US20120294831A1 - Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections - Google Patents

Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections Download PDF

Info

Publication number
US20120294831A1
US20120294831A1 US13/471,948 US201213471948A US2012294831A1 US 20120294831 A1 US20120294831 A1 US 20120294831A1 US 201213471948 A US201213471948 A US 201213471948A US 2012294831 A1 US2012294831 A1 US 2012294831A1
Authority
US
United States
Prior art keywords
administered
combination
thiazolide
thiazolide compound
cancer
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US13/471,948
Other languages
English (en)
Inventor
Jean-Francois Rossignol
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Romark Laboratories LC
Original Assignee
Romark Laboratories LC
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 Romark Laboratories LC filed Critical Romark Laboratories LC
Priority to US13/471,948 priority Critical patent/US20120294831A1/en
Assigned to ROMARK LABORATORIES L.C. reassignment ROMARK LABORATORIES L.C. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROSSIGNOL, JEAN-FRANCOIS
Publication of US20120294831A1 publication Critical patent/US20120294831A1/en
Assigned to U.S. BANK NATIONAL ASSOCIATION reassignment U.S. BANK NATIONAL ASSOCIATION SECURITY AGREEMENT Assignors: LAPICOR, N.V., ROMARK LABORATORIES, L.C., ROMARK MANUFACTURING, LLC
Assigned to LAPICOR, N.V., ROMARK LABORATORIES, L.C., ROMARK MANUFACTURING, LLC reassignment LAPICOR, N.V. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: U.S. BANK NATIONAL ASSOCIATION
Assigned to U.S. BANK NATIONAL ASSOCIATION reassignment U.S. BANK NATIONAL ASSOCIATION SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROMARK BIOSCIENCES S.À R.L. LLC, ROMARK LABORATORIES, L.C.
Priority to US15/861,234 priority patent/US10336058B2/en
Priority to US16/438,783 priority patent/US10814612B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F11/00—Rotary presses or machines having forme cylinders carrying a plurality of printing surfaces, or for performing letterpress, lithographic, or intaglio processes selectively or in combination
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F13/00—Common details of rotary presses or machines
    • B41F13/08—Cylinders
    • B41F13/18—Impression cylinders
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F13/00—Common details of rotary presses or machines
    • B41F13/08—Cylinders
    • B41F13/193—Transfer cylinders; Offset cylinders
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F7/00—Rotary lithographic machines
    • B41F7/02—Rotary lithographic machines for offset printing
    • B41F7/025—Multicolour printing or perfecting on sheets or on one or more webs, in one printing unit
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F7/00—Rotary lithographic machines
    • B41F7/02—Rotary lithographic machines for offset printing
    • B41F7/04—Rotary lithographic machines for offset printing using printing units incorporating one forme cylinder, one transfer cylinder, and one impression cylinder, e.g. for printing on webs
    • B41F7/06—Rotary lithographic machines for offset printing using printing units incorporating one forme cylinder, one transfer cylinder, and one impression cylinder, e.g. for printing on webs for printing on sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F7/00—Rotary lithographic machines
    • B41F7/02—Rotary lithographic machines for offset printing
    • B41F7/08—Rotary lithographic machines for offset printing using one transfer cylinder co-operating with several forme cylinders for printing on sheets or webs, e.g. sampling of colours on one transfer cylinder
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41F—PRINTING MACHINES OR PRESSES
    • B41F9/00—Rotary intaglio printing presses
    • B41F9/02—Rotary intaglio printing presses for multicolour printing
    • B41F9/021—Sheet printing presses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • 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 is directed to compositions and methods for immunomodulation, including preventing or treating viral diseases, cancer and diseases caused by intracellular protozoan infections.
  • Influenza is a highly contagious acute respiratory illness that affects all age groups and causes about 36,000 deaths and over 226,000 hospitalizations per year in the United States alone.
  • Classified (as types A, B, and C), according to antigenic differences in their nucleoprotein and matrix protein, the influenza viruses are enveloped, negative-stranded RNA viruses.
  • the many subtypes of influenza A virus differ in their two surface glycoproteins, hemagglutinin (“HA”) and neuraminidase (“NA”), which are the main targets of the protective immune response, and are labeled according to the type of hemagglutinin (denoted with an H number) and neuraminidase (denoted with an N number).
  • HA and NA vary continuously as a result of antigenic drift and antigenic shift. Sixteen H subtypes (or “serotypes”) and nine N subtypes are known.
  • Hepatitis B is an infectious illness caused by hepatitis B virus (HBV). About a quarter of the world's population, more than 2 billion people, have been infected with the hepatitis B virus. The acute illness causes liver inflammation, vomiting, jaundice and rarely, death. Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer-a fatal disease with very poor response to current chemotherapy.
  • the hepatitis B virus has a circular genome composed of partially double-stranded DNA and, similar to retroviruses, replicates through an RNA intermediate by reverse transcription. Although replication takes place in the liver, the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people.
  • Cancer is characterized by the uncontrolled growth and spread of abnormal cells. Because tumor cells are derived from normal cells, the host immune system does not recognize tumor cell antigens as foreign. Further, some tumor cells have developed ways to escape the host immune defense system, by eliminating antigens or reducing the number of receptors on the surface of the cell.
  • Melanoma is a malignant skin cancer that originates in melanocytes. If detected and treated early, it is nearly 100 percent curable. Without early treatment the cancer can advance, spread and be fatal. Melanoma is the skin cancer that causes the most deaths. Superficial spreading melanoma is the most common type of melanoma, especially among young people. This melanoma affects the top layer of the skin for a fairly long time before penetrating more deeply. Lentigo maligna is found most often in the elderly who are chronically exposed to the sun. Acral lentiginous melanoma also spreads superficially before penetrating more deeply and is the most common melanoma in African-Americans and Asians, and the least common among Caucasians. Nodular melanoma is usually invasive at the time it is first diagnosed and is the most aggressive form of melanoma.
  • Leukemia is a blood or bone marrow cancer characterized by an abnormal increase of white blood cells.
  • Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes in the bone marrow, which interfere with the production of normal white blood cells, red blood cells and platelets.
  • Chronic myeloid leukemia (CML) is a cancer of the white blood cells characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.
  • Non-Hodgkin lymphomas can be aggressive or indolent, may occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss.
  • B cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and mantle cell lymphoma.
  • T cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma.
  • Renal cell carcinoma which includes renal cell carcinoma, renal pelvis carcinoma and Wilms tumor, is the most common type of kidney cancer in adults. In 2010, there were 58,240 estimated new cases and 13,040 deaths in the United States alone.
  • MHC major histocompatibility complex
  • Nitazoxanide (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide) is a thiazolide antiparasitic agent having the following structure:
  • Tizoxanide is the active circulating metabolite of nitazoxanide. Following oral administration of nitazoxanide or mixtures of nitazoxanide plus tizoxanide in humans, these compounds are partially absorbed from the intestinal tract, and nitazoxanide is rapidly hydrolyzed to form tizoxanide in plasma. Tizoxanide is bound to plasma proteins and its urinary elimination half-life is 7.3 hours. Tizoxanide is glucurono-conjugated, and the drug is eliminated in urine and bile as tizoxanide or tizoxanide glucuronide. The half-life of tizoxanide in plasma is only approximately 1.5 hours. Tizoxanide has the following structure:
