[go: up one dir, main page]

WO2023105283A1 - Inhibiteurs nucléosidiques de la transcriptase inverse destinés à être utilisés dans le traitement du syndrome de down et de la maladie d'alzheimer - Google Patents

Inhibiteurs nucléosidiques de la transcriptase inverse destinés à être utilisés dans le traitement du syndrome de down et de la maladie d'alzheimer Download PDF

Info

Publication number
WO2023105283A1
WO2023105283A1 PCT/IB2022/000673 IB2022000673W WO2023105283A1 WO 2023105283 A1 WO2023105283 A1 WO 2023105283A1 IB 2022000673 W IB2022000673 W IB 2022000673W WO 2023105283 A1 WO2023105283 A1 WO 2023105283A1
Authority
WO
WIPO (PCT)
Prior art keywords
nrti
consequences
treatment
alzheimer
combination
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.)
Ceased
Application number
PCT/IB2022/000673
Other languages
English (en)
Inventor
María del Mar DIERSSEN SOTOS
María MARTÍNEZ DE LAGRÁN CABREDO
Aleix ELIZALDE-TORRENT
Roger PAREDES DEIRÓS
Bonaventura Clotet Sala
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.)
Fundacio Lluita Contra La Sida I Les Malalties Infeccioses
IrsiCaixa Institut de Recerca de la Sida
Fundacio Privada Centre de Regulacio Genomica CRG
Original Assignee
Fundacio Lluita Contra La Sida I Les Malalties Infeccioses
IrsiCaixa Institut de Recerca de la Sida
Fundacio Privada Centre de Regulacio Genomica CRG
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 Fundacio Lluita Contra La Sida I Les Malalties Infeccioses, IrsiCaixa Institut de Recerca de la Sida, Fundacio Privada Centre de Regulacio Genomica CRG filed Critical Fundacio Lluita Contra La Sida I Les Malalties Infeccioses
Publication of WO2023105283A1 publication Critical patent/WO2023105283A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to nucleoside reverse transcriptase inhibitors (NRTI) or their pharmaceutically acceptable salts for use in (a) the treatment of Down syndrome or the consequences thereof or (b) the prevention, inhibition of progression or treatment of Alzheimer' s disease or the consequences thereof.
  • NRTI nucleoside reverse transcriptase inhibitors
  • Pharmaceutical compositions comprising such NRTI and combinations of NRTI are provided. Kits including NRTI, combinations of NRTI, and pharmaceutical composition comprising such NRTI and combinations of NRTI are also described.
  • Down syndrome is the most commonly known genetic disorder associated with moderate to severe intellectual disability due to a total or partial trisomy of the autosomal chromosome 21 (HSA21) and a genetic form of Alzheimer’s disease (AD) (Dierssen M, et al., Nat Rev Neurosci 2012; 13(12):844-858).
  • HSA21 gene products such as DYRK1A, SOD1 or SIOOB has been proposed to contribute to the neurological and neurob ehavi oral DS phenotypes (Altafaj X, et al, Hum Mol Genet 2001; 10(18): 1915-1923, Gulesserian T, et aL, J Investig Med 2001; 49(l):41-46, Griffin W, et al., Proc Natl Acad Sci USA 1989; 86(19):7611-7615).
  • RNA transcripts containing intra-exonic junctions involving a myriad of genes, including the amyloid precursor protein (APP) (Palmer C, et al. , Proc Natl Acad Sci USA 2021 ; 118(47)).
  • APP amyloid precursor protein
  • increased brain transcription and increased copy numbers of APP have been linked to APP somatic gene recombination associated with sporadic AD and with DS, and could contribute to their cognitive deficits (Kaeser G, et al., Front Genet 2020; 11 :390).
  • Retrotransposable elements like the long interspersed nuclear element 1 are thought to participate in this process in mammals (Muotri A, etal., Nature 2005; 435(7044): 903-910). Increased retrotransposition is observed in cell senescence and with ageing and has been implicated in several neurodegenerative diseases including AD, frontotemporal dementia, prion disease, but also in developmental disorders such as Rett’s syndrome, autism or fragile X syndrome (Gorbunova V, et al., Nature 2021; 596(7870):43-53, Li W, et al, PLoS One 2012; 7(9):e44099).
  • NRTIs Nucleoside reverse transcriptase inhibitors
  • the present invention is directed to nucleoside reverse transcriptase inhibitors (NRTI) or their pharmaceutically acceptable salts for use in (a) the treatment of Down syndrome or the consequences thereof or (b) the prevention, inhibition of progression or treatment of Alzheimer' s disease or the consequences thereof.
  • the NRTI comprises abacavir, didanosine, dideoxycytidine, emtricitabine, entecavir, lamivudine, stavudine, tenofovir, zidovudine, their pharmaceutically acceptable salts or a combination thereof.
  • the NRTI is lamiduvine or its pharmaceutically acceptable salts.
  • the consequences thereof comprise cognitive deficit.
  • the present invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one NRTI or its pharmaceutically acceptable salts, a combination of NRTI their pharmaceutically acceptable salts or according to the invention for use in (a) the treatment of Down syndrome or (b) the prevention, inhibition of progression or treatment of Alzheimer's disease or the consequences thereof.
  • the NRTI or the combination thereof may be in the form of pharmaceutically acceptable salts, as generally described below.
  • the consequences thereof comprise cognitive deficit.
  • the present invention refers to Down syndrome and Alzheimer' s disease therapies based on the use of the NRTI, combinations of NRTI, and pharmaceutical compositions of the invention.
  • the present invention relates to a method for treating Down syndrome or the consequences thereof (e.g., cognitive deficit) which comprises administering a therapeutically effective amount of (a) at least one NRTI or a combination thereof (b) a pharmaceutical composition according to the present invention to a subject in need thereof.
  • the present invention is directed to a method for preventing, inhibiting the progression or treating Alzheimer’s disease or the consequences thereof (e.g., cognitive deficit) which comprises administering a therapeutically effective amount of (a) at least one NRTI or a combination thereof or (b) a pharmaceutical composition according to the present invention to a subject in need thereof.
  • kits comprising, according to the invention, (a) at least one NRTI or a pharmaceutically acceptable salt thereof, (b) a combination of NRTI or their pharmaceutically acceptable salts, (c) a pharmaceutical composition comprising at least one NRTI, a pharmaceutically acceptable salt thereof or a combination of NRTI or their pharmaceutically acceptable salts thereof.
  • the kits of the invention are used for (i) treating Down syndrome or the consequences or (ii) preventing, inhibiting the progression or treating Alzheimer’s disease or the consequences thereof in a subject in need thereof.
  • Fig- 1- Locomotor activity and anxiety-like behavior in TS and respective WT in basal conditions and after 1 or 4 months of treatment with lamivudine.
  • Boxplots extend from the 25th to 75th percentiles and the median is represented as a line in the box.
  • the whiskers correspond to the maximum and minimum value excluding outliers. * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.005.
  • AIDS refers to the symptomatic phase of HIV infection, and includes both acquired immune deficiency syndrome (commonly known as AIDS) and “ARC,” or AIDS-Related Complex (Adler M, etal., Brit. Med. J. 1987; 294: 1145-1147).
  • AIDS acquired immune deficiency syndrome
  • ARC AIDS-Related Complex
  • the immunological and clinical manifestations of AIDS are well known in the art and include, for example, opportunistic infections and cancers resulting from immune deficiency.
  • AD Alzheimer's disease
  • cognitive deficit e.g., persistent memory lapses, impaired thinking, and reasoning
  • reduced ability for making judgements and taking decisions e.g., decreased capacity for conducting routinary activities
  • personality and behavior e.g., mood swings, depression, aggressiveness
  • Down syndrome refers to a genetic disorder caused when abnormal cell division results in an extra full or partial copy of chromosome 21. This extra genetic material causes the developmental changes and physical features of Down syndrome. DS consequences include, but are not limited to, moderate cognitive deficit (e.g., impaired thinking and reasoning, delayed language development, reduced short- and long-term memory).
  • moderate cognitive deficit e.g., impaired thinking and reasoning, delayed language development, reduced short- and long-term memory.
  • enteral administration refers to any administration of a NRTI (e.g., lamivudine) or combination thereof according to the present invention or a pharmaceutical composition comprising said NRTI or combination thereof via the gastrointestinal tract.
  • Enteral administration includes, but is not limited to, the oral, sublingual, and rectal routes of administration.
  • HIV include HIV-1 and HIV-2, SHIV and SIV.
  • HIV-1 means the human immunodeficiency virus type-1. HIV-1 includes, but is not limited to, extracellular virus particles and the forms of HIV-1 associated with HIV-1 infected cells. The HIV-1 virus may represent any of the known major subtypes (Classes A, B, C, D E, F, G and H) or outlying subtype (Group O) including laboratory strains and primary isolates.
  • HIV-2 means the human immunodeficiency virus type-2. HIV-2 includes, but is not limited to, extracellular virus particles and the forms of HIV-2 associated with HIV-2 infected cells.
  • SIV refers to simian immunodeficiency virus which is an HIV-like virus that infects monkeys, chimpanzees, and other nonhuman primates. SIV includes, but is not limited to, extracellular virus particles and the forms of SIV associated with SIV infected cells.
  • kit refers to a product containing the different reagents necessary for carrying out the uses and methods of the invention which is packed so as to allow their transport and storage.
  • Materials suitable for packing the components of the kit include crystal, plastic (e.g., polyethylene, polypropylene, polycarbonate), bottles, vials, paper or envelopes.
  • Lamivudine refers to 4-amino-l-[(2R,5S)-2- (hydroxymethyl)-l,3-oxathiolan-5-yl]pyrimidin-2-one, a compound of chemical formula C8H11N3O3S and CAS [134678-17-4], Lamivudine is a nucleoside analogue and reverse transcriptase inhibitor used for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. In HIV, lamivudine inhibits HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue into viral DNA.
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • Lamivudine is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase (NCI04). Lamivudine is combined with other active agents, such as zidovudine, as part of the HIV antiretroviral therapy (ART) protocol.
  • ART HIV antiretroviral therapy
  • NRTI refers to active inhibitors of reverse transcriptase found in retroviruses such as the human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the different nucleoside reverse transcriptase inhibitors may be activated differently but they have the same mechanism of action.
  • NRTIs are activated generally by phosphorylation to the triphosphate form by cellular enzymes. It then competes with cellular triphosphates, which are substrates for proviral DNA by viral reverse transcriptase.
  • NRTIs are used in the treatment of HIV infection and acquired immune deficiency syndrome (AIDS).
  • NRTI examples include, but are not limited to, abacavir sulfate (Ziagen®), abacavir and lamivudine (Epzicom®), abacavir, zidovudine, and lamivudine (Trizivir®), delay ed-release didanosine (Videx EC®), didanosine (Videx®), dideoxycytidine (Hivid®), emtricitabine (Emtriva®), entecavir (Baraclude®), lamivudine (Epivir®), lamivudine and zidovudine (Combivir®), stavudine (Zerit®), tenofovir disoproxil fumarate (Viread®), tenofovir disoproxil fumarate and emtricitabine (Truvada®), tenofovir alafenamide and emtricitabine (De
  • parenteral administration refers to the administration of a NRTI or a combination thereof according to the present invention or a pharmaceutical composition according to the present invention characterized by the physical breaching of a tissue of a subject and the administration of the NRTI, combination or pharmaceutical composition through said breach in the tissue.
  • Parenteral administration includes, but is not limited to, the administration of a NRTI (e.g., lamivudine) or a combination thereof according to the present invention or a pharmaceutical composition comprising said NRTI or combination, by the application of the NRTI, combination or pharmaceutical composition through, for instance, a surgical incision or through a tissue-penetrating non- surgical wound.
  • parenteral administration includes, but is not limited to, the epidural, intraarterial, intradermal, intrathecal, intramuscular, intraperitoneal, intrasternal injection, intravascular, intravenous, intravenous infusion, spinal, subcutaneous, and subcutaneous depot routes of administration.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible with the NRTI of the invention.
  • prevention refers to inhibiting the inception or decreasing the occurrence of a disease in a subject.
  • the prevention may be complete (e.g., the total absence of pathological cells in a subject).
  • the prevention may also be partial, such as, for example, lowering the occurrence of pathological cells in a subject.
  • Prevention also refers to a reduced susceptibility to a clinical condition.
  • the terms “prevent,” “preventing” and “prevention”, refer specifically to averting or reducing the probability of that a subject develops Alzheimer's disease or any of the consequences related to Alzheimer' s disease (e.g., cognitive deficit).
  • subject refers to an individual or animal, such as a human, a nonhuman primate (e.g., chimpanzees and other apes and monkey species); farm animals, such as birds, fish, cattle, sheep, pigs, goats, and horses; domestic mammals, such as dogs and cats; laboratory animals including rodents, such as mice, rats, and guinea pigs.
  • farm animals such as birds, fish, cattle, sheep, pigs, goats, and horses
  • domestic mammals such as dogs and cats
  • laboratory animals including rodents, such as mice, rats, and guinea pigs.
  • the term does not denote a particular age or sex.
  • subject encompasses an embryo and a fetus. In some embodiments, the subject is a human.
  • terapéuticaally effective amount refers to the dose or amount of the NRTI or combination thereof according to the present invention or the pharmaceutical compositions of the present invention that produce a therapeutic response or desired effect in a subject.
  • Topical refers to any administration of a NRTI (e.g., lamivudine) or combination thereof according to the present invention or a pharmaceutical composition comprising said NRTI or combination by applying the NRTI, combination or pharmaceutical composition to a particular place on or in the body, such as the skin or a mucous membrane.
  • Topical administration includes, but is not limited to, the aural, cutaneous, nasal, transdermal, urethral, vaginal, and urethral routes of administration.
  • treat refers to the administration of at least one NRTI, a combination of NRTI or a pharmaceutical composition according to the present invention for controlling the progression of a disease after its clinical signs have appeared.
  • Control of the disease progression is understood to mean the beneficial or desired clinical results that include, but are not limited to, reduction of the symptoms, reduction of the duration of the disease, stabilization of pathological states (specifically to avoid additional deterioration), delaying the progression of the disease, improving the pathological state and remission (both partial and total).
  • the control of progression of the disease also involves an extension of survival compared with the expected survival if treatment was not applied.
  • the terms “treat” and “treatment” refer specifically to stopping or slowing the consequences (e.g., cognitive deficit) of (a) Down syndrome or (b) Alzheimer' s disease in a subject afflicted with such syndrome or disease. “Treatment” can also mean prolonging survival of a subject afflicted with Down syndrome or Alzheimer' s disease as compared to the expected survival of the subject if the subject does not receive any of the NRTI or pharmaceutical compositions according to the present invention.
  • the present invention refers to nucleoside reverse transcriptase inhibitors (NRTI) or their pharmaceutically acceptable salts for use in (a) the treatment of Down syndrome or the consequences thereof or (b) the prevention, inhibition of progression or treatment of Alzheimer' s disease or the consequences thereof.
  • the NRTI comprises abacavir, didanosine, dideoxycytidine, emtricitabine, entecavir, lamivudine, stavudine, tenofovir, zidovudine, their pharmaceutically acceptable salts or a combination thereof.
  • the NRTI is lamiduvine or its pharmaceutically acceptable salts.
  • the consequences thereof comprise cognitive deficit.
  • the present invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one NRTI or a combination of NRTI according to the invention for use in (a) the treatment of Down syndrome or (b) the prevention, inhibition of progression or treatment of Alzheimer' s disease or the consequences thereof.
  • the NRTI or the combination thereof may be in the form of pharmaceutically acceptable salts, as generally described below.
  • the consequences thereof comprise cognitive deficit.
  • Pharmaceutically acceptable salts of the NRTI of the present invention include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. See Stahl P, et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, DE, 2008).
  • the NRTI or combinations thereof described herein may be administered in the form of a pharmaceutical composition containing prodrugs of said NRTI or their combinations.
  • a prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group.
  • prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups in the compounds.
  • Methods of structuring a compound as prodrugs are known in the art. See Testa B, et al., Hydrolysis in Drug and Prodrug Metabolism (John Wiley, Hoboken, NJ, USA, 2006).
  • Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids.
  • compositions for use according to the present invention typically comprise an effective amount of at least on NRTI or a combination thereof and at least one pharmaceutical acceptable carrier.
  • the preparations may be prepared in a manner known in the art, which usually involves mixing the at least one NRTI according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary, under aseptic conditions. See US6372778, US6369086, US6369087, US6372733 and Remington: The Science and Practice of Pharmacy, 21st Ed. (Pharmaceutical Press, Philadelphia, PA, USA, 2011).
  • the compounds may be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the pharmaceutical preparations of the present invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • the NRTI, combinations thereof and pharmaceutical compositions of the invention can be administered by a variety of routes including the topical, enteral or parenteral routes, depending mainly on the specific preparation used.
  • a “therapeutically effective amount” of the NRTI or combination thereof would generally be administered to the subject in need thereof.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. See US6372778, US6369086, US6369087, US6372733, and Remington, 2011, supra.
  • Formulations containing one or more NRTI can be prepared in various pharmaceutical forms including, but not limited to, granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions or aerosols. In some embodiments, these formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets.
  • liquid dosage forms such as solutions, syrups, suspension, and shakes can also be utilized.
  • the formulation is administered topically.
  • suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels.
  • the topical formulation is a gel.
  • the formulation is administered intranasally.
  • Formulations containing one or more of the NRTI of the present invention may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions.
  • Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. Delayed release, extended release, and/or pulsatile release dosage formulations may be prepared as described in standard references. See Liberman A, et al.. Eds, Pharmaceutical Dosage Form Tablets (Marcel Dekker, Inc., New York City, NY, USA 1989), and Ansel H, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 10 th Edition, (Lippincott Williams & Wilkins, Baltimore, MD, 2014), and Remington, 2011, supra.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, methacrylic resins, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copolymers, methacrylic resins, and polysaccharides.
  • the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as “fillers”, are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and Veegum®, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or breakup after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross-linked polymers, such as crosslinked polyvinylpyrrolidone (PVP).
  • PVP crosslinked polyvinylpyrrolidone
  • Surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions.
  • anionic surfactants include, but are not limited to, sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl- -alanine, sodium N-lauryl-
  • the tablets, beads, granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents or preservatives.
  • the concentration of the compound(s) to carrier and/or other substances may vary from about 0.5 to about 100 wt % (weight percent).
  • the pharmaceutical formulation will generally contain from about 5 to about 100% by weight of the active material.
  • the pharmaceutical formulation will generally have from about 0.5 to about 50 wt % of the active material.
  • compositions described herein can be formulation for modified or controlled release.
  • controlled release dosage forms include extended-release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.
  • the extended-release formulations are generally prepared as diffusion or osmotic systems, according to procedures known in the art. See Remington, 2011, supra.
  • a diffusion system typically consists of two types of devices, a reservoir and a matrix.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol® 934, polyethylene oxides and mixtures thereof.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil or mixtures thereof.
  • the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl me
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units.
  • multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads or granules.
  • An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended-release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar.
  • Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose.
  • Natural and synthetic gums including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used.
  • Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
  • Extended-release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • the congealing method the drug is mixed with a wax material and either spray-congealed or congealed and screened and processed.
  • Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional “enteric” polymers.
  • Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available such as Eudragit® (Rohm Pharma, Westerstadt, DE), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates may also be used.
  • Pigments such as titanium dioxide may also be used.
  • Small quantities of an anti-foaming agent such as a silicone (e.g., simethicone), may also be added to the coating composition.
  • each dosage unit in the capsule may comprise a plurality of drugcontaining beads, granules or particles.
  • drug-containing “beads” refer to beads made with drug and one or more excipients or polymers.
  • Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a “core” comprising both drug and one or more excipients.
  • drugcontaining “granules” and “particles” comprise drug particles that may or may not include one or more additional excipients or polymers.
  • granules and particles do not contain an inert support. Granules generally comprise drug particles and require further processing.
  • particles are smaller than granules, and are not further processed.
  • beads, granules and particles may be formulated to provide immediate release, beads and granules are generally employed to provide delayed release.
  • the compound is formulated for topical administration.
  • suitable topical dosage forms include lotions, creams, ointments, and gels.
  • a “gel” is a semisolid system containing a dispersion of the active agent (e.g., Nox inhibitor), in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid may include a lipophilic component, an aqueous component or both.
  • Some emulsions may be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.
  • NRTI, combinations and pharmaceutical compositions of the invention can be administered adjunctively with other active compounds.
  • active compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, and anti-narcoleptics.
  • Adjunctive administration means the compounds can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • compositions of the invention may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic aqueous solution.
  • suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulations are especially suitable for parenteral administration but may also be used for oral administration.
  • Excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate, may also be added.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols or water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion or an aqueous or nonaqueous suspension.
  • Such a liquid formulation may be administered directly or filled into a soft gelatin capsule.
  • compositions of the application may be in the form of a sterile injectable preparation.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents as described before.
  • the present invention refers to Down syndrome and Alzheimer' s disease therapies based on the use of the NRTI, combinations of NRTI, and pharmaceutical compositions of the invention.
  • the present invention relates to a method for treating Down syndrome or the consequences thereof (e.g., cognitive deficit) which comprises administering a therapeutically effective amount of (a) at least one NRTI or a combination thereof (b) a pharmaceutical composition according to the present invention to a subject in need thereof.
  • the present invention is directed to a method for preventing, inhibiting the progression or treating Alzheimer’s disease or the consequences thereof (e.g., cognitive deficit) which comprises administering a therapeutically effective amount of (a) at least one NRTI or a combination thereof or (b) a pharmaceutical composition according to the present invention to a subject in need thereof.
  • the present invention relates also to the use of NRTI in the manufacture of a medicament for (a) treating Down syndrome or the consequences thereof or (b) preventing, inhibiting the progression or treating Alzheimer’s disease or the consequences thereof.
  • the subject is human.
  • the subject is also infected with HIV and/or is afflicted with AIDS.
  • the (a) at least one NRTI or a combination thereof or (b) the pharmaceutical composition according to the present invention is administered to the subject via a topical, enteral or parenteral route of administration.
  • the NRTI, combination of NRTI, and pharmaceutical compositions of the invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route or mode of administration will vary depending upon the desired results.
  • the active agents of the invention can be prepared with carriers that will protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems, as described above.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are generally known to in the art. See Robinson J, et al., Eds., Sustained and Controlled Release Drug Delivery Systems (Marcel Dekker, Inc., New York, NY, USA, 1978).
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased, as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention is dictated by, and directly dependent on, the unique characteristics of the active agent and the particular therapeutic effect to be achieved.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art.
  • the amount of active agent which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
  • the amount of active agent which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, this amount will range from about 0.001% to about 90% of active agent, preferably from about 0.005% to about 70% and, most preferably, from about 0.01% to about 30%.
  • NRTI NRTI
  • combinations of NRTI and pharmaceutical compositions according to the present invention may be varied for attaining the desired therapeutic response in a subject.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular agent of the invention employed, its amount, the route of administration, the time of administration, the rate of excretion or expression of the particular active agent employed, the duration of the treatment, other drugs, compounds or materials used in combination with the particular pharmaceutical compositions employed, the age, sex, weight, condition, general health, and prior medical history of the subject being treated and other similar factors known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the active agent(s) required.
  • a suitable daily dose of a composition of the invention will be that amount of the NRTI, combinations of NRTI and pharmaceutical compositions according to the present invention which is the lowest dose to be therapeutically effective.
  • Such therapeutically effective dose will generally depend upon the factors described above.
  • the therapeutically effective daily dose the NRTI, combinations of NRTI and pharmaceutical compositions according to the present invention may be administered as two, three, four, five, six or more sub-doses applied separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for an active agent of the invention to be administered alone, it is preferable to administer said agent as a pharmaceutical composition.
  • kits comprising, according to the invention, (a) at least one NRTI or a pharmaceutically acceptable salt thereof, (b) a combination of NRTI or their pharmaceutically acceptable salts, (c) a pharmaceutical composition comprising at least one NRTI, a pharmaceutically acceptable salt thereof or a combination thereof.
  • the kits of the invention are used for (i) treating Down syndrome or the consequences or (ii) preventing, inhibiting the progression or treating Alzheimer’s disease or the consequences thereof in a subject in need thereof.
  • the components of the kits of the invention may be optionally packed in suitable containers and be labeled for preventing, inhibiting the progression, and treating Down syndrome, Alzheimer’s disease or the consequences thereof (e.g., cognitive deficit).
  • kits may be stored in unit or multi-dose containers as a solid or aqueous, preferably sterile, solution.
  • the containers may be formed from a variety of materials such as glass or plastic and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the kits may further comprise more containers comprising a pharmaceutically acceptable carrier. They may further include other materials desirable from a commercial and user standpoint, including, but not limited to, buffers, diluents, filters, needles, syringes, culture medium for one or more of the suitable host cells or other active agents.
  • the kits can contain instructions customarily included in commercial packages of diagnostic and therapeutic products that contain information, for example, about the indications, usage, dosage, manufacture, administration, contraindications or warnings concerning the use of such diagnostic and therapeutic products.
  • Trisomic (Ts65Dn, TS) male mice were obtained by breeding B6EiC4Sn.BLiA- Ts(1716)65Dn/DnJ females with C57BL/6 x 6J01aHsd (B6C3Fl/01aHsd) hybrid males. Mice were genotyped, and ⁇ 25% of the offspring presented with trisomy. Wild-type (WT) littermates were used as controls. After weaning, male mice were group housed with 3-4 animals per cage on a conventional 12:12 light cycle in controlled environmental conditions of humidity (50-70%) and temperature (21 ⁇ 1°C). Water and standard rodent chow were available ad lib.
  • TS and WT mice were assigned using a simple randomization to either control conditions or lamivudine 3 mg/kg (Epivir, 10 mg/mL, oral solution) in the drinking water.
  • 15 TS and 20 WT mice were treated with lamivudine and 14 TS and 18 WT mice were used as control group and received water.
  • the treatment lasted 4 months.
  • Behavioral testing was performed before the treatment and 1 and 4 months after starting the treatment. Behavioral experiments were conducted during the light phase of the light/dark cycle between 10 am and 2 pm and were performed by trained observers blind to genotype.
  • novel object recognition test and plus maze were videotaped using a computer-assisted data acquisition system (SMART, Panlab Harvard Apparatus, ES). Less stressful tests were performed first, and each behavioral test was separated by at least 24 h. The order of the tests was as follows: (1) locomotor activity, (2) novel object recognition, and (3) elevated plus maze. All procedures were conducted according local, national, and European regulations relating to the use of animals for scientific purposes.
  • Spontaneous locomotor activity in the home cage was measured using an automated infrared light-beam monitoring system (ActiMot2, TSE system, DE) and the ambulatory beam breaks (X axis) were counted for 24 h. Total general activity was analyzed. Mice were isolated for assessing locomotor activity during 24 hours and immediately regrouped after the test.
  • mice were habituated to the arena for 5 min.
  • mice were presented with two identical objects, for 10 min. Subjects failing to complete a minimum of 20 s of exploration during the familiarization session were excluded for posterior analysis. 24 h after (test session), mice were presented with one familiar object and one novel one, for 5 min.
  • the discrimination index was calculated as ((time exploring the novel object - time exploring the familiar object)/total time of exploration) * 100 [48], Exploratory behavior was defined as the animal directing its nose towards the object at a distance of ⁇ 2 cm and manually registered by the experimenter. Sitting on or resting against the object was not considered as exploration. All the objects used were plastic made and induced similar exploration levels. The arena and objects were deeply cleaned between animals to avoid olfactory cues.
  • the elevated plus maze paradigm was used to study anxiety-related behavior.
  • the apparatus consists of a cross-shaped platform (four arms faced two to two with a length of 40 cm and 8 cm width) elevated 40 cm from the floor. Two opposing arms are protected by black walls and the other two are left unprotected. Because of the distance to the ground, the open arm is an aversive environment for the mouse, so it tends to remain in the closed arms. The proportion of time spent in open versus closed arms during 5 min is considered a measure of anxiety. Distance travelled was analyzed as a measure of the activity in the apparatus.
  • WT mice Upon lamivudine treatment, WT mice spent significantly more time in closed arms (Tukey’s post-hoc test, WT-BASAL vs WT-1M p ⁇ 0.005; WT-BASAL vs WT-4M p ⁇ 0.005) and less time in open arms (non-significant) and in the center of the maze (Tukey’s post- hoc test, WT-BASAL v WT-1M p ⁇ 0.005; WT-BASAL vs WT-4M p ⁇ 0.005) as compared to basal conditions, suggesting anxiety-like effects. In the case of the TS, although the tendency is similar, no significant differences were observed.
  • Recognition memory was evaluated using the novel object recognition paradigm that has been shown to be a robust and reproducible test for studying the Ts65Dn strain (Sierra C, et al., Front Behav Neurosci 2021; 15:772734).
  • no differences in the time of exploration were observed among the groups at baseline, 1 month or 4 months ( Figure 2A).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des inhibiteurs nucléosidiques de la transcriptase inverse (NRTI) ou leurs sels pharmaceutiquement acceptables pour une utilisation dans (a) le traitement du syndrome de Down ou des conséquences de celui-ci ou (b) la prévention, l'inhibition de la progression ou le traitement de la maladie d'Alzheimer ou des conséquences de celle-ci. L'Invention concerne également des compositions pharmaceutiques comprenant de tels NRTI et des combinaisons de NRTI. L'Invention concerne également des kits comprenant NRTI, des combinaisons de NRTI, ainsi que des compositions pharmaceutiques comprenant de tels NRTI et des combinaisons de NRTI.
PCT/IB2022/000673 2021-12-08 2022-12-07 Inhibiteurs nucléosidiques de la transcriptase inverse destinés à être utilisés dans le traitement du syndrome de down et de la maladie d'alzheimer Ceased WO2023105283A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163287169P 2021-12-08 2021-12-08
US63/287,169 2021-12-08

Publications (1)

Publication Number Publication Date
WO2023105283A1 true WO2023105283A1 (fr) 2023-06-15

Family

ID=84568938

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/000673 Ceased WO2023105283A1 (fr) 2021-12-08 2022-12-07 Inhibiteurs nucléosidiques de la transcriptase inverse destinés à être utilisés dans le traitement du syndrome de down et de la maladie d'alzheimer

Country Status (1)

Country Link
WO (1) WO2023105283A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
WO2020185676A1 (fr) * 2019-03-08 2020-09-17 University Of Virginia Patent Foundation Compositions et méthodes de traitement ou de prévention de la maladie d'alzheimer
US20210106586A1 (en) * 2019-01-25 2021-04-15 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders
US20210267995A1 (en) * 2018-06-20 2021-09-02 Sanford Burnham Prebys Medical Discovery Institute Anti-retroviral therapies and reverse transcriptase inhibitors for treatment of alzheimer's disease

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US20210267995A1 (en) * 2018-06-20 2021-09-02 Sanford Burnham Prebys Medical Discovery Institute Anti-retroviral therapies and reverse transcriptase inhibitors for treatment of alzheimer's disease
US20210106586A1 (en) * 2019-01-25 2021-04-15 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders
WO2020185676A1 (fr) * 2019-03-08 2020-09-17 University Of Virginia Patent Foundation Compositions et méthodes de traitement ou de prévention de la maladie d'alzheimer

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Dosage Form Tablets", 1989, MARCEL DEKKER, INC.
"Remington: The Science and Practice of Pharmacy", 2011, PHARMACEUTICAL PRESS
ADLER M ET AL., BRIT. MED. J., vol. 294, 1987, pages 1145 - 1147
ALTAFAJ X ET AL.: "Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome", HUM MOL GENET, vol. 10, no. 18, 2001, pages 1915 - 1923, XP002265254, DOI: 10.1093/hmg/10.18.1915
CAS , no. 134678-17-4
DE CECCO M ET AL.: "L1 drives IFN in senescent cells and promotes age-associated inflammation", NATURE, vol. 566, no. 7742, 2019, pages 73 - 78, XP036833109, DOI: 10.1038/s41586-018-0784-9
DE LA TORRE R ET AL.: "Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial", LANCET NEUROL, vol. 15, no. 8, 2016, pages 801 - 810, XP029570841, DOI: 10.1016/S1474-4422(16)30034-5
DE LA TORRE RAFAEL ET AL: "Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans", MOLECULAR NUTRITION & FOOD RESEARCH, vol. 58, no. 2, 14 September 2013 (2013-09-14), DE, pages 278 - 288, XP093032112, ISSN: 1613-4125, Retrieved from the Internet <URL:https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fmnfr.201300325> DOI: 10.1002/mnfr.201300325 *
DE TOMA I ET AL.: "Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome", PLOS COMPUT BIOL, vol. 17, no. 9, 2021, pages e1009317
DIERSSEN M ET AL.: "Down syndrome: the brain in trisomic mode", NAT REV NEUROSCI, vol. 13, no. 12, 2012, pages 844 - 858
ESCORIHUELA R ET AL.: "Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome", NEUROSCI LETT, vol. 247, no. 2-3, 1998, pages 171 - 4, XP002626670, DOI: 10.1016/S0304-3940(98)00317-6
FERNANDEZ F ET AL.: "Pharmacotherapy in Down's syndrome: which way forward?", LANCET NEUROL, vol. 15, no. 8, 2016, pages 776 - 777, XP029570843, DOI: 10.1016/S1474-4422(16)30056-4
FRUCTUOSO M ET AL.: "Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome", FREE RADIC BIOL MED, vol. 114, 2018, pages 122 - 130, XP085323076, DOI: 10.1016/j.freeradbiomed.2017.09.021
GARDNER E ET AL.: "Contribution of retrotransposition to developmental disorders", NAT COMMUN, vol. 10, no. 1, 2019, pages 4630
GENSOUS N ET AL.: "Down syndrome, accelerated aging and immunosenescence", SEMIN IMMUNOPATHOL, vol. 42, no. 5, 2020, pages 635 - 645, XP037291914, DOI: 10.1007/s00281-020-00804-1
GORBUNOVA V ET AL.: "The role of retrotransposable elements in ageing and age-associated diseases", NATURE, vol. 596, no. 7870, 2021, pages 43 - 53, XP037528388, DOI: 10.1038/s41586-021-03542-y
GRIFFIN W ET AL.: "Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease", PROC NATL ACAD SCI USA, vol. 86, no. 19, 1989, pages 7611 - 7615, XP001118366, DOI: 10.1073/pnas.86.19.7611
GULESSERIAN T ET AL.: "Superoxide dismutase SOD1, encoded on chromosome 21, but not SOD2 is overexpressed in brains of patients with Down syndrome", J INVESTIG MED, vol. 49, no. 1, 2001, pages 41 - 46
KAESER G ET AL.: "Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer's Disease", FRONT GENET, vol. 11, 2020, pages 390
LEE M ET AL.: "Somatic APP gene recombination in Alzheimer's disease and normal neurons", NATURE, vol. 563, no. 7733, 2018, pages 639 - 645
LEE MING-HSIANG ET AL: "Mosaic APP Gene Recombination in Alzheimer's Disease-What's Next?", JOURNAL OF EXPERIMENTAL NEUROSCIENCE, 16 May 2019 (2019-05-16), pages 1 - 4, XP093032191, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537494/pdf/10.1177_1179069519849669.pdf> [retrieved on 20230316] *
LI M ET AL.: "Lamivudine improves cognitive decline in SAMP8 mice: Integrating in vivo pharmacological evaluation and network pharmacology", J CELL MOL MED, vol. 25, no. 17, 2021, pages 8490 - 8503
LI W ET AL.: "Transposable elements in TDP-43-mediated neurodegenerative disorders", PLOS ONE, vol. 7, no. 9, 2012, pages e44099, XP002756466, DOI: 10.1371/journal.pone.0044099
LING K ET AL.: "Functional transcriptome analysis of the postnatal brain of the TslCje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks", BMC GENOMICS, vol. 15, 2014, pages 624, XP021191557, DOI: 10.1186/1471-2164-15-624
MANTI S ET AL.: "Inflammatory biomarkers and intellectual disability in patients with Down syndrome", J INTELLECT DISABIL RES, vol. 62, no. 5, 2018, pages 382 - 390
MARTINEZ DE LAGRAN MARIA ET AL: "Lamivudine, a reverse transcriptase inhibitor, rescues cognitive deficits in a mouse model of down syndrome ?| Aleix Elizalde-Torrent 2", J CELL MOL MED, 28 June 2022 (2022-06-28), pages 4210 - 4215, XP093031878, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344819/pdf/JCMM-26-4210.pdf> [retrieved on 20230315] *
MUOTRI A ET AL.: "Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition", NATURE, vol. 435, no. 7044, 2005, pages 903 - 910
PALMER C ET AL., PROC NATL ACAD SCI USA, 2021
PALMER C ET AL.: "Altered cell and RNA isoform diversity in aging Down syndrome brains", PROC NATL ACAD SCI U S A, vol. 118, no. 47, 2021
PATTERSON D ET AL.: "Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging", MECH AGEING DEV, vol. 133, no. 4, 2012, pages 133 - 7, XP028917740, DOI: 10.1016/j.mad.2011.10.001
ROBINSON J ET AL.: "Sustained and Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
RODGERS S ET AL.: "Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult", MOL NEURODEGENER, vol. 7, 2012, pages 28, XP021116915, DOI: 10.1186/1750-1326-7-28
SIANGPHOE U ET AL.: "Associations of antiretroviral therapy and comorbidities with neurocognitive outcomes in HIV-1-infected patients", AIDS, vol. 34, no. 6, 2020, pages 893 - 902
SIERRA C ET AL.: "Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome", FRONT BEHAV NEUROSCI, vol. 15, 2021, pages 772734
SIMON M ET AL.: "LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation", CELL METAB, vol. 29, no. 4, 2019, pages 871 - 885
STAHL P ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2008, WILEY-VCH
SULLIVAN K ET AL.: "Trisomy 21 consistently activates the interferon response", ELIFE, 2016, pages 5
TESTA B ET AL.: "Hydrolysis in Drug and Prodrug Metabolism", 2006, JOHN WILEY

Similar Documents

Publication Publication Date Title
Chou et al. Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications
CN102065858B (zh) 使用唑尼沙胺和阿坎酸治疗阿尔茨海默病和相关病症的组合组合物
DK1919458T5 (en) Enteric-coated cysteamine, cystamine and derivatives thereof
ES2847929T3 (es) Tratamiento de la demencia
ES2909557T3 (es) Utilización de la pridopidina para el tratamiento del síndrome de Rett
JP2018203790A (ja) ハロフジノンの剤形およびその使用
US11517571B2 (en) Use of kinase inhibitors to manage tuberculosis and other infectious diseases
US20150125526A1 (en) Use of Cysteamine and Derivatives Thereof to Treat Mitochondrial Diseases
TW202112359A (zh) sGC活化劑於治療眼科疾病之用途
JP7481593B2 (ja) Ｓｍａの新たな処置
US20230263748A1 (en) Application of benflumetol and derivatives thereof in treatment of coronavirus infection
US20190127372A1 (en) S1pr2 antagonists and uses therefor
US20170022179A1 (en) Compositions, dosages, and methods of using tetrahydrocannabinol derivatives
JPWO2021007245A5 (fr)
WO2023105283A1 (fr) Inhibiteurs nucléosidiques de la transcriptase inverse destinés à être utilisés dans le traitement du syndrome de down et de la maladie d&#39;alzheimer
WO2016073716A1 (fr) Méthodes de traitement de la maladie de huntington au moyen de compositions de cystéamine
CA3054822A1 (fr) Prophylaxie du vih post-exposition
JP2015512948A (ja) ハロフェナートまたはハロフェン酸および抗炎症剤を用いる痛風に罹っている患者の高尿酸血症の治療方法
US10487082B2 (en) S1PR2 antagonists and uses therefor
US6432966B2 (en) Antiviral combinations
US11389420B2 (en) Pharmaceutical compositions and methods utilizing neostigmine and an NK-1 antagonist for treating myasthenia gravis
US20220362219A1 (en) Retina regeneration through epigenetics manipulation
WO2017190713A1 (fr) Dérivé de benzodiazépine ayant une activité sur le système nerveux central et vasculaire
US20210315843A1 (en) Endoxifen for the treatment of bipolar i disorder
CN115697383A (zh) 治疗病毒感染和健康问题的方法

Legal Events

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

Ref document number: 22829577

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE