viruses are described herein.
  • the Influenza virus can be an Influenza B virus.
  • the Influenza virus can be an Influenza C virus.
  • the methods described herein can also treat or prevent a disease or condition caused by or associated with a oseltamivir (TAMIFLU) resistant Influenza virus infection.
  • TAMIFLU oseltamivir
  • the disease or condition of the methods described herein is acute influenza caused by or associated with the Influenza virus, such as an Influenza A virus Influenza B virus, or Influenza C virus.
  • the disease or condition of the methods described herein is acute influenza caused by or associated with an Influenza A virus, e.g., an HI, H2, H3, H5, H7, H9, or H10 subtype.
  • the disease or condition of the methods described herein is acute influenza caused by or associated with an H1N1 subtype Influenza A virus or an H3N2 subtype Influenza A virus.
  • the methods are directed to the treatment of uncomplicated acute illness due to influenza infection, such as infection with Influenza A virus, Influenza B virus, or Influenza C virus.
  • the methods are directed to the treatment of uncomplicated acute illness due to influenza infection with an Influenza A virus, e.g., an HI, H2, H3, H5, H7, H9, or H10 subtype.
  • the methods are directed to the treatment of uncomplicated acute illness due to influenza infection with an H1N1 subtype Influenza A virus or an H3N2 subtype Influenza A virus.
  • the methods are directed to treating complicated acute illness due to influenza infection.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered in the methods of this disclosure according to various dosing regimens which vary parameters such as dosing frequencies, amounts, and time points of administration relative to infection.
  • UV-4 or the pharmaceutically acceptable salt thereof can be any organic compound [0051]
  • UV-4 or the pharmaceutically acceptable salt thereof can be any organic compound [0051]
  • each single administration may be spaced apart from the next single administration by one or more days.
  • the method comprises administering a first dose of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof, such as UV-4B, in a first single administration step, wherein the first single administration step is the only administration of UV-4 to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the UV-4 or pharmaceutically acceptable salt thereof is administered only once over the course of treatment.
  • the first single administration step is followed by a second single administration step of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first single administration step and the second single administration step are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered only two times over the course of treatment.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, from 2 days to 5 days.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, not exceeding 48 hours.
  • the second single administration step can take place about
  • the second single administration step can take place about 8 hours, about 12 hours, about 16 hours, about 24 hours, about 36 hours, about 48 hours, or any ranges between the recited values, after the first single administration step.
  • the second single administration step takes place about 24 hours after the first single administration step.
  • the second single administration step takes place over 48 hours up to 10 days after the first single administration step.
  • the second single administration step can take place about 3 days, about 4 days, about 5 days, about 7 days, or about 10 days, or any ranges between the recited values, after the first single administration step.
  • the first single administration step is followed by a second single administration step and a third single administration step of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first single administration step, the second single administration step, and the third single administration steps are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered only three times over the course of treatment.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, from 2 days to 5 days.
  • UV-4 or the first single administration step is followed by a second single administration step and a third single administration step of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first single administration step, the second single administration step, and the third single administration steps are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Influenza virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered only three times over the course of treatment.
  • pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, not exceeding 48 hours.
  • the second single administration step can take place
  • the third single administration step can take place about 8 hours to about 48 hours after the second administration step.
  • the third single administration step can take place about 8 hours, about 12 hours, about 16 hours, about 24 hours, about 36 hours, about 48 hours, or any ranges between the recited values, after the second administration step.
  • the third single administration step takes place about 24 hours after the second single
  • the third single administration step can also take place over 48 hours up to 10 days after the second single administration step.
  • the third single administration step can take place about 3 days, about 4 days, about 5 days, about 7 days, or about 10 days, or any ranges between the recited values, after the second single administration step.
  • UV-4 or the pharmaceutically acceptable salt thereof is not administered daily.
  • the amount of UV-4 dosed in a given single administration is at least 100 mg/kg body weight and up to about 1,000 mg/kg body weight, for example, about 120 mg/kg body weight, about 150 mg/kg body weight, about 200 mg/kg body weight, about 250 mg/kg body weight, about 300 mg/kg body weight, about 350 mg/kg body weight, about 400 mg/kg body weight, about 450 mg/kg body weight, about 500 mg/kg body weight, about 550 mg/kg body weight, about 600 mg/kg body weight, about 650 mg/kg body weight, about 700 mg/kg body weight, about 750 mg/kg body weight, about 800 mg/kg body weight, about 850 mg/kg body weight, about 900 mg/kg body weight, about 1,000 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can range from about 20 mg/kg body weight to about 100 mg/kg body weight, e.g., about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, about 100 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration is at least 3700 mg/m 2 body surface area and up to about 37000 mg/m 2 body surface area, for example, 3700 mg/m 2 body surface area, about 5000 mg/m 2 body surface area, about 10000 mg/m 2 body surface area, about 15000 mg/m 2 body surface area, about 20000 mg/m 2 body surface area, about 25000 mg/m 2 body surface area, about 30000 mg/m 2 body surface area, about 35000 mg/m 2 body surface area, about 37000 mg/m 2 body surface area, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can be about 740 mg/m 2 and up to about 3700 mg/m 2 , for example, about 740 mg/m 2 , about 1500 mg/m 2 , about 2000 mg/m 2 , about 2500 mg/m 2 , about 3000 mg/m 2 , about 3500 mg/m 2 , about 3700 mg/m 2 , or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • the amount of UV-4 can be 1.1 grams, about 1.2 grams, about 1.4 grams, about 1.6 grams, about 1.8 grams, about 2 grams, about 2.2 grams, about 2.4 grams, about 2.6 grams, about 2.8 grams, about 3 grams, about 3.2 grams, about 3.4 grams, about 3.6 grams, about 3.8 grams, about 4 grams, about 4.2 grams, about 4.4 grams, about 4.6 grams, about 4.8 grams, about 5 grams, about 5.2 grams, about 5.4 grams, about 5.6 grams, about 5.8 grams, about 6 grams, about 6.2 grams, about 6.4 grams, about 6.6 grams, about 6.8 grams, about 7 grams, about 7.2 grams, about 7.4 grams, about 7.5 grams, about 8 grams, about 8.5 grams, about 9 grams, about 9.5 grams, about 10 grams, or any ranges between the specified values.
  • the amount of UV-4 administered in a given single administration ranges from about 2 grams to about 5 grams.
  • the amount of UV-4 administered in a given single administration can be about 2 grams, about 2.2 grams, about 2.4 grams, about 2.6 grams, about 2.8 grams, about 3 grams, about 3.2 grams, about 3.4 grams, about 3.6 grams, about 3.8 grams, about 4 grams, about 4.2 grams, about 4.4 grams, about 4.6 grams, about 4.8 grams, about 5 grams, or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • Suitable amounts of UV-4 for administration in the methods described herein, such as for the first single administration step, the second or third single administration step as described above, can range from about 20 mg/kg body weight to about 1,000 mg/kg body weight.
  • the amount of UV-4 can range from about 20 mg/kg body weight to about 100 mg/kg body weight, e.g., about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, about 100 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can be about 740 mg/m 2 body surface area and up to about 3700 mg/m 2 body surface area, for example, about 740 mg/m 2 body surface area, about 1500 mg/m 2 body surface area, about 2000 mg/m 2 body surface area, about 2500 mg/m 2 body surface area, about 3000 mg/m 2 body surface area, about 3500 mg/m 2 body surface area, about 3700 mg/m 2 body surface area, or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • the first single administration step can take place at various time points in relation to the subject's exposure or potential exposure to the Influenza virus. For example, for subjects having a high risk of being exposed to and/or infected by the Influenza virus, such as health workers including doctors, nurses, etc., the first single administration step can take place before the subjects' exposure or expected exposure to the Influenza virus. That is, UV-4 can be given prophylactically. Thus, in some embodiments, the first single administration step can take place up to about 24 hours before the subject's anticipated exposure to the Influenza virus.
  • the first single administration step can take place about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, about 24 hours, or any ranges between the specified values, before the subject's anticipated exposure to the Influenza virus.
  • the first single administration step can take place about 1 hour to about 8 hours before the subject is exposed to the Influenza virus. In some embodiments, the first single administration can take place about 1 hour to about 4 hours before the subject is exposed to the Influenza virus.
  • the first single administration step can also take place at about the same time of or after the subjects' exposure to the Influenza virus.
  • UV-4 can be given as post-exposure prophylaxis.
  • the first single administration step can take place about the same time such as within 30 minutes or less, of the subject's exposure to the Influenza virus.
  • the first single administration step can take place up to about 72 hours after the subject's exposure to the Influenza virus.
  • the first single administration step can take place up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 8 hours, up to about 12 hours, up to about 16 hours, up to about 24 hours, up to about 48 hours, up to about 72 hours, or any ranges between the specified values, after the subject's exposure to the Influenza virus.
  • the first single administration step can take place up to about 4 hours or up to about 24 hours after the subject is infected with the Influenza virus. In some embodiments, the first single administration step can take place up to about 4 hours or up to about 12 hours after the subject is infected with the Influenza virus. In some embodiments, the first single administration step takes place about 8 hours after the subject is infected with the Influenza virus.
  • the first single administration step can also take place after the subject has shown symptoms of Influenza virus infection or after being diagnosed as infected with the Influenza virus. In some embodiments, the first single administration step can take place after the subject has shown symptoms of Influenza virus infection. For example, the first single administration step can take place immediately after, not more than 1 hour after, up to about 4 hours after to up to about 12 hours after, up to 1 day after, up to 2 days after, or up to 3 days after the subject shows symptoms of Influenza virus infection.
  • the first single administration step can take place after the subject has been diagnosed as infected with the Influenza virus.
  • the first single administration step can take place immediately after, not more than 1 hour after, up to about 4 hours or up to about 12 hours after being diagnosed, up to 1 day after, up to 2 days after, or up to 3 days after the subject has been diagnosed as infected with the Influenza virus.
  • the first single administration step can take place not more than 3 days after the subject is diagnosed as infected with the Influenza virus.
  • the first single administration step can take place not more than 2 days, not more than 1 day, not more than 12 hours after the subject is diagnosed as infected with the Influenza virus.
  • the first single administration step can take place not more than 3 days after the subject has shown symptoms of Influenza virus infection.
  • the first single administration step can take place not more than 2 days, not more than 1 day, not more than 12 hours after the subject has shown symptoms of Influenza virus infection.
  • the first single administration step can take place not more than 2 days after the subject has shown symptoms of Influenza virus infection.
  • the first single administration step can take place not more than 2 days after the subject has been diagnosed as infected with the Influenza virus. [0066]
  • the first single administration step takes place as early as possible after either (a) the subject has shown symptoms of Influenza virus infection, or (b) the subject has been diagnosed as infected with the Influenza virus.
  • the first single administration step takes place either (a) within 48 hours of a human subject showing symptoms of Influenza virus infection; or (b) within 48 hours of a human subject being diagnosed as infected with the Influenza virus. In some embodiments, the first single administration step takes place either (a) within 24 hours of a human subject showing symptoms of Influenza virus infection; or (b) within 24 hours of a human subject being diagnosed as infected with the Influenza virus.
  • the first single administration step can take place either (a) within about 12 hours, such as within about 8 hours, within about 4 hours, or within about 1 hour of the human subject showing symptoms of Influenza virus infection; or (b) within about 12 hours, such as within about 8 hours, within about 4 hours, or within about 1 hour of the human subject being diagnosed as infected with the Influenza virus.
  • the amounts of UV-4 administered to a subject in need thereof in multiple single administrations can be the same or different. That is, the amount of UV-4 administered in the first single administration step can be the same as or different from the amount of UV- 4 administered in any second single administration step which can be the same as or different from the amount of UV-4 administered in any third single administration step. In some embodiments, the amounts of UV-4 or the pharmaceutically acceptable salt thereof are the same for the first single administration step and the second single administration step. In some embodiments, the amounts of UV-4 or the pharmaceutically acceptable salt thereof are the same for the first single administration step, the second single administration step, and the third single administration step.
  • more than three doses of UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over the course of treatment.
  • a single daily dose of UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of 2 days to 5 days.
  • Suitable daily dose for administration include any of the suitable amounts of UV-4 or the pharmaceutically acceptable salt thereof described herein.
  • the UV-4 or pharmaceutically acceptable salts thereof are orally administered to the subject.
  • the UV-4 is administered as UV-4B.
  • the present disclosure also provides a method for treating or preventing Dengue virus infection.
  • this disclosure provides a method of treating or preventing a disease or condition caused by or associated with a Dengue virus in a subject in need thereof.
  • the method comprises administering to the human subject an amount of N-(9-methoxynonyl)deoxynojirimycin or an equivalent amount of a pharmaceutically acceptable salt thereof over a period of time not exceeding 48 hours. In certain embodiments, the period of time does not exceed 42 hours, 36 hours, 30 hours, 24 hours, 18 hours, 12 hours, or 6 hours.
  • the amount ranges from at least 1.1 grams to about 30 grams over the 48 hours, provided that at least 1.1 g of N-(9- methoxynonyl)deoxynojirimycin is given within a 24 hour period.
  • At least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 grams of N-(9-methoxynonyl)deoxynojirimycin is given within the 24 hour period, e.g., to a human subject.
  • the method comprises administering to the subject in a first single administration step a first dose of UV-4 or an equivalent amount of a
  • the subject is a human subject.
  • the first single administration step is the only
  • the first dose of UV-4 or the equivalent amount of the pharmaceutically acceptable salt thereof ranges from about 20 mg/kg body weight to about 100 mg/kg body weight. In some embodiments, the first dose of UV-4 or the equivalent amount of the pharmaceutically acceptable salt thereof ranges from at least 1.1 grams to about 10 grams.
  • the UV-4 or the pharmaceutically acceptable salt thereof can be formulated for oral administration.
  • the UV-4 or the pharmaceutically acceptable salt thereof is formulated in a dosage form including but not limited to an aqueous oral solution, tablet, or capsule.
  • the UV-4 or pharmaceutically acceptable salt thereof is formulated as aqueous oral solution in water or other pharmaceutically acceptable vehicle.
  • the UV-4 or pharmaceutically acceptable salt thereof can be formulated in a solid dosage form, such as one or more pills including tablets or capsules.
  • the UV-4 or pharmaceutically acceptable salt thereof can be formulated for parenteral administration, such as for intravenous injection.
  • the administration of UV-4 or the pharmaceutically acceptable salt thereof can be oral administration.
  • the UV-4 is administered as UV-4B in the first, or any subsequent, single administration step.
  • the methods described in this disclosure can treat or prevent a disease or
  • the Dengue virus is a Dengue 1 virus, a Dengue 2 virus, a Dengue 3 virus, a Dengue 4 virus, or a combination thereof. In some embodiments, the Dengue virus is a Dengue 2 virus.
  • the diseases or conditions caused by or associated with Dengue viruses include:
  • Dengue fever In some embodiments, the disease or condition associated with Dengue virus is acute, uncomplicated Dengue fever. In other embodiments, the Dengue fever can be complicated, for example DHF or dengue shock syndrome (DSS).
  • DFS dengue shock syndrome
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered for treating Dengue virus infection according to various dosing regimens which vary parameters such as dosing frequencies, amounts, and time points of administration relative to infection.
  • UV-4 or the pharmaceutically acceptable salt thereof can be any organic compound [0076]
  • UV-4 or the pharmaceutically acceptable salt thereof can be any organic compound [0076]
  • each single administration may be spaced apart from the next single administration by one or more days.
  • the method comprises administering a first dose of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof, such as UV-4B, in a first single administration step, wherein the first single administration step is the only administration of UV-4 to treat or prevent the disease or condition caused by or associated with the Dengue virus.
  • the UV-4 or pharmaceutically acceptable salt thereof is administered only once over the course of treatment.
  • the first single administration step is followed by a second single administration step of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first single administration step and the second single administration step are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Dengue virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered only two times over the course of treatment.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, from 2 days to 5 days.
  • UV-4 or the first single administration step and the second single administration step are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Dengue virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered only two times over the course of treatment.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, from 2 days to 5 days.
  • pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, not exceeding 48 hours.
  • the second single administration step can take place about
  • the second single administration step can take place about 8 hours, about 12 hours, about 16 hours, about 24 hours, about 36 hours, about 48 hours, or any ranges between the recited values, after the first single administration step.
  • the second single administration step takes place about 24 hours after the first single administration step.
  • the second single administration step takes place over 48 hours up to 10 days after the first single administration step.
  • the second single administration step can take place about 3 days, about 4 days, about 5 days, about 7 days, or about 10 days, or any ranges between the recited values, after the first single administration step.
  • the first single administration step is followed by a second single administration step and a third single administration step of UV-4 or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the first single administration step, the second single administration step, and the third single administration steps are the only administrations of UV-4 to treat or prevent the disease or condition caused by or associated with the Dengue virus.
  • the UV-4 or pharmaceutically acceptable salts thereof is administered three times over the course of treatment.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, from 2 days to 5 days.
  • UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of, for example, not exceeding 48 hours.
  • the second single administration step can take place
  • the third single administration step can take place about 8 hours to about 48 hours after the second administration step.
  • the third single administration step can take place about 8 hours, about 12 hours, about 16 hours, about 24 hours, about 36 hours, about 48 hours, or any ranges between the recited values, after the second administration step.
  • the third single administration step takes place about 24 hours after the second single
  • the third single administration step can also take place over 48 hours up to 10 days after the second single administration step.
  • the third single administration step can take place about 3 days, about 4 days, about 5 days, about 7 days, or about 10 days, or any ranges between the recited values, after the second single administration step.
  • UV-4 or the pharmaceutically acceptable salt thereof is not administered daily.
  • the amount of UV-4 dosed in a given single administration to treat a disease or condition associated with Dengue virus infection is at least 100 mg/kg body weight and up to about 1,000 mg/kg body weight, for example, about 120 mg/kg body weight, about 150 mg/kg body weight, about 200 mg/kg body weight, about 250 mg/kg body weight, about 300 mg/kg body weight, about 350 mg/kg body weight, about 400 mg/kg body weight, about 450 mg/kg body weight, about 500 mg/kg body weight, about 550 mg/kg body weight, about 600 mg/kg body weight, about 650 mg/kg body weight, about 700 mg/kg body weight, about 750 mg/kg body weight, about 800 mg/kg body weight, about 850 mg/kg body weight, about 900 mg/kg body weight, about 1,000 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can range from about 20 mg/kg body weight to about 100 mg/kg body weight, e.g., about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, about 100 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration is at least 3700 mg/m 2 body surface area and up to about 37000 mg/m 2 body surface area, for example, 3700 mg/m 2 body surface area, about 5000 mg/m 2 body surface area, about 10000 mg/m 2 body surface area, about 15000 mg/m 2 body surface area, about 20000 mg/m 2 body surface area, about 25000 mg/m 2 body surface area, about 30000 mg/m 2 body surface area, about 35000 mg/m 2 body surface area, about 37000 mg/m 2 body surface area, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can be about 740 mg/m 2 body surface area and up to about 3700 mg/m 2 body surface area, for example, about 740 mg/m 2 body surface area, about 1500 mg/m 2 body surface area, about 2000 mg/m 2 body surface area, about 2500 mg/m 2 body surface area, about 3000 mg/m 2 body surface area, about 3500 mg/m 2 body surface area, about 3700 mg/m 2 body surface area, or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • the amount of UV-4 can be 1.1 grams, about 1.2 grams, about 1.4 grams, about 1.6 grams, about 1.8 grams, about 2 grams, about 2.2 grams, about 2.4 grams, about 2.6 grams, about 2.8 grams, about 3 grams, about 3.2 grams, about 3.4 grams, about 3.6 grams, about 3.8 grams, about 4 grams, about 4.2 grams, about 4.4 grams, about 4.6 grams, about 4.8 grams, about 5 grams, about 5.2 grams, about 5.4 grams, about 5.6 grams, about 5.8 grams, about 6 grams, about 6.2 grams, about 6.4 grams, about 6.6 grams, about 6.8 grams, about 7 grams, about 7.2 grams, about 7.4 grams, about 7.5 grams, about 8 grams, about 8.5 grams, about 9 grams, about 9.5 grams, about 10 grams, or any ranges between the specified values.
  • the amount of UV-4 administered in a given single administration ranges from about 2 grams to about 5 grams.
  • the amount of UV-4 administered in a given single administration can be about 2 grams, about 2.2 grams, about 2.4 grams, about 2.6 grams, about 2.8 grams, about 3 grams, about 3.2 grams, about 3.4 grams, about 3.6 grams, about 3.8 grams, about 4 grams, about 4.2 grams, about 4.4 grams, about 4.6 grams, about 4.8 grams, about 5 grams, or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • Suitable amounts of UV-4 for administration in the methods described herein, such as for the first single administration step, the second single administration step, or third single administration step as described above, can range from about 20 mg/kg body weight to about 1,000 mg/kg body weight.
  • the amount of UV-4 can range from about 20 mg/kg body weight to about 100 mg/kg body weight, e.g., about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, about 100 mg/kg body weight, or any ranges between the specified values.
  • the amount of UV-4 dosed in a given single administration can be about 740 mg/m 2 body surface area and up to about 3700 mg/m 2 body surface area, for example, about 740 mg/m 2 body surface area, about 1500 mg/m 2 body surface area, about 2000 mg/m 2 body surface area, about 2500 mg/m 2 body surface area, about 3000 mg/m 2 body surface area, about 3500 mg/m 2 body surface area, about 3700 mg/m 2 body surface area, or any ranges between the specified values.
  • an equivalent amount of UV-4B is dosed in a given single administration.
  • the first single administration step can take place at various time points in relation to the subject's exposure or potential exposure to the Dengue virus. For example, for subjects having a high risk of being exposed to and/or infected by the Dengue virus, such as health workers including doctors, nurses, etc., the first single administration step can take place before the subjects' anticipated or actual exposure to the Dengue virus. That is, UV-4 can be given prophylactically. Thus, in some embodiments, the first single administration step can take place up to about 24 hours before the subject's anticipated exposure to the Dengue virus.
  • the first single administration step can take place up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 8 hours, up to about 12 hours, up to about 16 hours, up to about 24 hours, or any ranges between the specified values, before the subject's anticipated exposure to the Dengue virus.
  • the first single administration step can take place about 1 hour to about 8 hours before the subject is exposed to the Dengue virus. In some embodiments, the first single administration can take place about 1 hour to about 4 hours before the subject is exposed to the Dengue virus.
  • the first single administration step can also take place at about the same time of or after the subjects' exposure to the Dengue virus.
  • UV-4 can be given as post-exposure prophylaxis.
  • the first single administration step can take place about the same time such as within 30 minutes or less, of the subject's exposure to the Dengue virus.
  • the first single administration step can take place up to about 72 hours after the subject's exposure to the Dengue virus.
  • the first single administration step can take place up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 8 hours, up to about 12 hours, up to about 16 hours, up to about 24 hours, up to about 48 hours, or up to about 72 hours, or any ranges between the specified values, after the subject's exposure to the Dengue virus.
  • the first single administration step can take place up to about 4 hours or up to about 24 hours after the subject is infected with the Dengue virus. In some embodiments, the first single administration step can take place up to about 4 hours or up to about 12 hours after the subject is infected with the Dengue virus. In some embodiments, the first single administration step takes place about 8 hours after the subject is infected with the Dengue virus. In some embodiments, the first single administration step takes place more than 1 day and up to about 3 days after the subject is infected with the Dengue virus. For example, the first single administration step can take place about 32 hours, about 2 days, about 3 days, or any ranges between the specified values after the subject is infected with the Dengue virus.
  • the first single administration step takes place more than 3 days after the subject is infected with the Dengue virus.
  • the first single administration step can take place more than 4 days, more than 5 days, or more than 10 days after the subject is infected with the Dengue virus.
  • the first single administration step can also take place after the subject has shown symptoms of Dengue virus infection or after being diagnosed as infected with the Dengue virus. In some embodiments, the first single administration step can take place after the subject has shown symptoms of Dengue virus infection. For example, the first single administration step can take place immediately after, not more than 1 hour after, up to about 4 hours or up to about 12 hours after, up to 1 day after, up to
  • the first single administration step can take place after the subject has been diagnosed as infected with the Dengue virus.
  • the first single administration step can take place immediately after, not more than 1 hour after, up to about 4 hours, up to about 12 hours after, up to 1 day after, up to 2 days after, or up to
  • the first single administration step can take place not more than 3 days after the subject is diagnosed as infected with the Dengue virus.
  • the first single administration step can take place not more than 2 days, not more than 1 day, not more than 12 hours after the subject is diagnosed as infected with the Dengue virus.
  • the first single administration step can take place not more than 3 days after the subject has shown symptoms of Dengue virus infection.
  • the first single administration step can take place not more than 2 days, not more than 1 day, not more than 12 hours after the subject showing symptoms of Dengue virus infection.
  • the first single administration step can take place not more than 2 days after the subject has shown symptoms of Dengue virus infection. In some embodiments, the first single administration step can take place not more than 2 days after the subject has been diagnosed as infected with the Dengue virus.
  • the first single administration step takes place as early as possible after either (a) the subject has shown symptoms of Dengue virus infection, or (b) the subject has been diagnosed as infected with the Dengue virus.
  • the first single administration step can take place either (a) within 72 hours of a human subject showing symptoms of Dengue virus infection; or (b) within 72 hours of a human subject being diagnosed as infected with the Dengue virus.
  • the first single administration step can take place either (a) within 48 hours of a human subject showing symptoms of Dengue virus infection; or (b) within 48 hours of a human subject being diagnosed as infected with the Dengue virus.
  • the first single administration step can take place either (a) within 24 hours of a human subject showing symptoms of Dengue virus infection; or (b) within 24 hours of a human subject being diagnosed as infected with the Dengue virus. In other embodiments, the first single administration step can take place either (a) within about 12 hours, such as within about 8 hours, within about 4 hours, or within about 1 hour of the human subject showing symptoms of Dengue virus infection; or (b) within about 12 hours, such as within about 8 hours, within about 4 hours, or within about 1 hour of the human subject being diagnosed as infected with the Dengue virus.
  • the amounts of UV-4 administered to a subject in need thereof in multiple single administrations can be the same or different. That is, the amount of UV-4 administered in the first single administration step can be the same as or different from the amount of UV- 4 administered in any second single administration step which can be the same as or different from the amount of UV-4 administered in any third single administration step. In some embodiments, the amounts of UV-4 or the pharmaceutically acceptable salt thereof are the same for the first single administration step and the second single administration step. In some embodiments, the amounts of UV-4 or the pharmaceutically acceptable salt thereof are the same for the first single administration step, the second single administration step, and the third single administration step.
  • more than three doses of UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over the course of treatment.
  • a single daily dose of UV-4 or the pharmaceutically acceptable salt thereof can be administered to the subject over a period of 2 days to 5 days.
  • Suitable daily dose for administration include any of the suitable amounts of UV-4 or the pharmaceutically acceptable salt thereof described herein.
  • the UV-4 or pharmaceutically acceptable salts thereof are orally administered to the subject.
  • the UV-4 is administered as UV-4B.
  • UV-4B The efficacy of UV-4B provided as a single dose was examined using a lethal mouse model with Influenza A/Texas/36/91 (HlNl). UV-4B doses >250 mg/kg provided once at 8 hours after infection resulted in significant increases in survival as compared to animals treated with vehicle alone (Figure 1).
  • intranasally with a lxLD 90 of the Influenza A/Texas/36/91 (HlNl) strain and subsequently treated with a single dose of 100, 250, 500, 750, or lOOOmg/kg UV-4B via oral gavage 8 hours following virus infection.
  • a vehicle (water only) control was administered in a similar manner.
  • additional groups of mice were administered multiple doses of either an efficacious (lOOmg/kg) or sub-efficacious (20mg/kg) dose of UV-4B or vehicle via oral gavage starting 8 hours post-infection and continuing TID for a total of five days. Readouts for the study were weight, health and mortality.
  • the single dose vehicle treated mice displayed 0% survival and a median survival time of 10 days. See Figures 1A-1C. None of the treated mice displayed 100% survival, but those mice that received either a single dose of UV-4B at 750 or lOOOmg/kg displayed statistically significant survival (80%) (Figure 1A). Mice receiving single doses of UV-4B at 100, 250, or 500mg/kg displayed ⁇ 50% survival. The group receiving an efficacious dose of UV-4B (lOOmg/kg TID) displayed 80% survival while the vehicle control given TID displayed 40% survival, similar to the sub-efficacious dose group (20mg/kg TID).
  • mice treated with single doses of either 750mg/kg or lOOOmg/kg UV-4B had noticeably less weight loss than those treated once with ⁇ 500mg/kg of UV-4B, those treated TID with UV-4B, or the vehicle control treated animals (Figure IB).
  • Mice receiving a single dose of UV-4B at 750 or lOOOmg/kg also had less adverse health changes than those observed in the other groups ( Figure 1C).
  • UV-4B was highly protective against Influenza A (HlNl) infection when administered 8 hours postinfection.
  • mice were administered varying doses of UV-4B (100, 250, 500, 750 or lOOOmg/kg) via oral gavage at various time points (Table 1). Specifically, groups 1-6 received a single dose of UV-4B or a vehicle control 8 hours post-infection while groups 7-8 received a single dose of UV-4B at 24 hours post-infection and groups 9-10 received a single dose of UV-4B at 48 hours post-infection. Group 1 1 served as the positive control for the study and received lOOmg/kg UV-4B via oral gavage TID for 5 days starting 8 hours post-infection. Group 12 served as the negative control for the study and received a vehicle control in a similar manner. Compounds were administered orally at ⁇ 5mL/kg final volume. Readouts for the study were weight, health and mortality.
  • mice receiving either 750mg/kg or lOOOmg/kg of UV-4B at 24 or 48 hours postinfection displayed little to no survival (0-20%) with an MTTD of 9-10 days.
  • Mice treated with single doses of UV-4B at 8 hours after infection had noticeably less weight loss than those treated once with similar doses of UV-4B at 24 or 48 hours after infection or the vehicle control treated animals.
  • those animals receiving a higher dose of UV-4B had less weight loss than those animals receiving a lower dose.
  • Mice receiving a single dose of UV-4B at 8 hours after infection had less adverse health changes than those in groups receiving a single dose of UV-4B at 24 or 48 hours after infection or the vehicle control treated animals.
  • mice were administered varying doses of UV-4B (500 or 750 mg/kg) via oral gavage at three different time points, 8 hours post-infection, 16 hours post-infection, and 24 hours post-infection.
  • mice were administered a single dose of water at 8 hours post-infection. All of the mice in the negative control group died.
  • mice received lOOmg/kg UV-4B via oral gavage TID for 5 days starting 8 hours post-infection.
  • UV-4B was protective against Influenza A (HlNl) infection when administered within 24 hours post-infection.
  • UV-4B against a mouse-adapted strain of Influenza A/PA/2010 (H3N2sw) virus infection in BALB/c mice Sixty-nine female BALB/c mice weighing 15-19 grams at study initiation were infected intranasally with one LD 80 (80% lethal dose) having 10,000 50% tissue culture infectious dose (TCID50)/0.1 mL with the mean day of death expected to be between Days 8 and 9 with 70-100%) mortality for untreated mice. Five groups of 10 mice exposed to the Influenza A/Pennsylvania/10/2010 (H3N2sw) virus were orally administered UV-4B once at eight hours after virus exposure at 100, 250, 500, 750, or 1000 mg/kg/dose.
  • mice As a positive control, another group of 10 mice was exposed to the Influenza virus and was orally administered oseltamivir at 10 mg/kg/dose diluted in physiological saline (PSS) twice a day for six days for a total of 20 mg/kg/day. Doses were given about eight hours apart beginning eight hours after virus exposure. In addition, a group of 9 mice was administered vehicle (placebo) only, water for injection (WFI) once orally, which served as the negative control. Mice were observed daily for 20 days for adverse events, weight changes and mortality. Adverse events for which observations were made included ruffling of fur, lethargy, paralysis, incontinence, repetitive circular motion, bloody rectum, and aggression.
  • PSS physiological saline
  • WFI water for injection
  • mice Six of the nine placebo-treated mice succumbed after infection with a mean day of death of 7.7 days, as expected. A single administration of 750 and 250 mg/kg dose equivalent of UV-4B significantly protected mice from death with seven of 10 mice surviving in each of these groups ( Figure 5). In addition, all mice treated with the 1000 mg/kg dose of UV-4B or oseltamivir survived, as one would expect for treatments that significantly ameliorated weight loss. There was no survival benefit in mice treated with 100 or 500mg/kg of UV-4B as compared to the placebo-treated mice.
  • mice exposed to Influenza A/PA/10/2010 (H3N2)sw virus were orally administered UV-4B once at eight hours after virus exposure at 100, 250, 500, 750, or 1000 mg/kg.
  • the 1000 mg/kg dose of UV-4B was efficacious in protecting mice against the complications of virus infection; all mice survived the infection and these mice lost significantly less weight in the advanced stages of the infection when compared to placebo-treated mice.
  • the 750 and 250 mg/kg UV-4B dose levels significantly promoted the survival of mice. However, these dose levels were less efficacious in ameliorating the negative effects of the virus infection; they did not significantly protect against weight loss.
  • a single administration of 100 or 500 mg/kg of UV-4B did not provide survival or weight loss benefit as compared to the placebo-treated mice.
  • UV-4B can be highly protective against Influenza A (H3N2sw) infection when administered 8 hours post-infection.
  • mice were administered doses of 100 mg/kg, 250 mg/kg, 500 mg/kg, 750 mg/kg, or 1000 mg/kg, by oral gavage 8 hours post-infection.
  • Oseltamivir was used as a positive control and was administered to mice by oral gavage at lOmg/kg/dose BID for five days, starting 8 hours post-infection with each dose given approximately 12 hours apart.
  • Mice were treated with WFI as the placebo/handling control group using the same dosing regimen described for UV-4B. Survival data was obtained up to day 13.
  • AG129 mice that had received 5 ⁇ g of 2H2 (anti-prM/M) one hour before they were infected with 1 LD 90 of a Dengue 2 strain via intravenous injection, were administered UV-4B at a single dose of 250 mg/kg, 500 mg/kg, 750 mg/kg, or 1000 mg/kg, by oral gavage 8 hours post-infection.
  • AG129 mice are 129/Sv mice lacking receptors for both alpha/beta interferon and interferon gamma.
  • UV- 4B was administered to mice by oral gavage at lOOmg/kg/dose TID for five days, starting 8 hours post-infection with each dose given approximately 8 hours apart. Mice treated with water were administered a single dose via oral gavage 8 hours post infection and represent the placebo/handling control group. Survival and body weight data were obtained up to day 10.
  • UV-4B against Dengue infection at various time points relative to infection as compared to TID treatments were similar to those described in Example 7, except that the dosing regimens for UV-4B were different. Mice treated with water using the same dosing regimen described for UV-4B represent the placebo/handling control group. Survival data was obtained up to day 10.
  • Figure 8A shows that a single dose of 250 mg/kg; 375 mg/kg, or 750 mg/kg UV-4B once at 8 hours postinfection can be protective against Dengue 2 virus infection when administered 8 hours post-infection.
  • Figure 8B shows that either three doses of 250 mg/kg UV-4B at 8 hours, 16 hours, and 24 hours post-infection or two doses of 375 mg/kg UV-4B at 8 hours and 16 hours post-infection are highly effective in protecting against Dengue virus infection.
  • Figures 8C-8E show the results of various two-doses regimens.
  • Figure 8C shows that administering two doses of 250 mg/kg, 375 mg/kg, or 750 mg/kg of UV-4B at 8 hours and 24 hours post-infection provided significant protection against Dengue virus infection.
  • Figure 8D shows that administering two doses of 375 mg/kg or 750 mg/kg of UV-4B at 16 hours and 32 hours post-infection improved efficacy against Dengue virus infection compared to the corresponding doses administered at 8 hours and 24 hours postinfection.
  • Figure 8E further shows that significant protection against Dengue virus was achieved by administering two doses of 375 mg/kg or 750 mg/kg of UV-4B at 24 hours and 40 hours post-infection, 36 hours and 52 hours post-infection, or 48 hours and 64 hours post-infection. These studies showed that for a two-dose regimen, the initial administration of UV-4B can start at 48 hours post-infection or even later.
  • UV-4B with a high intensity dosing strategy in the lethal Dengue 2 ADE mouse model.
  • the mice received 5 ⁇ g of 2H2 antibody one hour before infection with 1 LD 90 dose of DENV2-S221 IV.
  • Groups of mice received a single dose of 750mg/kg of UV-4 via oral gavage administered in the hydrochloride salt form, UV-4B, vehicle (water) only at 36 hours post-infection, or double doses of 750mg/kg of UV-4B via oral gavage administered at 36 and 52 hours post-infection.
  • the study assessed the efficacy of UV- 4B in restricting dengue virus replication in the blood (serum) at 36, 44, 52, 60 or 72 hours post-infection.
  • the viral loads in each sample were determined by q-rt-pcr.
  • the objective of this study was to determine viral loads and cytokine responses in the serum of mice administered UV-4B with a high intensity dosing strategy in a lethal dengue antibody dependent enhancement (ADE) mouse model.
  • ADE lethal dengue antibody dependent enhancement
  • mice of 5-6 week old AG129 mice of both sexes received 5 ⁇ g of 2H2 (anti-prM/M, stock concentration 8.17 mg/mL) antibody one hour before infection with 1 LD 90 dose (10 9 genomic equivalents (GE)) of DENV2-S221 intravenously (IV) (Table 3).
  • Groups 3 and 5 received a single dose of 750mg/kg of UV-4B via oral gavage at 36 hours post-infection.
  • Groups 7 and 9 received doses of 750mg/kg of UV-4B via oral gavage at 36 and 52 hours post-infection.
  • Groups 2, 4, 6, and 8 served as negative controls for the study and received a vehicle control in a similar manner.
  • Viral RNA was isolated from serum using Qiagen Viral RNA isolation kits.
  • Dengue virus 2 qRT-PCR was performed on all samples, and genomic equivalent (GE) per ml of serum or in tissue determined.
  • Figure 10 The results of this study are shown in Figure 10. Statistically lower viral titers were observed in all groups of mice that were treated with UV-4B when compared to the water treated mice at the same number of hours post-infection (hpi). Figure 10 shows that a single dose (as demonstrated at 44 and 52 hpi time points) or two doses (as demonstrated at 60 and 72 hpi time points) can significantly decrease the viral load in Dengue 2 infected mice.
  • MSD's sample dilution buffer in duplicate was performed according to the manufacturer's protocol.
  • the data templates were prepared according to the calibrator concentrations, which were specific for each lot. The concentrations were determined by using the average concentration of the neat sample in pg/mL. All samples were performed in duplicate. All analyses were performed automatically based on the protocols provided by MSD's software (DISCOVERY WORKBENCH). [0131] The results for this study are shown in Figures 11 A, 11B, 12A, 12B, 13A, 13B,
  • cytokines in the blood were assessed using serum samples collected at 44, 52, 60 and 72 hpi and analyzed by MSD platform for IFN- ⁇ , IL- 1 ⁇ , IL-6, IL-10, IL-12/IL-23p40, IL-17A, IL-22, KC-GRO, VEGF-A, and T F-a, as shown in Figures 11-20, respectively.
  • Figures 11A, 11B, 12A, 12B, 13A, 13B, 14A, 14B, 15A, and 15B show that levels of all cytokines tested were lower in the UV-4B treated mice at 72 hpi, when compared to the corresponding levels of the respective cytokines in the water treated mice at 72 hpi.
  • Figures 11A, 12B, 13A, 14B, and 15B show that levels of IFN- ⁇ , IL-10, IL-12/IL-23p40, KC-GRO, and TNF-a, respectively, were significantly lower in the UV-4B treated mice at 60 hpi, when compared to the corresponding levels of the respective cytokines in the water treated mice at 60 hpi.
  • Figure 15B shows levels of TNF-a were significantly lower in the UV-4B treated mice at 52 hpi, when compared to the levels of TNF-a in the water treated mice at 52 hpi.
  • This study will evaluate the safety and tolerability of a single-ascending oral dose of UV-4B in healthy subjects and will determine pharmacokinetic parameters describing absorption and elimination following a single dose of UV-4B in healthy subjects.
  • UV-4B will be used as an aqueous solution, with anticipated dose range from
  • Each cohort will consist of 8 subjects (6 active, 2 placebo). Within each cohort, subjects will be randomized to receive a single oral dose of UV 4B or placebo under fasted conditions. Two subjects within each cohort (i.e. sentinel group: 1 active/1 placebo) will be dosed at least 48 hours prior to the remainder of the cohort. Safety and available exposure data from all subjects in each cohort will be reviewed by the Safety Review Committee (SRC) after all subjects in a given cohort have completed evaluations on Day 4. If specific safety criteria are met, then new subjects that meet all screening criteria and none of the exclusion criteria may be enrolled into the next higher dose cohort.
  • SRC Safety Review Committee
  • the primary objective of this study is to evaluate the safety profile, tolerability and effect of UV-4B compared to placebo in total virus shedding (measured by area under the curve [AUC]) in swabs of the nasal mucosa, measured by viral culture, from Day 1 to Day 7, after viral inoculation with Influenza A (H1N1).
  • Other objectives include the duration, time to peak, and daily incidence of influenza symptoms; and the proportion (from Day 1 to Day 7), duration, time to peak, and daily incidence of the components of the following influenza symptoms: Fever; Malaise; Myalgia; Cough; Sore throat;
  • Rhinorrhea Nasal congestion; Chest pain/pleurisy; Mucus weight (from Day 1 to Day 7); Peak value, time to peak, duration, and daily incidence of virus shedding from the nasal mucosa measured by viral culture.
  • the active for this study is UV-4B in an aqueous solution, with anticipated doses ranging from 2000mg to 5000mg, in 30mL total volume, containing lOmL taste-masking agent (OraSweet-SF or appropriate alternative).
  • the placebo for this study is Taste- masking agent, OraSweet-SF, (lOmL) diluted with potable water (20mL). Influenza Ca/04/2009/HlNlr Challenge Virus will be used.
  • Enrolled subjects are planned to be randomly assigned to 1 of 2 treatment arms and will be dosed 1 : 1 (active: placebo) to receive one of the following:
  • UV-4B regimen or Placebo [dosed TID (every 8 hours ⁇ 0.5 hours) for 5 days]
  • the primary endpoint is the functional virus shedding as assessed by changes in log-transformed viral load as measured by TCID 50 , from nasopharyngeal swabs from Day

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de traitement ou de prévention d'une maladie ou d'une affection causée par ou associée à un virus de la grippe ou un virus de la dengue chez un sujet en ayant besoin. Les procédés peuvent comprendre l'administration au sujet dans une première étape d'administration unique d'une première dose de N-(9-méthoxynonyl)désoxynojirimycine ou d'une quantité équivalente d'un sel pharmaceutiquement acceptable de celle-ci, la première dose pouvant être, par exemple, dans la plage d'au moins 1,1 gramme à environ 10 grammes.
PCT/US2017/032875 2016-05-16 2017-05-16 Procédés de traitement d'une infection virale WO2017201030A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662337167P 2016-05-16 2016-05-16
US62/337,167 2016-05-16

Publications (1)

Publication Number Publication Date
WO2017201030A1 true WO2017201030A1 (fr) 2017-11-23

Family

ID=60326582

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/032875 WO2017201030A1 (fr) 2016-05-16 2017-05-16 Procédés de traitement d'une infection virale

Country Status (1)

Country Link
WO (1) WO2017201030A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111904959A (zh) * 2020-08-21 2020-11-10 牡丹江医学院 α-L-岩藻糖苷酶抑制剂在制备治疗小儿肺炎的药物中的用途
WO2021188601A1 (fr) * 2020-03-16 2021-09-23 University Of Southern California Procédés pour prévenir, soulager et traiter des complications d'infections virales
WO2023203004A1 (fr) * 2022-04-20 2023-10-26 Pavone Luigi Michele Compositions thérapeutiques avec des iminosucres pour le traitement de maladies d'accumulation du sulfate d'héparane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065752A1 (en) * 2009-09-04 2011-03-17 United Therapeutics Corporation Methods of treating orthomyxoviral infections
US20110065753A1 (en) * 2009-09-04 2011-03-17 United Therapeutics Corporation Methods of treating poxviral infections
WO2015039010A2 (fr) * 2013-09-16 2015-03-19 Unither Virology, Llc Dérivés de déoxynojirimycine et leurs méthodes d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065752A1 (en) * 2009-09-04 2011-03-17 United Therapeutics Corporation Methods of treating orthomyxoviral infections
US20110065753A1 (en) * 2009-09-04 2011-03-17 United Therapeutics Corporation Methods of treating poxviral infections
WO2015039010A2 (fr) * 2013-09-16 2015-03-19 Unither Virology, Llc Dérivés de déoxynojirimycine et leurs méthodes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STAVALE ET AL.: "In Vivo Therapeutic Protection against Influenza A (H1N1) Oseltamivir- Sensitive and Resistant Viruses by the Iminosugar UV-4", PLOS ONE, 2015, pages 1 - 14, XP055296656 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021188601A1 (fr) * 2020-03-16 2021-09-23 University Of Southern California Procédés pour prévenir, soulager et traiter des complications d'infections virales
CN111904959A (zh) * 2020-08-21 2020-11-10 牡丹江医学院 α-L-岩藻糖苷酶抑制剂在制备治疗小儿肺炎的药物中的用途
WO2023203004A1 (fr) * 2022-04-20 2023-10-26 Pavone Luigi Michele Compositions thérapeutiques avec des iminosucres pour le traitement de maladies d'accumulation du sulfate d'héparane

Similar Documents

Publication Publication Date Title
O’Hanlon et al. Baloxavir marboxil: the new influenza drug on the market
Hui et al. The role of adjuvant immunomodulatory agents for treatment of severe influenza
EP3579833B1 (fr) Procédés pour traiter la grippe
Tarbet et al. Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice
Zarubaev et al. Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo
Lee et al. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection
RU2702133C2 (ru) Производные дезоксинойиримицина и способы их применения
Leneva et al. Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010–2011 influenza season in Russia
EA037529B1 (ru) Способ получения соединения для ингибирования репликации вирусов гриппа
Cai et al. 14-Deoxy-11, 12-didehydroandrographolide attenuates excessive inflammatory responses and protects mice lethally challenged with highly pathogenic A (H5N1) influenza viruses
WO2017201030A1 (fr) Procédés de traitement d'une infection virale
Smee et al. Treatment of oseltamivir-resistant influenza A (H1N1) virus infections in mice with antiviral agents
Boltz et al. Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice
Popov et al. Combined therapy of influenza with antiviral drugs with a different mechanism of action in comparison with monotherapy
Masihi et al. Low dose oral combination chemoprophylaxis with oseltamivir and amantadine for influenza A virus infections in mice
US20090318379A1 (en) Statins for the Treatment of Viral Influenza Infections
US7341988B2 (en) Method of treating influenza with geranyl-geranyl acetone
Prober Antiviral therapy for influenza virus infections
A Babizhayev et al. L-carnosine modulates respiratory burst and reactive oxygen species production in neutrophil biochemistry and function: may oral dosage form of non-hydrolized dipeptide L-carnosine complement anti-infective anti-influenza flu treatment, prevention and self-care as an alternative to the conventional vaccination?
CN107286044B (zh) 一种能够抑制流感病毒pb2蛋白与rna帽结合的化合物
Zhao et al. Protection from infection with influenza A H7N9 virus in a mouse model by equine neutralizing F (ab′) 2
RU2502512C2 (ru) Способ лечения гриппа птиц
CN108721264B (zh) 异克舒令在制备治疗或预防流感病毒感染的药物中的应用
Meseko et al. Antiviral options and therapeutics against influenza: history, latest developments and future prospects
CN110559291A (zh) 联苯苄唑在制备治疗或预防流感病毒感染的药物中的应用

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17800003

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17800003

Country of ref document: EP

Kind code of ref document: A1