  • RM-4848 is a substituted thiazolide having the same structure as tizoxanide, but including a chloro group substituted for the nitro group, thus resulting in the compound N-(5-chlorothiazol-2-yl)-2-hydroxybenzamide.
  • Nitazoxanide (Alinia®, NTZ) and tizoxanide (TIZ) are thiazolide compounds with activity against parasites, anaerobic bacteria, and viruses.
  • NTZ is approved in the United States for the treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia .
  • NTZ and TIZ also inhibit replication of RNA and DNA viruses including influenza A and hepatitis C viruses. In clinical trials, NTZ was shown to be effective in treating rotavirus gastroenteritis, norovirus gastroenteritis and chronic hepatitis C, and is in late-stage clinical development for treatment of influenza.
  • the invention provides for the use of pharmaceutical compositions comprising a thiazolide for immunomodulating a subject in need thereof, including for the prevention and/or treatment of viral diseases, cancer and diseases caused by intracellular protozoan or bacterial infections.
  • the invention provides a method of stimulating an immune response in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound.
  • Acceptable thiazolide compounds of the invention include those disclosed in U.S. Pat. Nos.
  • the thiazolide agent is nitazoxanide.
  • the thiazolide agent is tizoxanide.
  • the thiazolide agent is RM-4848 or its ester prodrug, RM-5038.
  • the subject suffers from a viral infection.
  • the subject is at risk of developing a viral infection.
  • the viral infection is influenza.
  • the influenza may be caused by a virus selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7.
  • the viral infection is Hepatitis B.
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a neuraminidase inhibitor, such as Laninamivir, Oseltamivir, Zanamivir or Peramivir, or an immunostimulant, such as Imiquimod or Resiquimod, or an adamantine analogue, or a recombinant sialidase fusion protein, or an anti-hepatitis B drug.
  • a neuraminidase inhibitor such as Laninamivir, Oseltamivir, Zanamivir or Peramivir
  • an immunostimulant such as Imiquimod or Resiquimod, or an adamantine analogue, or a recombinant sialidase fusion protein, or an anti-hepatitis B drug.
  • the thiazolide compound is administered in combination with a vaccine.
  • the subject suffers from a cancer.
  • the subject is at risk of developing a cancer.
  • the cancer is leukemia.
  • the leukemia is hairy cell leukemia or chronic myeloid leukemia.
  • the cancer is melanoma.
  • the cancer is non-Hodgkin lymphoma.
  • the cancer is renal cell carcinoma.
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a vaccine, or an immunostimulant, or an anticancer drug.
  • the anticancer drug may include, but is not limited to, STI571, CGP 74588, 1- ⁇ -D-Arabinofuranosylcytosine (Ara-C), doxorbicin, dacarbazine, cisplatin, bleomycin, vincristine, lomustine, vinblastine, carmustine, DTIC, tamoxifen, sunitinib, sorafenib and interferon- ⁇ .
  • the subject suffers from an intracellular protozoan infection.
  • the subject is at risk of developing an intracellular protozoan infection.
  • the intracellular protozoan infection is Cryptosporidium spp.
  • the intracellular protozoan infection is Leishmania spp.
  • the intracellular protozoan infection is Toxoplasma gondii .
  • the intracellular protozoan infection is Trypanosoma cruzii .
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a vaccine, or an immunostimulant, or an antiprotozoal drug.
  • the antiprotozoal drug may include, but is not limited to, trimethoprim/sulfamethoxazole, atovaquone, clindamycin, pyrimethamine, spiramycin, diminazine, homidium, suramin, melarsamine, sodium stibogluconate and meglumine antimoniate.
  • the subject suffers from an intracellular bacterial infection.
  • the subject is at risk of developing an intracellular bacterial infection.
  • the intracellular bacterial infection is Mycobacterium tuberculosis.
  • the invention provides a method of treating or preventing a viral infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound.
  • a thiazolide agent is nitazoxanide.
  • the thiazolide agent is tizoxanide.
  • the thiazolide agent is RM-4848 or a pharmaceutically acceptable prodrug thereof.
  • the viral infection is influenza.
  • the influenza may be caused by a virus selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7.
  • the viral infection is Hepatitis B.
  • the viral infection is diarrhea or gastroenteritis caused by rotavirus or norovirus.
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a neuraminidase inhibitor, such as Laninamivir, Oseltamivir, Zanamivir or Peramivir, or an immunostimulant, such as Imiquimod or Resiquimod, or an adamantine analogue, or a recombinant sialidase fusion protein, or an anti-hepatitis B drug.
  • a neuraminidase inhibitor such as Laninamivir, Oseltamivir, Zanamivir or Peramivir
  • an immunostimulant such as Imiquimod or Resiquimod, or an adamantine analogue, or a recombinant sialidase fusion protein, or an anti-hepatitis B drug.
  • the thiazolide compound is administered in combination with a vaccine.
  • the invention provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound.
  • the thiazolide agent is nitazoxanide.
  • the thiazolide agent is tizoxanide.
  • the thiazolide agent is RM-4848.
  • the cancer is leukemia.
  • the leukemia is hairy cell leukemia or chronic myeloid leukemia.
  • the cancer is melanoma.
  • the cancer is non-Hodgkin lymphoma.
  • the cancer is renal cell carcinoma.
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a vaccine, or an immunostimulant, or an anticancer drug.
  • the anticancer drug may include, but is not limited to, STI571, CGP 74588, 1- ⁇ -D-Arabinofuranosylcytosine (Ara-C), doxorbicin, dacarbazine, cisplatin, bleomycin, vincristine, lomustine, vinblastine, carmustine, DTIC, tamoxifen, sunitinib, sorafenib and interferon- ⁇ .
  • the invention provides a method of treating or preventing intracellular protozoan infections in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a thiazolide compound.
  • the thiazolide agent is nitazoxanide.
  • the thiazolide agent is tizoxanide.
  • the thiazolide agent is RM-4848.
  • the intracellular protozoan infection is Cryptosporidium spp.
  • the cancer is melanoma.
  • the intracellular protozoan infection is Leishmania spp.
  • the intracellular protozoan infection is Toxoplasma gondii .
  • the intracellular protozoan infection is Trypanosoma cruzii .
  • the thiazolide compound is administered alone.
  • the thiazolide compound is administered in combination with a vaccine, or an immunostimulant, or an antiprotozoal drug.
  • the antiprotozoal drug may include, but is not limited to, trimethoprim/sulfamethoxazole, atovaquone, clindamycin, pyrimethamine, spiramycin, diminazine, homidium, suramin, melarsamine, sodium stibogluconate and meglumine antimoniate.
  • the immune response required to effectively treat or prevent a viral disease, cancer or intracellular protozoan or bacterial infection may not be produced by thiazolides using the dosing regimen that is typically used to successfully treat a subject with a fully competent immune system.
  • Subjects with extreme immune deficiencies may not be good candidates for treatment with thiazolides.
  • Subjects with moderate immune deficiencies may require higher doses of thiazolide treatment, more frequent dosing, or dosing for a longer period of time than subjects with fully competent immune systems.
  • Subjects with HIV infection who have not developed immune deficiencies may be effectively treated with thiazolides, while subjects with immune deficiencies associated with HIV infection may require treatment with antiretroviral drugs to reduce HIV viral titer and partially restore immune function before or simultaneously with thiazolide therapy.
  • antiretroviral drugs to reduce HIV viral titer and partially restore immune function before or simultaneously with thiazolide therapy.
  • the use of thiazolides to stimulate immune response may be tailored for patients based on immune status.
  • FIGS. 1A , 1 B, and 1 C are graphs expressing CD14+ monocytes in the absence or presence of different doses of Tizoxanide in unstimulated and Flu-stimulated conditions. Mean values, S.E. and p values are indicated.
  • FIGS. 2A , 2 B, and 2 C are graphs expressing Tizoxanide modulation of the TLR pathway in unstimulated and Flu-stimulated PBMCs in the absence or presence of different doses of Tizoxanide in unstimulated and Flu-stimulated conditions. Mean values are indicated.
  • FIGS. 3A , 3 B, and 3 C are graphs expressing Tizoxanide modulation of the IFN pathway in unstimulated and Flu-stimulated PBMCs in the absence or presence of different doses of Tizoxanide in unstimulated and Flu-stimulated conditions. Mean values are indicated.
  • FIGS. 4A and 4B are graphs expressing T helper functions IFNg- and IL2-secreting CD4+ T cells in the absence or presence of different doses of Tizoxanide in unstimulated and Flu-stimulated conditions. Mean values, S.E. and p values are indicated.
  • FIGS. 5A , 5 B, and 5 C are graphs expressing Cytotoxic T cell functions. Perforin-, granzyme-, and Fas-expressing CD8+ T cells in the absence or presence of different doses of Tizoxanide in unstimulated and Flu-stimulated conditions. Mean values, S.E. and p values are indicated.
  • FIGS. 6A , 6 B, and 6 C are graphs expressing percentage of TLR3- ( FIG. 6A ), TLR7- ( FIG. 6B ) and TLR8- ( FIG. 6C ) expressing CD14+ cells in unstimulated and flu-stimulated conditions. Data obtained in the absence or in the presence of five different doses of RM44848 (0.5 82 g/ml; 1.0 ⁇ g/ml; 10 ⁇ g/ml; 20 ⁇ g/ml; 40 ⁇ g/ml) are indicated. Mean values, S.E. and p values are shown.
  • FIGS. 7A and 7B are graphs expressing toll-Like Receptor signalling pathway mRNA expression following stimulation with three different doses of RM4848 (1.0 ⁇ g/ml; 10 ⁇ g/ml; 20 ⁇ g/ml) in un-stimulated ( FIG. 7A ) and flu-stimulated ( FIG. 7B ) conditions.
  • the expression of 84 genes involved in the Toll-Like Receptor signalling pathway has been assessed by real-time quantitative RT-PCR, calculated relative to five housekeeping genes and shown as fold-change expression from the unstimulated sample. Only the targets showing different expression levels following Tizoxanide stimulation are indicated in the figure.
  • FIGS. 8A and 8B are graphs expressing type I interferon signalling pathway mRNA expression following stimulation with three different doses of RM4848 (1.0 ⁇ g/ml; 10 ⁇ g/ml; 20 ⁇ g/ml) in un-stimulated ( FIG. 8A ) and flu-stimulated ( FIG. 8B ) conditions.
  • the expression of 84 genes involved in the Type I interferon signalling pathway has been assessed by real-time quantitative RT-PCR, calculated relative to five housekeeping genes and shown as fold-change expression from the unstimulated sample. Only the targets showing different expression levels following Tizoxanide stimulation are indicated in the figure.
  • FIGS. 9A and 9B are graphs expressing percentage of IFN ⁇ - ( FIG. 9A ) and IL2-( FIG. 9B ) secreting CD4+ T cells in unstimulated and flu-stimulated conditions. Data obtained in the absence or in the presence of five different doses of RM4848 (0.5 ⁇ g/ml; 1.0 ⁇ g/ml; 10 ⁇ g/ml; 20 ⁇ g/ml; 40 ⁇ g/ml) are indicated. Mean values, S.E. and p values are shown.
  • FIGS. 10A , 10 B, and 10 C are graphs expressing an embodiment of the invention wherein percentage of granzyme- ( FIG. 10A ), perforin- ( FIG. 10B ) and Fas- ( FIG. 10C ) expressing CD8+ T cells in unstimulated and flu-stimulated conditions. Data obtained in the absence or in the presence of five different doses of RM4848 (0.5 ⁇ g/ml; 1.0 ⁇ g/ml; 10 ⁇ g/ml; 20 ⁇ g/ml; 40 ⁇ g/ml) are indicated. Mean values, S.E. and p values are shown.
  • FIG. 11 shows graphs expressing an embodiment of the invention wherein inhibition of HIV-1 replication: p24 levels in PBMC exposed to HIV (Panel A) and percentage of HIV replication inhibition (Panel B) in the absence/presence of different doses of tizoxanide (1.0 ⁇ g/ml; 10 ⁇ g/ml) are evaluated at 5 days post-infection. Mean values, S.E., and p values are indicated.
  • compositions and methods of the present invention are for stimulating an immune response in a subject in need thereof, thereby preventing and treating infections and/or cancer conditions.
  • the aim of the invention is to provide effective, non-invasive methods to prevent and treat a viral infection, a cancer condition and/or diseases caused by intracellular protozoan infections in a subject in need thereof, by stimulating a strong immune response in the subject, which is mediated by both the innate and the acquired immune systems.
  • the innate immune system which confers immediate, short-term defense against infection, provides for the recruitment of phagocytes and especially neutrophils at the site of inflammation, which in turn stimulate the release of leukocytes and lymphocytes, with the concomitant production of cytokines, including TNF, HMGB1 and IL-1.
  • Innate leukocytes include natural killer cells, mast cells, eosinophils, basophils and phagocytes, including macrophages, neutrophils and dendritic cells.
  • Toll-like receptors (TLRs) are key components of the innate immune system, as they detect microbial infection and trigger anti-microbial host defense responses.
  • TLRs control multiple dendritic cell functions and trigger the cascade that leads to the acquired immune system response, including the production of type I interferons (I IFNs).
  • TLRs 3, 7, 8 and 9 are involved in viral detection and recognize pathogen nucleic acids.
  • TLRs 7, 8 and 9 are located in intracellular endolysosomal compartments.
  • the acquired or adaptive immune system which is triggered in vertebrates when a pathogen evades the innate immune system, is responsible for the recognition of specific “non-self” antigens during antigen presentation and for the immune response aimed at eliminating foreign pathogens or pathogen infected cells.
  • the B cells are involved in the humoral immune response, and the T cells are responsible for cell-mediated immune responses.
  • Antigen presentation by the dendritic cells stimulates T cells to become either “cytotoxic” CD8+ cells or “helper” CD4+ cells.
  • the dendritic cells present the “non-self” antigens on their surface by coupling them to the Major histocompatibility complex (MHC, also known in humans as Human leukocyte antigen (HLA)), which is recognized by the T cells passing through the lymph nodes.
  • MHC Major histocompatibility complex
  • HLA Human leukocyte antigen
  • Exogenous antigens are usually displayed on MHC class II molecules, which activate CD4+ helper T-cells.
  • Endogenous antigens produced by viruses which replicate within a host cell are typically displayed on MHC class I molecules, and activate CD8+ cytotoxic T-cells.
  • the acquired immune system includes cytotoxic T cells, also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL).
  • CTL cytotoxic T-lymphocyte
  • T cell receptor TCR
  • TCR T cell receptor
  • cytotoxins such as perforin and granulysin
  • CTL activation is regulated by CD4+ lymphocytes or helper T cells.
  • Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules.
  • Effector CD4+ T helper cells may respond to an infection by triggering a Th1 or Th2 type response.
  • the Th1 response leads to cell-mediated immunity and is characterized by the production of Interferon-gamma, which activates macrophages and induces B cells to produce antibodies.
  • Th2 response leads to humoral immunity and is characterized by the release of Interleukin 4, with the consequent activation of B cells and production of neutralizing antibodies.
  • Th1 responses are more effective against intracellular pathogens, such as viruses and bacteria that are inside host cells, while Th2 responses are more effective against extracellular bacteria, parasites and toxins.
  • thiazolide agents in particular nitazoxanide, tizoxanide and RM-4848, or a prodrug thereof, result from the immunomodulatory activity of these agents, which are capable of stimulating a strong immune response by activating both the innate and the acquired immune systems.
  • nitazoxanide, tizoxanide and RM-4848 stimulate T helper cell and CTL activity, TLR7 and TLR8 expression and type I interferon response, by inducing an increase in: I) IFN ⁇ - and IL2-secreting CD4+ T cells, 2) CTL degranulation, 3) Fas-expressing CD8+ T cells, 4) TLR8-expressing monocytes, 5) IFN ⁇ - and IFN ⁇ - mRNA expression, 6) mRNA specific for type 1 IFN inducible genes (MXA, PRKCZ, ADAR, CXCL10, IRF1, PRKRA), and 7) mRNA specific for gene involved in MHC class presentation (HLA-A, HLA-B, TAP1).
  • these thiazolide agents may be used for stimulating an immune response in a subject in need thereof, and in particular in subjects who are at risk of developing or are suffering from a disease where a strong immune response is needed, such as viral infection, a cancer or a disease caused by intracellular protozoan infection(s). Additionally, the methods of the invention can be used to alleviate the symptoms of the disease, or as a preventative measure in a subject.
  • subject and “patient” are used interchangeably, and are meant to refer to any mammal, including humans, that has, or is at risk of developing, a viral infection or a cancer condition.
  • the subject or patient is typically human, however, other suitable subjects or patients include, but are not limited to, laboratory animals, such as mouse, rat, rabbit, or guinea pig, farm animals and domestic animals or pets. Non-human primates are also included.
  • treating refers to a reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause (e.g., prophylactic therapy), improvement or remediation of damage, or reduction in intensity of infection.
  • a “therapeutically effective amount” is an amount effective to elicit a cellular response that is clinically significant.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. and Drug administration.
  • thiazolide compounds of the invention are those disclosed in U.S. Pat. Nos. 7,645,783, 7,550,493, 7,285,567, 6,117,894, 6,020,353, 5,968,961, 5,965,590, 5,935,591, 5,886,013, which are herein incorporated by reference in their entirety.
  • Preferred thiazolide compounds are nitazoxanide, tizoxanide or RM-4848, or its ester prodrug, RM-5038. It is understood that other prodrugs analogous or homologous to RM-5038 are also envisioned, and are an embodiment of this invention.
  • thiazolide refers to a thiazolide, a thiazolide analogue or a substituted thiazolide.
  • nitazoxanide refers to both nitazoxanide (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide) and to a nitazoxanide analogue, e.g., to one of the compounds disclosed in U.S. Pat. No. 7,285,567 or US 2007/0167504.
  • tizoxanide refers to tizoxanide, a tizoxanide analogue or a substituted tizoxanide.
  • Nitazoxanide, tizoxanide, RM-4848 or any of the thiazolide analogues may be administered in the form of the compound per se, and/or, where suitable, in the form of a salt, polymorph, ester, amide, prodrug, derivative, or the like, provided the salt, polymorph, ester, amide, prodrug or derivative is suitable pharmacologically.
  • Such salts, esters, amides, prodrugs and other derivatives of these active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).
  • the total amount of nitazoxanide or tizoxanide in the compositions of the invention is typically about 60% to 75% by weight of the composition.
  • the compositions may be formulated for immediate release, controlled release or sustained release.
  • the compositions may contain one or more additional pharmaceutically acceptable additives or excipients. These excipients are therapeutically inert ingredients that are well known and appreciated in the art.
  • inert ingredient refers to those therapeutically inert ingredients that are well known in the art of pharmaceutical science, which can be used singly or in various combinations, and include, for example, diluents, disintegrants, binders, suspending agents, glidants, lubricants, fillers, coating agents, solubilizing agent, sweetening agents, coloring agents, flavoring agents, and antioxidants. See, for example, Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa.
  • diluents or fillers include, but are not limited to, starch, lactose, xylitol, sorbitol, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, dicalcium phosphaste dehydrate, calcium sulfate, and the like.
  • the amount of diluents or fillers may be in a range between about 2% to about 15% by weight of the entire composition.
  • disintegrants include, but are not limited to, alginic acid, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, sodium croscarmellose, crospovidone, polacrilin potassium, sodium starch glycolate, starch, including corn or maize starch, pregelatinized starch and the like. Disintegrant(s) typically represent about 2% to about 15% by weight of the entire composition.
  • binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, and the like.
  • the amount of binders is about 0.2% to about 14% by weight of the entire composition.
  • glidants include, but are not limited to, silicon dioxide, colloidal anhydrous silica, magnesium trisilicate, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, powdered cellulose, starch, talc, and the like.
  • the amount of glidant(s) is about 0.01% to about 0.3% by weight of the entire composition.
  • lubricants include, but are not limited to, magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, stearic acid, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, talc, hydrogenated vegetable oil and the like.
  • the amount of lubricant(s) is about 0.2% to about 1.0% by weight of the entire composition.
  • compositions may contain a binder that is a low-viscosity polymer.
  • low-viscosity polymers include, but are not limited to, low-viscosity hydroxypropyl methylcellulose polymers such as those sold by Dow Chemical under the tradename “MethoceL®” (e.g., Methocel E50LV®, Methocel K100LV®, and Methocel F50LV®) and low-viscosity hydroxyethylcellulose polymers.
  • the low-viscosity polymer is typically present at about 10% to about 20%, or about 10% to about 15%, or preferably about 12%, of the total weight of the entire composition, or, in those embodiments having controlled release and immediate release portions, the low-viscosity polymer in the controlled release portion is typically present at about 15% to about 20%, preferably about 18%, of the weight of the controlled release portion.
  • compositions may further comprise a coating material.
  • the coating material is typically present as an outer layer on the dosage form that completely covers the formulation.
  • the dosage form is an oral tablet in which the controlled release portion forms a first layer of the tablet and the immediate release portion forms a second layer that is deposited on top of the first layer to form a core tablet.
  • the coating material can be in the form of an outer coating layer that is deposited on top of the core tablet.
  • the coating material typically is about 1% to about 5% by weight of the composition, and may comprise hydroxypropylmethylcellulose and/or polyethylene glycol, and one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, coloring agents, antitacking agents and the like.
  • excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, coloring agents, antitacking agents and the like. Examples of film-coating substances and methods for using such coating substances are well known to those of skill in the art.
  • the present compositions can be used effectively to stimulate the immune system in a subject in need thereof, thereby treating or preventing a viral infection, a cancer or diseases caused by intracellular protozoan or bacterial infections.
  • the viral infection may be influenza, in particular an influenza caused by a virus selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, 1-17N3, and H10N7, or Hepatitis B, or diarrhea or gastroenteritis caused by rotavirus or norovirus.
  • the cancer may be leukemia, including hairy cell leukemia and chronic myeloid leukemia, melanoma, non-Hodgkin lymphoma, or renal cell carcinoma.
  • the disease caused by intracellular protozoan infection may be Cryptosporidium spp., Leishmania spp., Toxoplasma gondii, Trypanosoma cruzii .
  • the disease caused by intracellular bacterial infection may be Mycobacterium tuberculosis .
  • the compositions may be administered for any length of time suitable for effectively treat or prevent a viral infection, a cancer or disease caused by intracellular protozoan infection. Any appropriate dosage and regimen may be used for the compositions. Administration can typically be carried out over a period of about 3 days to about 104 weeks, but may be carried out over a period longer than 104 weeks and may even be carried out indefinitely. Appropriate regimens can be determined by a physician.
  • the thiazolide compounds may be administered alone or in combination with one or more additional active agents, including a neuraminidase inhibitor, such as Laninamivir, Oseltamivir, Zanamivir or Peramivir, an immunostimulant, such as Imiquimod or Resiquimod, an adamantine analogue, and a recombinant sialidase fusion protein.
  • additional active agents including an antiprotozoal drug.
  • the antiprotozoal drug may include, but is not limited to, trimethoprim/sulfamethoxazole, atovaquone, clindamycin, pyrimethamine, spiramycin, diminazine, homidium, suramin, melarsamine, sodium stibogluconate and meglumine antimoniate.
  • the thiazolide compounds may be administered prophylactically in combination with a vaccine, or in combination with an anticancer drug.
  • the anticancer drug may include, but is not limited to, STI571, CGP 74588, 1- ⁇ -D-Arabinofuranosylcytosine (Ara-C), doxorbicin, dacarbazine, cisplatin, bleomycin, vincristine, lomustine, vinblastine, carmustine, DTIC, tamoxifen, sunitinib, sorafenib and interferon- ⁇ .
  • the composition and the additional active agent e.g., an interferon
  • the immune response required to effectively treat or prevent a viral disease, cancer or intracellular protozoan or bacterial infection may not be produced by thiazolides using the dosing regimen that is typically used to successfully treat a subject with a fully competent immune system.
  • Subjects with extreme immune deficiencies may not be good candidates for treatment with thiazolides.
  • Subjects with moderate immune deficiencies may require higher doses of thiazolide treatment, more frequent dosing, or dosing for a longer period of time than subjects with fully competent immune systems.
  • Subjects with HIV infection who have not developed immune deficiencies may be effectively treated with thiazolides, while subjects with immune deficiencies associated with HIV infection may require treatment with antiretroviral drugs to reduce HIV viral titer and partially restore immune function before or simultaneously with thiazolide therapy.
  • antiretroviral drugs to reduce HIV viral titer and partially restore immune function before or simultaneously with thiazolide therapy.
  • the use of thiazolides to stimulate immune response may be tailored for patients based on immune status.
  • Mononuclear blood cells have an important role in the immune response system, as they produce different cytokines in response to pathogen infections. Accordingly, the immunomodulatory effects of tizoxanide (TIZ) in peripheral mononuclear blood cells (PMBCs) obtained from ten (10) healthy donors and isolated by centrifugation on Ficoll-Paque. The PMBCs were cultured in RPMI-1640 media supplemented with 10% human serum in the presence or absence of three different doses of TIZ (0.5, 1.0 and 10 mg/ml) in both unstimulated and flu-stimulated conditions.
  • TIZ tizoxanide
  • the unstimulated and stimulated PMBCs were analyzed for T helper and CTL activity as well as for TLR7 and TLR8 expression and type I IFN responses in the absence or presence of different doses of tizoxanide.
  • the immunological analyses were as follows:
  • T helper functions were detected by determining the amount of IFN ⁇ - and IL-2-secreting CD4+ T cells.
  • CTL activity was detected by determining the amount of perforin-, granzyme- and Fas-expressing CD8+ T cells.
  • TLR expression was detected by measuring TLR8-, TLR7- and TLR3-expressing CD14+ monocytes.
  • Tizoxanide modulation of the TLR pathway was detected by PCR array analysis of Human Type I Interferon (IFN).
  • TIZ immunomodulating effects were determined in unstimulated and flu-stimulated PMBCs by analysis of the following:
  • Interferons Ligands for Interferon-alpha and Interferon-beta Receptors: IFNA1, IFNA4, IFNB1, IFNK, IFNW1.
  • Ligands for Interferon-gamma Receptors IFNG.
  • Ligands for Hematopoietin and Interferon-class (D200-domain) Cytokine Receptors IFNA14, IFNA2, IFNA21, IFNA5, IFNA6, IFNA8, IFNE1, IL15.
  • Other Genes Related to Interferons IFRD1, IFRD2, IL28A, IL29, IL6.
  • Interferon Receptors Interferon-alpha and Interferon-beta Receptors: IFNAR1, IFNAR2.
  • Interferon-gamma Receptors IFNGR1, IFNGR2.
  • Interferon Regulatory Factors Transcriptional Regulators: IRF1, IRF2, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8. Other Interferon Regulatory Proteins: IRF2BP1, IRF2BP2.
  • Interferon-Inducible Proteins Genes Involved in the Response to Virus: ISG15 (G1P2), IF116, IF135, IF144, IFIH1, MX1, OAS1.
  • Transcriptional Regulators IFI16, SP110.
  • Adaptors & TLR Interacting Proteins BTK, CD14, HMGB1, HRAS, HSPA1A, HSPD1, LY86 (MD-1), LY96 (MD-2), MAPK81P3, MYD88, PELII, RIPK2, SARM1, TICAM2, TIRAP, TOLLIP, TRIF.
  • CASP8 EIF2AK2, FADD, IRAK1, IRAK2, MAP3K7 (TAK1), MAP3K7IP1 (TAB1), NR2C2, PPARA, PRKRA, SITPEC, TRAF6, UBE2N, UBE2V1.
  • NF ⁇ B Pathway CCL2, CHUK, CSF2 (GMCSF), CSF3 (GCSF), IFNA1, IFNB1, IFNG, IKBKB, IL1A, IL1B, IL2, IL6, IL8, IL10, IL12A, LTA, MAP3K1, MAP4K4, NFKB1, NFKB2, NFKBIA, NFKBIL1, NFRKB, REL, RELA, TNF, TNFRSF1A.
  • JNK/p38 Pathway ELK1, FOS (c-Fos), JUN, MAP2K3, MAP2K4 (JNKK1), MAP3K1 (MEKK), MAPK8 (JNK I).
  • NF/IL6 Pathway CLECSF9, PTGS2.
  • IRF Pathway CXCLIO, IFN ⁇ I, IFNB 1, IFNG, IRF I, IRF3, TBKI.
  • TIZ showed potent immunomodulatory effects inducing an increase in: 1) IFN ⁇ - and IL2-secreting CD4+ T cells ( FIGS. 4A and 4B ); 2) CTL degranulation ( FIG. 5B ); 3) Fas-expressing CD8+ T cells ( FIG. 5C ); 4) TLR3-, TLR8- and TLR7- expression on monocytes ( FIGS. 1A-C ); 5) IFN ⁇ - and IFN ⁇ - mRNA expression ( FIG. 3A ), 6) mRNA specific for type I IFN inducible genes (MXA, PRKCZ, ADAR, CXCL10, IRF1, PRKRA) ( FIG. 3B ); and 7) mRNA specific for gene involved in MHC class I presentation (HLA-A, HLA-B, TAP1) ( FIG. 3C ).
  • TIZ has remarkable immumodulatory activity and stimulates a strong immune response, which is mediated by both the innate and the acquired immune systems.
  • TLR3, TLR7 and TLR8 expression was evaluated on CD14+ cells (monocytes) both in un-stimulated and in flu-stimulated conditions.
  • RM-4848 To determine whether an effect exerted by RM-4848 on TLR expression is dependent on a differential modulation of the TLR-associated transduction pathways, we used a Real-time PCR array, which screens for the expression of 84 genes that are involved in TLR- pathway activation.
  • the data obtained in un-stimulated PBMC following 3 hours of incubation with RM-4848 shows that only 3 of the 84 genes are up regulated with approximately a 5-fold increase of IL1A and IL1B and a 6-fold increase of the IL6 at the 20 ⁇ g/ml dose as indicated in FIG. 2A .
  • results of the analyses performed in flu-stimulated PBMC incubated with RM-4848 showed that 12 of the 84 genes tested were up regulated.
  • the data obtained in flu-stimulated PBMC following 3 hours of incubation with RM-4848 show a 10-fold increase for INFA1 and INFA4, a 8-fold increase for INFB1 and a 6-fold increase for IFNA2 at the low 1 ⁇ g/ml dose.
  • the three dose levels moderately up-regulated the ISGs, IFI27 and IFIT1 with a more pronounced effect at the 10 ⁇ g/ml dose (>4-fold) ( FIG. 3B ).
  • IFN- ⁇ and IL2 production by CD4+ T cells was evaluated both in basal condition and after stimulation with Flu-specific antigens.
  • Granzyme-, Perforin- and Fas-expressing CD8+ T cells were analysed in unstimulated condition and upon Flu-antigen-stimulation.
  • RM-4848 at the three higher dose levels tested, induced a degranulation of CTLs, evaluated by reduction in perforin expression ( FIG. 5B ).
  • RM4848 which stimulates the immune system to fight viral infection. It is particularly remarkable that the drug is not only stimulating an innate immune response probably responsible for clearing most infections before they cause perceptible disease even if many pathogens have evolved mechanisms for obstructing their detection. From a clinical standpoint it would suggest that RM4848 and likely the other thiazolides with a similar immuno-stimulating profile could be used to prevent diseases or to limitate the spread of a disease. The activity of RM4848 against the adaptive immunity is not only remarkable because it comes in addition to its effect against innate immunity but also because it is the mechanism by which viral diseases are cured.
  • Adaptive immunity is based on lymphocytes, which have a single type of receptors but an essentially unlimited repertoire of variants recognizing antigens, an operationally defined term that reflects their versatility. In addition to the productions of several lymphocytes, helpers or killers they will culminate with the production of antibodies by the B cells. If adaptive immunity is delayed to a few days upon the onset of a specific infection, its action in producing particles toxic to the pathogen and the development of immune memory are a most powerful anti-viral mechanism that that observed with innate immunity while both are necessary and inter-related.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mechanical Engineering (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US13/471,948 2011-05-16 2012-05-15 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections Abandoned US20120294831A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/471,948 US20120294831A1 (en) 2011-05-16 2012-05-15 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
US15/861,234 US10336058B2 (en) 2011-05-16 2018-01-03 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
US16/438,783 US10814612B2 (en) 2011-05-16 2019-06-12 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161486728P 2011-05-16 2011-05-16
US13/471,948 US20120294831A1 (en) 2011-05-16 2012-05-15 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/861,234 Continuation US10336058B2 (en) 2011-05-16 2018-01-03 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Publications (1)

Publication Number Publication Date
US20120294831A1 true US20120294831A1 (en) 2012-11-22

Family

ID=47175068

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/471,948 Abandoned US20120294831A1 (en) 2011-05-16 2012-05-15 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
US15/861,234 Expired - Fee Related US10336058B2 (en) 2011-05-16 2018-01-03 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
US16/438,783 Expired - Fee Related US10814612B2 (en) 2011-05-16 2019-06-12 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Family Applications After (2)

Application Number Title Priority Date Filing Date
US15/861,234 Expired - Fee Related US10336058B2 (en) 2011-05-16 2018-01-03 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
US16/438,783 Expired - Fee Related US10814612B2 (en) 2011-05-16 2019-06-12 Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Country Status (15)

Country Link
US (3) US20120294831A1 (https=)
EP (1) EP2709453B1 (https=)
JP (3) JP6138764B2 (https=)
KR (1) KR102037162B1 (https=)
CN (2) CN103648282B (https=)
AU (1) AU2012255962B2 (https=)
BR (1) BR112013029505A2 (https=)
CA (1) CA2836253C (https=)
DK (1) DK2709453T3 (https=)
EA (1) EA024063B1 (https=)
ES (1) ES2767304T3 (https=)
IL (1) IL229459B (https=)
MX (2) MX2013013115A (https=)
WO (1) WO2012158699A1 (https=)
ZA (1) ZA201308617B (https=)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105683392A (zh) * 2013-03-15 2016-06-15 博德研究所 树突细胞应答基因表达、物质组合物及其使用方法
WO2016123073A1 (en) * 2015-01-26 2016-08-04 Children's Medical Center Corporation Treatment of infectious diseases
WO2017173056A1 (en) 2016-03-31 2017-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
US10100023B2 (en) 2014-11-11 2018-10-16 Romark Laboratories, L.C. Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof
US10117855B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
WO2020208208A1 (en) * 2019-04-12 2020-10-15 Genfit Nitazoxanide and thiazolides for use in the treatment of diseases associated with oxidative stress
US11173149B2 (en) 2017-04-18 2021-11-16 Romark Laboratories L.C. Inhibition of protein disulfide-isomerase A3
WO2022020243A1 (en) 2020-07-20 2022-01-27 Romark Laboratories L.C. Crystalline salts of tizoxanide and 2-hydroxy-n-(5-chloro-1,3-thiazol-2-yl)benzamide (rm-4848) with ethanolamine, morpholine, propanolamine, piperazine and n-methylpiperazine
WO2022046622A1 (en) 2020-08-24 2022-03-03 Romark Laboratories L.C. Use of thiazolides against coronaviruses
CN116539887A (zh) * 2023-01-09 2023-08-04 重庆医科大学 Psme1作为药物靶点在筛选或制备治疗乙型肝炎的药物中的应用

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103648282B (zh) * 2011-05-16 2017-02-15 罗马克实验室有限公司 噻唑化物类化合物用于预防和治疗病毒性疾病、癌症和由细胞内感染引起的疾病的用途
KR101508611B1 (ko) 2013-09-02 2015-04-08 가톨릭대학교 산학협력단 아파티닙을 포함하는 톡소포자충 감염증의 예방 및 치료용 조성물
KR101508610B1 (ko) * 2013-09-02 2015-04-08 가톨릭대학교 산학협력단 다코미티닙을 포함하는 톡소포자충 감염증의 예방 및 치료용 조성물
WO2015030504A1 (ko) * 2013-09-02 2015-03-05 가톨릭대학교 산학협력단 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충감염증의 예방 또는 치료용 약학 조성물
CN105998036B (zh) * 2016-05-19 2018-07-27 洛阳市兽药厂 一种猪禽用复方磺胺硝唑尼特可溶性粉
JP7365054B2 (ja) * 2017-11-17 2023-10-19 ケスター，ヒューバート リンパ管平滑筋腫症及びその他の疾患に使用するための［２－［（５－ニトロ－１，３－チアゾール－２－イル）カルバモイル］フェニル］エタノエート
CN118903087A (zh) 2019-07-26 2024-11-08 埃斯佩尔维塔治疗股份有限公司 可用于预防或治疗疾病的官能化的长链烃一元和二元羧酸
CN113398125B (zh) 2020-03-16 2024-05-03 绍兴君科臻元医药科技有限公司 替唑尼特药物组合物及其医药用途
CA3209453A1 (en) 2021-01-25 2022-07-28 Espervita Therapeutics, Inc. Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives therof, and their use for the prevention or treatment of disease
US11730712B2 (en) 2021-01-25 2023-08-22 Espervita Therapeutics, Inc. Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease
WO2023077711A1 (zh) * 2021-11-03 2023-05-11 南方科技大学 预防前列腺癌的药剂的筛选方法及硝唑尼特在制药中的应用
CN114231611A (zh) * 2021-12-07 2022-03-25 中南大学湘雅二医院 干扰素诱导基因ifit3对b淋巴细胞活化及分化影响的研究方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100081713A1 (en) * 2008-03-19 2010-04-01 CombinatoRx, (Singapore) Pte. Ltd. Compositions and methods for treating viral infections
WO2010151577A1 (en) * 2009-06-26 2010-12-29 Romark Laboratories L.C. Compounds and methods for treating influenza
US20110020272A1 (en) * 2009-07-24 2011-01-27 Ulrich Schubert Combination therapy for treating hepatitis viral infection
WO2011106445A1 (en) * 2010-02-24 2011-09-01 Gilead Sciences, Inc. Antiviral compounds
WO2012139028A2 (en) * 2011-04-06 2012-10-11 The Trustees Of Princeton University Anti-viral combination therapy
US8633230B2 (en) * 2006-01-09 2014-01-21 Jean-Francois Rossignol Viral hepatitis treatment

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968961A (en) 1997-05-07 1999-10-19 Romark Laboratories, L.C. Pharmaceutical compositions of tizoxanide and nitazoxanide
US5965590A (en) * 1994-09-08 1999-10-12 Romark Lab Lc Method for treatment of opportunistic infections with pharmaceutical compositions of tizoxanide and nitazoxanide
US5859038A (en) * 1994-09-08 1999-01-12 Romark Laboratories, L.C. Method for treatment of helicobacter pylori infections
MX9604483A (es) 1994-09-08 1998-02-28 Jean-Francois Rossignol Derivados de benzamida, composiciones que contienen dicho derivado y uso de las mismas.
US5958038A (en) * 1997-11-07 1999-09-28 S3 Incorporated Computer processor with two addressable memories and two stream registers and method of data streaming of ALU operation
US5935591A (en) 1998-01-15 1999-08-10 Romark Laboratories, L.C. Method for treatment of equine protozoal myeloencephalitis with thiazolides
US7985422B2 (en) * 2002-08-05 2011-07-26 Torrent Pharmaceuticals Limited Dosage form
UA90864C2 (en) 2004-09-09 2010-06-10 Ромарк Лебораториз, Л.К. Halogenated benzamide derivatives
CA2604640A1 (en) 2005-04-12 2006-10-19 Romark Laboratories L.C. Methods for treating diseases through interruption of protein maturation, compounds that inhibit the function of molecular chaperones such as protein disulfide isomerases or interfere with glycosylation, pharmaceutical compositions comprising them, and screening methods for identifying therapeutic agents
JP2011506290A (ja) * 2007-12-06 2011-03-03 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム インフルエンザ組成物
AU2009333580B2 (en) * 2008-12-09 2016-07-07 Genentech, Inc. Anti-PD-L1 antibodies and their use to enhance T-cell function
US8962652B2 (en) * 2009-10-22 2015-02-24 Gilead Sciences, Inc. Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections
US9439878B2 (en) * 2010-06-03 2016-09-13 Douglas Tyler McKenzie Use of lumefantrine and related compounds in the treatment of cancer
CN103648282B (zh) * 2011-05-16 2017-02-15 罗马克实验室有限公司 噻唑化物类化合物用于预防和治疗病毒性疾病、癌症和由细胞内感染引起的疾病的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8633230B2 (en) * 2006-01-09 2014-01-21 Jean-Francois Rossignol Viral hepatitis treatment
US20100081713A1 (en) * 2008-03-19 2010-04-01 CombinatoRx, (Singapore) Pte. Ltd. Compositions and methods for treating viral infections
WO2010151577A1 (en) * 2009-06-26 2010-12-29 Romark Laboratories L.C. Compounds and methods for treating influenza
US20110020272A1 (en) * 2009-07-24 2011-01-27 Ulrich Schubert Combination therapy for treating hepatitis viral infection
WO2011106445A1 (en) * 2010-02-24 2011-09-01 Gilead Sciences, Inc. Antiviral compounds
WO2012139028A2 (en) * 2011-04-06 2012-10-11 The Trustees Of Princeton University Anti-viral combination therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Fox, Nature Biotechnology, 2007, 25(12):1395-1402. *
Tan et al., "Systems biology and the host response to viral infection", 2007, Nature, 25(12):1383-1389. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2971116A4 (en) * 2013-03-15 2016-12-14 Broad Inst Inc GENE EXPRESSION OF DENDRITIC CELL REACTION, SUBSTANCE COMPOSITIONS AND METHOD FOR USE THEREOF
CN105683392A (zh) * 2013-03-15 2016-06-15 博德研究所 树突细胞应答基因表达、物质组合物及其使用方法
US10870885B2 (en) 2013-03-15 2020-12-22 The Broad Institute, Inc. Dendritic cell response gene expression, compositions of matters and methods of use thereof
US10358428B2 (en) 2014-11-11 2019-07-23 Romark Laboratories, L.C. Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof
US10100023B2 (en) 2014-11-11 2018-10-16 Romark Laboratories, L.C. Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof
US10577337B2 (en) 2014-11-11 2020-03-03 Romark Laboratories, L.C. Compositions and methods of treatment with prodrugs of tizoxanide, an analogue or salt thereof
WO2016123073A1 (en) * 2015-01-26 2016-08-04 Children's Medical Center Corporation Treatment of infectious diseases
US10765664B2 (en) 2015-01-26 2020-09-08 Children's Medical Center Corporation Treatment of infectious diseases
US11135202B2 (en) 2016-03-31 2021-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
EP3677282A1 (en) 2016-03-31 2020-07-08 Romark Laboratories, L.C. Thiazolide compounds for treating viral infections
WO2017173056A1 (en) 2016-03-31 2017-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
US10130613B2 (en) 2016-04-11 2018-11-20 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10130612B2 (en) 2016-04-11 2018-11-20 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10117856B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10117855B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
US11173149B2 (en) 2017-04-18 2021-11-16 Romark Laboratories L.C. Inhibition of protein disulfide-isomerase A3
WO2020208208A1 (en) * 2019-04-12 2020-10-15 Genfit Nitazoxanide and thiazolides for use in the treatment of diseases associated with oxidative stress
CN113710247A (zh) * 2019-04-12 2021-11-26 基恩菲特公司 用于治疗氧化应激相关疾病的硝唑尼特和噻唑化物
WO2022020243A1 (en) 2020-07-20 2022-01-27 Romark Laboratories L.C. Crystalline salts of tizoxanide and 2-hydroxy-n-(5-chloro-1,3-thiazol-2-yl)benzamide (rm-4848) with ethanolamine, morpholine, propanolamine, piperazine and n-methylpiperazine
WO2022046622A1 (en) 2020-08-24 2022-03-03 Romark Laboratories L.C. Use of thiazolides against coronaviruses
CN116539887A (zh) * 2023-01-09 2023-08-04 重庆医科大学 Psme1作为药物靶点在筛选或制备治疗乙型肝炎的药物中的应用

Also Published As

Publication number Publication date
EP2709453A4 (en) 2014-11-19
JP2017149764A (ja) 2017-08-31
KR20140028034A (ko) 2014-03-07
KR102037162B1 (ko) 2019-10-29
CN107096032A (zh) 2017-08-29
CN103648282B (zh) 2017-02-15
IL229459A0 (en) 2014-01-30
CA2836253C (en) 2021-02-16
ES2767304T3 (es) 2020-06-17
BR112013029505A2 (pt) 2020-01-07
AU2012255962B2 (en) 2016-05-12
EP2709453B1 (en) 2019-10-23
DK2709453T3 (da) 2020-01-20
US20190291404A1 (en) 2019-09-26
JP2014513725A (ja) 2014-06-05
MX2013013115A (es) 2014-02-27
US10814612B2 (en) 2020-10-27
IL229459B (en) 2021-05-31
JP6138764B2 (ja) 2017-05-31
EA024063B1 (ru) 2016-08-31
US10336058B2 (en) 2019-07-02
CA2836253A1 (en) 2012-11-22
MX378726B (es) 2025-03-11
US20180126722A1 (en) 2018-05-10
EP2709453A1 (en) 2014-03-26
EA201391616A1 (ru) 2014-05-30
WO2012158699A1 (en) 2012-11-22
CN103648282A (zh) 2014-03-19
ZA201308617B (en) 2020-07-29
JP2019052175A (ja) 2019-04-04

Similar Documents

Publication Publication Date Title
US10814612B2 (en) Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
AU2012255962A1 (en) Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
Holicek et al. Type I interferon and cancer
Gibbert et al. IFN‐α subtypes: distinct biological activities in anti‐viral therapy
Sin et al. Activation and regulation of interferon-β in immune responses
JP2013522302A (ja) 酵母系免疫療法を使用した感染症の薬理ゲノミクス及び治療反応性ガイド治療
Bergman et al. Interferons as therapeutic agents for infectious diseases
AU2018211247B2 (en) Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
JP2008528673A (ja) トリインフルエンザの治療のための方法およびインターフェロン組成物の使用
Dec et al. Use of oromucosally administered IFN-α in the prevention and treatment of animal diseases
HK1240084A1 (en) A method of stimulating an immune response in a subject in need thereof
HK1192415B (en) Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
HK1192415A (en) Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections
AU746648B2 (en) Use of IFN-alpha and amantadine for the treatment of chronic hepatitis C
CA3158591A1 (en) Methods of treating hiv-1 infection
Poulas Imiquimod-A Toll like Receptor 7 Agonist-IS an Ideal Option for Management of COVID 19
JP2009504706A (ja) ＨＢＶ処置のためのＰＥＧ−ＩＦＮαおよびリバビリン
Masihi C7 Anti-infective activity of immunomodulators

Legal Events

Date Code Title Description
AS Assignment

Owner name: ROMARK LABORATORIES L.C., FLORIDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ROSSIGNOL, JEAN-FRANCOIS;REEL/FRAME:028669/0103

Effective date: 20120516

AS Assignment

Owner name: U.S. BANK NATIONAL ASSOCIATION, MASSACHUSETTS

Free format text: SECURITY AGREEMENT;ASSIGNORS:ROMARK LABORATORIES, L.C.;ROMARK MANUFACTURING, LLC;LAPICOR, N.V.;REEL/FRAME:031156/0923

Effective date: 20130830

AS Assignment

Owner name: ROMARK LABORATORIES, L.C., FLORIDA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:U.S. BANK NATIONAL ASSOCIATION;REEL/FRAME:035108/0474

Effective date: 20150306

Owner name: LAPICOR, N.V., BELGIUM

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:U.S. BANK NATIONAL ASSOCIATION;REEL/FRAME:035108/0474

Effective date: 20150306

Owner name: ROMARK MANUFACTURING, LLC, FLORIDA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:U.S. BANK NATIONAL ASSOCIATION;REEL/FRAME:035108/0474

Effective date: 20150306

AS Assignment

Owner name: U.S. BANK NATIONAL ASSOCIATION, MASSACHUSETTS

Free format text: SECURITY INTEREST;ASSIGNORS:ROMARK BIOSCIENCES S.A R.L. LLC;ROMARK LABORATORIES, L.C.;REEL/FRAME:044472/0001

Effective date: 20171222

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION