WO2024019953A1 - Méthode permettant d'améliorer la récupération après un covid long - Google Patents

Méthode permettant d'améliorer la récupération après un covid long Download PDF

Info

Publication number
WO2024019953A1
WO2024019953A1 PCT/US2023/027864 US2023027864W WO2024019953A1 WO 2024019953 A1 WO2024019953 A1 WO 2024019953A1 US 2023027864 W US2023027864 W US 2023027864W WO 2024019953 A1 WO2024019953 A1 WO 2024019953A1
Authority
WO
WIPO (PCT)
Prior art keywords
pkc activator
covid
administered
pkc
weeks
Prior art date
Application number
PCT/US2023/027864
Other languages
English (en)
Inventor
Daniel L. Alkon
Original Assignee
Synaptogenix, Inc.
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 Synaptogenix, Inc. filed Critical Synaptogenix, Inc.
Publication of WO2024019953A1 publication Critical patent/WO2024019953A1/fr

Links

Classifications

    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/80—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for detecting, monitoring or modelling epidemics or pandemics, e.g. flu
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • 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

Definitions

  • Long COVID refers to a continued state of health problems in a subject stemming from an initial contraction of COVID.
  • the symptoms of long COVID are varied and may include ongoing or intermittent fatigue, lack of energy, respiratory problems (e.g., difficulty breathing or persistent coughing), chest pain, joint pain, muscle pain or soreness, vascular problems (e.g., blood clotting, which may result in pulmonary embolism), neurological problems (e.g., persistent headaches, insomnia, dizziness, loss of smell or taste, depression, or anxiety), and/or skin conditions (e.g., rashes).
  • the symptoms of long COVID typically persist for more than a month after the initial contraction, and may continue for many months or even years thereafter.
  • cardiovascular disease e.g., cardiovascular disease, MS, infection, autoimmune disease, or cancer.
  • a subject afflicted with or predisposed to or at risk of long COVID is administered a PKC activator (i.e.
  • the PKC activating compound such as a bryostatin or bryolog
  • the PKC activating compound may be, for example, a macrocyclic lactone compound, such as a bryostatin compound (e.g., bryostatin-1) or bryolog compound, a polyunsaturated fatty acid (PUFA) or cyclopropanated or epoxidized derivative thereof, or a growth factor (e.g., BDNF, HGF, NGF, and IGF) or growth factor activating compound.
  • a bryostatin compound e.g., bryostatin-1
  • bryolog compound e.g., a polyunsaturated fatty acid (PUFA) or cyclopropanated or epoxidized derivative thereof
  • PUFA polyunsaturated fatty acid
  • a growth factor e.g., BDNF, HGF, NGF, and IGF
  • the presently described treatment methods provide synaptic resurrection strategies for enhancing recovery from CNS sequelae caused by long COVID.
  • the PKC activating compound is administered in an initial loading dose that is 15-25% greater in dosage than successive weekly dosages.
  • the PKC activating compound is administered at an initial loading dose of about 15 micrograms per week for two consecutive weeks followed by about 12 micrograms on alternate weeks for a least four, six, eight, ten, or twelve weeks.
  • the PKC activating compound is administered at an initial loading dose of about 24 micrograms per week for two consecutive weeks followed by about 20 micrograms on alternate weeks for at least four weeks.
  • the PKC activating compound is administered at an initial loading dose of about 48 micrograms per week for two consecutive weeks followed by about 40 micrograms on alternate weeks for a least four, six, eight, ten, or twelve weeks.
  • DETAILED DESCRIPTION [0004] The present disclosure is foremost directed to a method for treating or preventing long COVID in a subject who has contracted or is at risk of contracting COVID, and wherein the subject may or may not be in long COVID at the start of treatment, wherein the start of treatment corresponds to when administration of the PKC activator begins.
  • Long COVID is generally characterized by health problems due to COVID that persist at least one, two, or three months since contracting COVID or since exhibiting the first signs of COVID.
  • the subject may have tested positive for COVID without exhibiting any signs of COVID or exhibiting relatively minor symptoms associated with COVID (e.g., non- debilitating tiredness and/or slight cough or respiratory distress). However, in other embodiments, the subject may have experienced more severe symptoms upon contraction of COVID, such as debilitating fatigue, severe respiratory distress, or temporary or permanent organ (e.g., lung, heart, or liver) damage. In some cases, after severe symptoms of COVID, the subject may experience a significant improvement, but subsequently (e.g., at least one, two, or three months after the initial symptoms or amelioration of serious symptoms) the subject may continue to experience one or more symptoms, as enumerated above, commonly experienced in long COVID.
  • severe symptoms of COVID the subject may experience a significant improvement, but subsequently (e.g., at least one, two, or three months after the initial symptoms or amelioration of serious symptoms) the subject may continue to experience one or more symptoms, as enumerated above, commonly experienced in long CO
  • COVID refers to COVID-19 and any variant thereof, e.g., alpha, beta, delta, epsilon, and omicron variants, and sub-variants thereof.
  • a subject who has contracted COVID or is at risk of contracting COVID is administered a pharmaceutically effective amount of a PKC activator to result in prevention, reduction, or attenuation of symptoms associated with long COVID.
  • the symptoms of long COVID may be, more particularly, ongoing or intermittent fatigue, lack of energy, respiratory problems (e.g., difficulty breathing or persistent coughing), chest pain, joint pain, muscle pain or soreness, vascular problems (e.g., blood clotting, which may result in pulmonary embolism), neurological problems (e.g., persistent headaches, insomnia, dizziness, memory loss, loss of smell or taste, depression, or anxiety), and/or skin conditions (e.g., rashes). Any one of the foregoing symptoms may also be deemed acute, moderate, or mild.
  • a bryostatin or bryolog is administered in an efficacious amount to prevent, mitigate, or reverse any one or more symptoms associated with long COVID.
  • the treatment with PKC activator may be administered before or during initial contraction of COVID and before or after the start of long COVID.
  • the therapeutically effective amount of PKC activator is administered according to any suitable dosing schedule or regimen described.
  • the administration of the PKC activator should result in prevention, stabilization, mitigation, or reversal of one or more symptoms associated with long COVID, such as any one or more symptoms enumerated earlier above.
  • administration of the PKC activator also results in an increase in the number of fully mature mushroom spine synapses.
  • administration of the PKC activator results in at least partial or full restoration of mature mushroom spines or mushroom spine synapses.
  • PKC activation can increase the number of mushroom spines, which can enhance learning and memory per se, even in the absence of neuropathology or neurologic compromise.
  • PKC activators can be non-specific or specific activators.
  • PKC Protein kinase C
  • PKC Protein kinase C
  • PKC is one of the largest gene families of protein kinase.
  • PKC isozymes are expressed in the brain, including PKC ⁇ , PKC ⁇ 1, PKC ⁇ II, PKC ⁇ , PKC ⁇ , and PKC ⁇ .
  • PKC is primarily a cytosolic protein, but with stimulation it translocates to the membrane.
  • PKC activators have been associated with various diseases and conditions. For example, PKC has been shown to be involved in numerous biochemical processes relevant to AD, and PKC activators have demonstrated neuroprotective activity in animal models of AD.
  • PKC activation has a crucial role in learning and memory enhancement, and PKC activators have been shown to increase memory and learning (Sun and Alkon, Eur J Pharmacol. 2005;512:43-51; Alkon et al., Proc Natl Acad Sci USA. 2005;102:16432-16437). PKC activation also has been shown to induce synaptogenesis in rat hippocampus suggesting the potential of PKC-mediated anti-apoptosis and synaptogenesis during conditions of neurodegeneration (Sun and Alkon, Proc Natl Acad Sci USA. 2008; 105(36): 13620-13625). In fact, synaptic loss appears to be a pathological finding in the brain that is closely correlated with the degree of dementia in AD patients.
  • PKC activation has further been shown to protect against traumatic brain injury-induced learning and memory deficits (Zohar et al., Neurobiology of Disease, 2011, 41: 329-337), has demonstrated neuroprotective activity in animal models of stroke (Sun et al., Eur. J. Pharmacol., 2005, 512: 43-51), and has shown neuroprotective activity in animal models of depression (Sun et al., Eur. J. Pharmacol., 2005, 512: 43-51).
  • Neurotrophins particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are key growth factors that initiate repair and regrowth of damaged neurons and synapses.
  • BDNF brain-derived neurotrophic factor
  • NGF nerve growth factor
  • PKC neurotrophins
  • PKC ⁇ Activation of some PKC isoforms, particularly PKC ⁇ and PKC ⁇ , protect against neurological injury, most likely by upregulating the production of neurotrophins such as BDNF (Weinreb et al., FASEB Journal.2004;18:1471- 1473).
  • the activation of PKC ⁇ also increases brain postsynaptic density anchoring protein (PSD-95) which is an important marker for synaptogenesis.
  • PSD-95 brain postsynaptic density anchoring protein
  • changes in dendritic spine density form the basis of learning- and memory- induced changes in synaptic structure that increase synaptic strength. Abnormalities in the number and morphology of dendritic spines have been observed in many cognitive disorders, such as attention deficit hyperactivity disorder, schizophrenia, autism, mental retardation, and fragile X syndrome.
  • fatty acid refers to a compound composed of a hydrocarbon chain and ending in a free acid, an acid salt, or an ester.
  • fatty acid is meant to encompass all three forms. Those skilled in the art understand that certain expressions are interchangeable.
  • methyl ester of linolenic acid is the same as “linolenic acid methyl ester,” which is the same as “linolenic acid in the methyl ester form.”
  • cyclopropanated or “CP” refers to a compound wherein at least one carbon-carbon double bond in the molecule has been replaced with a cyclopropane ring.
  • the cyclopropyl group may be in cis or trans configuration. Unless otherwise indicated, the cyclopropyl group is in the cis configuration. Compounds with multiple carbon-carbon double bonds have many cyclopropanated forms.
  • CP1 form a polyunsaturated compound in which only one double bond has been cyclopropanated is herein referred to as being in “CP1 form.”
  • CP6 form indicates that six double bonds are cyclopropanated.
  • Docosahexaenoic acid (“DHA”) methyl ester has six carbon-carbon double bonds, and thus, can have 1-6 cyclopropane rings.
  • DHA docosahexaenoic acid
  • CP6 forms Shown below are the CP1 and CP6 forms.
  • the cyclopropane group(s) can occur at any of the carbon-carbon double bonds.
  • HGF activator refers to a substance that increases the rate of the reaction catalyzed by HGF.
  • HGF is well known in the art, as described in, for example, T. Nakamura et al., Proc., Jpn. Acad. Ser. B Phys. Biol. Sci., 86(6), 588-610, 2010.
  • the PKC activator is an HGF activator.
  • cholesterol refers to cholesterol and derivatives thereof. For example, “cholesterol” may or may not include the dihydrocholesterol species.
  • the word “synaptogenesis” refers to a process involving the formation of synapses.
  • the word “synaptic networks” refer to a multiplicity of neurons and synaptic connections between the individual neurons. Synaptic networks may include extensive branching with multiple interactions. Synaptic networks can be recognized, for example, by confocal visualization, electron microscopic visualization, and electrophysiologic recordings.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce adverse reactions when administered to a subject. The pharmaceutically acceptable substance is typically approved by a regulatory agency or listed in the U.S.
  • pharmaceutically acceptable carrier generally refers to a liquid or solid chemical substance in which the active ingredient may be combined and which, following the combination, can be used to deliver the active ingredient to a subject.
  • the carrier can also be, for example, a diluent, adjuvant, excipient, or vehicle for the compound being administered.
  • therapeutically effective amount refers to an amount of a therapeutic agent that results in a measurable or observable therapeutic response.
  • a therapeutic response may be, for example, any response that a person of sound medical adjustment (e.g., a clinician or physician) will recognize as an effective response to the therapy, including improvement of symptoms and surrogate clinical markers.
  • a therapeutic response will generally be a mitigation, amelioration, or inhibition of one or more symptoms long COVID.
  • a measurable therapeutic response may also include a finding that the disorder is prevented or has a delayed onset or is otherwise attenuated by the therapeutic agent.
  • the term “subject,” as used herein, refers to a human or other mammal in need of treatment with the PKC activating compound.
  • the subject may be, for example, a human having COVID or long COVID or at risk for COVID or long COVID.
  • mammals other than humans include dogs, cats, monkeys, and apes.
  • the subject has an age of 20-45 years.
  • the terms “approximately” and “about” mean to be nearly the same as a referenced number or value including an acceptable degree of error for the quantity measured given the nature or precision of the measurements.
  • the terms “approximately” and “about” are generally understood to encompass ⁇ 20% or ⁇ 10% of a specified amount, frequency or value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term “about” or “approximately” can be inferred when not expressly stated.
  • administer refers to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his/her authorized agent or under his/her direction a composition according to the disclosure, and (2) putting into, taking, or consuming by the patient or person himself or herself, a composition according to the disclosure.
  • administration of a composition includes any route of administration, including oral, intravenous, subcutaneous, intraperitoneal, and intramuscular.
  • weekly dosing regimen is used when the subject is administered a dose of a therapeutic agent (drug) every week for a predetermined number of consecutive weeks. For example, the subject may receive a single dose of a therapeutic agent each week for three consecutive weeks.
  • the phrases “spaced dosing regimen” and “intermittent dosing regimen” are herein used interchangeably and refer to an “on/off” dosing regimen of a defined periodicity.
  • a spaced dosing regimen or intermittent dosing regimen may be used for administering a PKC activating compound to a subject.
  • intermittent dosing of a PKC activator results in restoring or upregulating BDNF, increasing the postsynaptic density of the anchoring protein PSD-95, and/or lowering or preventing the downregulation of PCK- ⁇ .
  • the spaced or intermittent dosing regimen may entail, for example, administering a PKC activating compound to the subject once a week for two or three consecutive weeks followed by cessation of administration or dosing for two or three consecutive weeks.
  • the administration may continue in alternating intervals of administering the PKC activator once a week for two or three consecutive weeks, followed by cessation of administration or dosing for two or three consecutive weeks, and continuing those alternating intervals over a period of about 4 months, about 8 months, about 1 year, about 2 years, about 5 years, or otherwise for the duration of therapy with the PKC activator.
  • the PKC activator may be administered according to any suitable dosing schedule or regimen.
  • the PKC activator such as a bryostatin (e.g., bryostatin-1)
  • the amount administered is precisely, about, up to, or less than 0.01 ⁇ g/m 2 , 0.05 ⁇ g/m 2 , 0.1 ⁇ g/m 2 , 0.5 ⁇ g/m 2 , 1 ⁇ g/m 2 , 5 ⁇ g/m 2 , 10 ⁇ g/m 2 , 15 ⁇ g/m 2 , 20 ⁇ g/m 2 , 25 ⁇ g/m 2 , 30 ⁇ g/m 2 , 35 ⁇ g/m 2 , 40 ⁇ g/m 2 , 45 ⁇ g/m 2 , 50 ⁇ g/m 2 , 55 ⁇ g/m 2 , 60 ⁇ g/m 2 , 65 ⁇ g/m 2 , 70 ⁇ g/m 2 , 75 ⁇ g/m 2 , 80 ⁇ g/m 2 , 85 ⁇ g/m 2 , 90 ⁇ g/m 2 , 95 ⁇ g/m 2 , or 100 ⁇ g/m 2 , or an amount within a
  • the amount may range from about 10 - 40 ⁇ g/m 2 , or more particularly, about 15 ⁇ g/m 2 , about 20 ⁇ g/m 2 , about 25 ⁇ g/m 2 , about 30 ⁇ g/m 2 , about 35 ⁇ g/m 2 , or about 40 ⁇ g/m 2 , or about 45 ⁇ g/m 2 , or about 50 ⁇ g/m 2 , or an amount within a range bounded by any two of the foregoing values.
  • any of the amounts above or below expressed as “ ⁇ g/m 2 ” may alternatively be interpreted in terms of micrograms ( ⁇ g) or micrograms per 50 kg body weight “ ⁇ g/50 kg”.
  • 25 ⁇ g/m 2 may be interpreted as 25 ⁇ g or 25 ⁇ g/50 kg.
  • any of the foregoing amounts (which may be within any of the exemplary ranges disclosed above) may be administered per day, every other day, once every three days, precisely or at least once per week, precisely or at least once every two weeks, and any of the foregoing administrations may be continued as a dosing regimen for at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve weeks, or for at least four, five, six, seven, eight, nine, ten, eleven, or twelve months.
  • the therapeutically effective amount of the PKC activator is about 25 ⁇ g/m 2 .
  • the PKC activator is administered as a dose in the range of about 0.01 to 100 ⁇ g/m 2 /week.
  • the dose may be administered each week in a range of about 0.01 to about 25 ⁇ g/m 2 /week; about 1 to about 20 ⁇ g/m 2 /week, about 5 to about 20 ⁇ g/m 2 /week, or about 10 to about 20 ⁇ g/m 2 /week.
  • the dose may be about or less than, for example, 5 ⁇ g/m 2 /week, 10 ⁇ g/m 2 /week, 15 ⁇ g/m 2 /week, 20 ⁇ g/m 2 /week, 25 ⁇ g/m 2 /week, or 20 ⁇ g/m 2 /week.
  • Any of the foregoing dosages may be administered over a suitable time period, e.g., three weeks, four weeks, (approximately 1 month), two months, three months (approximately 12 or 13 weeks), four months, five months, six months, or a year.
  • any of the amounts above or below expressed as “ ⁇ g/m 2 ” may alternatively correspond to micrograms ( ⁇ g) or micrograms per 50 kg body weight “ ⁇ g/50 kg” per dosage or amount per week.
  • the PKC activator e.g., a bryostatin
  • the PKC activator is administered in an amount of precisely or about 20 ⁇ g, 30 ⁇ g, or 40 ⁇ g (20 ⁇ g/m 2 , 30 ⁇ g/m 2 , or 40 ⁇ g/m 2 ) every week or every two weeks for a total period of time of, e.g., four weeks, (approximately 1 month), five weeks, six weeks, eight weeks, ten weeks, twelve weeks, four months, five months, six months, or a year.
  • the administration may alternatively start with an initial single higher amount (e.g., 10%, 15%, 20%, or 25% higher amount than successive administrations).
  • the PKC activator may be administered in an amount of precisely or about 15 ⁇ g, 24 ⁇ g, or 48 ⁇ g for the first week or first two or three consecutive weeks followed by administrations of 12 ⁇ g, 20 ⁇ g or 40 ⁇ g, respectively, every week or alternately every two or three weeks for at least four weeks (approximately 1 month), six weeks, eight weeks, ten weeks, twelve weeks, fifteen weeks, eighteen weeks, or for at least three months, four months, five months, six months, or a year.
  • the term “alternately,” as used herein, indicates a period of time in which the PKC activator is not being administered. For example, “alternately every two or three weeks” indicates, respectively, regular one-week periods of no administration or regular two-week periods of no administration (also referred to herein as “1 on/1 off” and “1 on/2 off” dosing regimens). Other alternating dosing regimens are possible, including, for example, “2 on/1 off”, “2 on/2 off”, “1 on/3 off”, “2 on/3 off”, “3 on/3 off”, “3 on/1 off”, and “3 on/2 off”.
  • the PKC activator is administered in an amount of 10-50 ⁇ g/m 2 weekly for at least 1 week, 2 weeks, or 3 weeks.
  • the PKC activator is administered in an amount of 20-40 ⁇ g/m 2 weekly for at least 1 week, 2 weeks, or 3 weeks.
  • the PKC activator is administered in an amount of 25-40 ⁇ g/m 2 weekly for at least 1 week, 2 weeks, or 3 weeks.
  • the PKC activator is administered in an amount of 20-50 ⁇ g/m 2 weekly for at least 1 week, 2 weeks, or 3 weeks. In a fifth set of embodiments, the PKC activator is administered in an amount of 30-50 ⁇ g/m 2 weekly for at least 1 week, 2 weeks, or 3 weeks.
  • the PKC activator may be administered weekly at the indicated dosage for precisely or at least four, five, six, seven, eight, nine, ten, eleven, or twelve weeks, or for a longer period of time (e.g., four, five, or six months, or one, two, or three years).
  • the subject before administering the PKC activator, the subject is first confirmed to have COVID or long COVID.
  • the subject may be confirmed to have COVID by any of the known testing methods, such as nasal swab, saliva, or blood test.
  • the test may be a rapid antigen test or molecular (e.g., PCR) test, which may be provided in a medical facility or obtained commercially and used by self-testing.
  • the subject may be confirmed to have long COVID if the subject has been confirmed to have contracted COVID and continues to experience one or more symptoms associated with COVID at least one, two, or three months following contraction of COVID, or after experiencing the first symptoms of COVID, or after the first indication of improvement following an acute case of COVID.
  • the PKC activator is selected from macrocyclic lactones, bryostatins, bryologs, diacylglycerols, isoprenoids, octylindolactam, gnidimacrin, ingenol, iripallidal, napthalenesulfonamides, diacylglycerol inhibitors, growth factors, polyunsaturated fatty acids, monounsaturated fatty acids, cyclopropanated polyunsaturated fatty acids, cyclopropanated monounsaturated fatty acids, fatty acids alcohols and derivatives, and fatty acid esters.
  • the PKC activator is a macrocyclic lactone.
  • Macrocyclic lactones also known as macrolides
  • Macrolides belong to the polyketide class of natural products. Macrocyclic lactones and derivatives thereof are described for example in US Patent Nos 6187568; 6043270; 5,393,897; 5,072,004; 5,196,447; 4,833,257; and 4,611,066; and 4,560,774; each incorporated by reference herein in its entirety.
  • Those patents describe various compounds and various uses for macrocyclic lactones including their use as an anti-inflammatory or anti-tumor agents.
  • the macrocyclic lactone is a bryostatin.
  • Bryostatins include, for example, Bryostatin-1, Bryostatin-2, Bryostatin-3, Bryostatin-4, Bryostatin-5, Bryostatin- 6, Bryostatin-7, Bryostatin-8, Bryostatin-9, Bryostatin-10, Bryostatin-11, Bryostatin-12, Bryostatin-13, Bryostatin-14, Bryostatin-15, Bryostatin-16, Bryostatin-17, and Bryostatin-18.
  • the macrocyclic lactone may alternatively be a neristatin, such as neristatin-1.
  • the bryostatin is Bryostatin-1 (shown below).
  • the macrocyclic lactone is selected from macrocyclic derivatives of cyclopropanated PUFAs such as, 24-octaheptacyclononacosan-25-one (cyclic DHA-CP6) (shown below).
  • the macrocyclic lactone is a bryolog, wherein bryologs are analogues of bryostatin. Bryologs can be chemically synthesized or produced by certain bacteria.
  • bryologs exist that modify, for example, the rings A, B, and C (see Bryostatin-1, figure shown above) as well as the various substituents. Generally, bryologs are considered less specific and less potent than bryostatin but are easier to prepare. [0037] Table 1 summarizes structural characteristics of several bryologs and their affinity for PKC (ranging from 0.25 nM to 10 ⁇ M). While Bryostatin-1 has two pyran rings and one 6- membered cyclic acetal, in most bryologs one of the pyrans of Bryostatin-1 is replaced with a second 6-membered acetal ring.
  • Bryologs may reduce the stability of bryologs, relative to Bryostatin-1, for example, in strong acid or base, but has little significance at physiological pH. Bryologs also tend to have a lower molecular weight (ranging from about 600 g/mol to 755 g/mol), as compared to Bryostatin-1 (988), a property which may facilitate transport across the blood-brain barrier.
  • Table 1 Bryologs [0038] Analog 1 exhibits the highest affinity for PKC. Wender et al., Curr. Drug Discov. Technol. (2004), vol.1, pp.1-11; Wender et al. Proc. Natl. Acad. Sci.
  • Analog 1 exhibits a higher affinity for PKC than Bryostatin-1.
  • Analog 2 which lacks the A ring of Bryostatin-1, is the simplest analog that maintains high affinity for PKC.
  • Analog 7d which is acetylated at position 26, has virtually no affinity for PKC.
  • B-ring bryologs may also be used in the present disclosure. These synthetic bryologs have affinities in the low nanomolar range. Wender et al., Org Lett. (2006), vol.8, pp.5299- 5302, incorporated by reference herein in its entirety. B-ring bryologs have the advantage of being completely synthetic, and do not require purification from a natural source.
  • a third class of suitable bryostatin analogs are the A-ring bryologs. These bryologs generally have slightly lower affinity for PKC than Bryostatin-1 (6.5 nM, 2.3 nM, and 1.9 nM for bryologs 3, 4, and 5, respectively) and a lower molecular weight. A-ring substituents are important for non-tumorigenesis.
  • Bryostatin analogs are described, for example, in U.S. Patent Nos.6,624,189 and 7,256,286. Methods using macrocyclic lactones to improve cognitive ability are also described in U.S. Patent No.6,825,229 B2.
  • the PKC activator may also include derivatives of diacylglycerols (DAGs).
  • DAGs diacylglycerols
  • Activation of PKC by diacylglycerols is transient, because they are rapidly metabolized by diacylglycerol kinase and lipase. Bishop et al. J. BioI. Chem.
  • diacylglycerols having an unsaturated fatty acid may be most active.
  • the stereoisomeric configuration is important; fatty acids with a 1,2-sn configuration may be active while 2,3-sn-diacylglycerols and 1,3-diacylglycerols may not bind to PKC.
  • Cis- unsaturated fatty acids may be synergistic with diacylglycerols.
  • the PKC activator excludes DAG or DAG derivatives.
  • the PKC activator may also include isoprenoids.
  • Farnesyl thiotriazole for example, is a synthetic isoprenoid that activates PKC with a K d of 2.5 ⁇ M.
  • Farnesyl thiotriazole for example, is equipotent with dioleoylglycerol, but does not possess hydrolyzable esters of fatty acids.
  • Farnesyl thiotriazole and related compounds represent a stable, persistent PKC activator.
  • PKC activators include octylindolactam V, gnidimacrin, and ingenol.
  • Octylindolactam V is a non-phorbol protein kinase C activator related to teleocidin.
  • Gnidimacrin is a daphnane-type diterpene that displays potent antitumor activity at concentrations of 0.1 nM - 1 nM against murine leukemias and solid tumors.
  • Iripallidal is a bicyclic triterpenoid isolated from Iris pallida.
  • the PKC activator may also include the class of napthalenesulfonamides, including N- (n-heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) and N-(6-phenylhexyl)-5-chloro-1- naphthalenesulfonamide.
  • SC-10 may activate PKC in a calcium-dependent manner, using a mechanism similar to that of phosphatidylserine. Ito et al., Biochemistry (1986), vol. 25, pp. 4179-4184, incorporated by reference herein.
  • Naphthalenesulfonamides act by a different mechanism than bryostatin and may show a synergistic effect with bryostatin or member of another class of PKC activators. Structurally, naphthalenesulfonamides are similar to the calmodulin (CaM) antagonist W-7, but are reported to have no effect on CaM kinase.
  • the PKC activator may also include the class of diacylglycerol kinase inhibitors, which indirectly activate PKC.
  • diacylglycerol kinase inhibitors include, but are not limited to, 6-(2-(4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl)ethyl)-7-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one (R59022) and [3-[2-[4-(bis-(4- fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone (R59949).
  • the PKC activator may also be a growth factor, such as fibroblast growth factor 18 (FGF-18) and insulin growth factor, which function through the PKC pathway. FGF-18 expression is up-regulated in learning, and receptors for insulin growth factor have been implicated in learning. Activation of the PKC signaling pathway by these or other growth factors offers an additional potential means of activating PKC.
  • the PKC activator may or may not also include a hormone or growth factor activator, e.g., a 4-methyl catechol derivative, such as 4-methylcatechol acetic acid (MCBA), which stimulates the synthesis and/or activation of growth factors, such as NGF and BDNF.
  • a hormone or growth factor activator e.g., a 4-methyl catechol derivative, such as 4-methylcatechol acetic acid (MCBA), which stimulates the synthesis and/or activation of growth factors, such as NGF and BDNF.
  • the PKC activator may also be a polyunsaturated fatty acid (“PUFA”). These compounds are essential components of the nervous system and have numerous health benefits. In general, PUFAs increase membrane fluidity, rapidly oxidize to highly bioactive products, produce a variety of inflammatory and hormonal effects, and are rapidly degraded and metabolized. The inflammatory effects and rapid metabolism is likely the result of their active carbon-carbon double bonds.
  • the PUFA is selected from linoleic acid (shown below).
  • the PKC activator may also be a PUFA or MUFA derivative.
  • the PUFA or MUFA derivative is a cyclopropanated derivative.
  • Certain cyclopropanated PUFAs such as DCPLA (i.e., linoleic acid with cyclopropane at both double bonds), may be able to selectively activate PKC- ⁇ . See Journal of Biological Chemistry, 2009, 284(50): 34514-34521; see also U.S. Patent Application Publication No.2010/0022645 A1. Like their parent molecules, PUFA derivatives are thought to activate PKC by binding to the PS site. [0055] Cyclopropanated fatty acids exhibit low toxicity and are readily imported into the brain where they exhibit a long half-life (t 1/2 ).
  • omega-3 PUFA derivatives are selected from cyclopropanated docosahexaenoic acid, cyclopropanated eicosapentaenoic acid, cyclopropanated rumelenic acid, cyclopropanated parinaric acid, and cyclopropanated linolenic acid (CP3 form shown below).
  • omega-6 PUFA derivatives are selected from cyclopropanated linoleic acid (“DCPLA,” CP2 form shown below), cyclopropanated arachidonic acid, cyclopropanated eicosadienoic acid, cyclopropanated dihomo-gamma-linolenic acid, cyclopropanated docosadienoic acid, cyclopropanated adrenic acid, cyclopropanated calendic acid, cyclopropanated docosapentaenoic acid, cyclopropanated jacaric acid, cyclopropanated pinolenic acid, cyclopropanated podocarpic acid, cyclopropanated tetracosatetraenoic acid, and cyclopropanated tetracosapentaenoic acid.
  • DCPLA cyclopropanated linoleic acid
  • arachidonic acid cyclopropanated eicosadie
  • Vernolic acid is a naturally occurring compound. However, it is an epoxyl derivative of linoleic acid and therefore, as used herein, is considered an omega-6 PUFA derivative.
  • cyclopropanated vernolic acid (shown below) is an omega-6 PUFA derivative.
  • Another class of PKC-activating fatty acids is the class of omega-9 PUFA derivatives.
  • the omega-9 PUFA derivatives are selected from cyclopropanated eicosenoic acid, cyclopropanated mead acid, cyclopropanated erucic acid, and cyclopropanated nervonic acid.
  • PKC-activating fatty acids is the class of monounsaturated fatty acid (“MUFA”) derivatives.
  • the MUFA derivatives are selected from cyclopropanated oleic acid (shown below), [0062] and cyclopropanated elaidic acid (shown below).
  • PKC-activating MUFA derivatives include epoxylated compounds such as trans-9,10- epoxystearic acid (shown below).
  • Another class of PKC-activating fatty acids is the class of omega-5 and omega-7 PUFA derivatives.
  • the omega-5 and omega-7 PUFA derivatives are selected from cyclopropanated rumenic acid, cyclopropanated alpha-elostearic acid, cyclopropanated catalpic acid, and cyclopropanated punicic acid.
  • Another class of PKC activators is the class of fatty acid alcohols and derivatives thereof, such as cyclopropanated PUFA and MUFA fatty alcohols. It is thought that these alcohols activate PKC by binding to the PS site. These alcohols can be derived from different classes of fatty acids.
  • the PKC-activating fatty alcohols are derived from omega-3 PUFAs, omega-6 PUFAs, omega-9 PUFAs, and MUFAs, especially the fatty acids noted above.
  • the fatty alcohol is selected from cyclopropanated linolenyl alcohol (CP3 form shown above), cyclopropanated linoleyl alcohol (CP2 form shown above), cyclopropanated elaidic alcohol (shown above), cyclopropanated DCPLA alcohol, and cyclopropanated oleyl alcohol.
  • Another class of PKC activators includes fatty acid esters and derivatives thereof, such as cyclopropanated PUFA and MUFA fatty esters.
  • the cyclopropanated fatty esters are derived from omega-3 PUFAs, omega-6 PUFAs, omega-9 PUFAs, MUFAs, omega-5 PUFAs, and omega-7 PUFAs. These compounds are thought to activate PKC through binding on the PS site.
  • One advantage of such esters is that they are generally considered to be more stable that their free acid counterparts.
  • the PKC-activating fatty acid esters derived from omega-3 PUFAs are selected from cyclopropanated eicosapentaenoic acid methyl ester (CP5 form shown below) [0069] and cyclopropanated linolenic acid methyl ester (CP3 form shown below).
  • the omega-3 PUFA esters are selected from esters of DHA- CP6 and aliphatic and aromatic alcohols.
  • the ester is cyclopropanated docosahexaenoic acid methyl ester (CP6 form shown below).
  • PKC-activating fatty esters derived from omega-6 PUFAs are selected from cyclopropanated arachidonic acid methyl ester (CP4 form shown below), [0072] cyclopropanated vernolic acid methyl ester (CP1 form shown below), and [0073] vernolic acid methyl ester (shown below).
  • the PKC activating compound is an ester derivative of DCPLA (CP6-linoleic acid).
  • the ester of DCPLA is an alkyl ester.
  • the alkyl group of the DCPLA alkyl esters may be linear, branched, and/or cyclic.
  • the alkyl groups may be saturated or unsaturated.
  • the cyclic alkyl group may be aromatic.
  • the alkyl group may be selected from, for example, methyl, ethyl, propyl (e.g., isopropyl), and butyl (e.g., tert-butyl) esters.
  • DCPLA in the methyl ester form (“DCPLA-ME”) is shown below.
  • the esters of DCPLA are derived from a benzyl alcohol (unsubstituted benzyl alcohol ester shown below).
  • the esters of DCPLA are derived from aromatic alcohols such as phenols used as antioxidants and natural phenols with pro-learning ability. Some specific examples include estradiol, butylated hydroxytoluene, resveratrol, polyhydroxylated aromatic compounds, and curcumin.
  • Another class of PKC activators includes fatty esters derived from cyclopropanated MUFAs.
  • the cyclopropanated MUFA ester is selected from cyclopropanated elaidic acid methyl ester (shown below), [0077] and cyclopropanated oleic acid methyl ester (shown below).
  • PKC activators includes sulfates and phosphates derived from PUFAs, MUFAs, and their derivatives.
  • the sulfate is selected from DCPLA sulfate and DHA sulfate (CP6 form shown below).
  • the phosphate is selected from DCPLA phosphate and DHA phosphate (CP6 form shown below).
  • any two or more of the above disclosed PKC activators may be administered to the subject in combination.
  • the PKC activator is an epoxidized derivative of a PUFA or MUFA, such as any of the PUFAs or MUFAs provided above.
  • the epoxidized PUFA or MUFA may be derived from any of the cyclopropanated derivatives provided above by replacing one or more of the cyclopropane rings with epoxy (oxirane) rings.
  • An example of an epoxidized PUFA is the following compound:
  • R is a hydrogen atom or an alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or t-butyl).
  • the PKC activator e.g., bryostatin or bryolog
  • the PKC activator is administered in combination with one or more other substances (i.e., co-drugs, typically, non-PKC activating) known to help diminish any one or more symptoms associated with long COVID, or one or more co-drugs that favorably or synergistically augment the efficacy of the PKC activator in treating or preventing long COVID.
  • the one or more co-drugs may be administered separately (e.g., same or different days or weeks) but in tandem with the administration of the PKC activator, or the one or more co-drugs may be included within the same pharmaceutical formulation as the PKC activator, thereby being administered to the subject at the same time within the same dosage form.
  • the co-drug may be, for example, a hormone (e.g., melatonin), antibiotic (e.g., minocycline), steroid or corticosteroid (e.g., corticotrophin, cortisone, or methylprednisolone), cytokine in the interferon family (e.g., interferon beta-1a or interferon beta 1-alpha), or statin (e.g., simvastatin).
  • a hormone e.g., melatonin
  • antibiotic e.g., minocycline
  • corticosteroid e.g., corticotrophin, cortisone, or methylprednisolone
  • cytokine in the interferon family e.g., interferon beta-1a or interferon beta 1-alpha
  • statin e.g., simvastatin
  • Parenteral administration includes intravenous, intra-arteriolar, intramuscular, intradermal, subcutaneous, intraperitoneal, intraventricular, intrathecal, ICV, intracisternal injections or infusions and intracranial administration.
  • a suitable route of administration may be chosen to permit crossing the blood- brain barrier. See e.g., J. Lipid Res. (2001) vol. 42, pp. 678-685, incorporated by reference herein.
  • the PKC activators can be compounded into a pharmaceutical composition suitable for administration to a subject using general principles of pharmaceutical compounding.
  • the pharmaceutically acceptable formulation comprises a PKC activator and a pharmaceutically acceptable carrier.
  • One or more co-drugs, as described above, may or may not also be included in the formulation.
  • compositions described herein may be prepared by any suitable method known in the art.
  • preparatory methods include bringing at least one of the active ingredients into association with a carrier. If necessary or desirable, the resultant product can be shaped or packaged into a desired single- or multi-dose unit.
  • carriers include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
  • the carrier is an aqueous or hydrophilic carrier.
  • the carrier may be water, saline, or dimethylsulfoxide.
  • the carrier is a hydrophobic carrier.
  • Exemplary hydrophobic carriers include, for example, inclusion complexes, dispersions (such as micelles, microemulsions, and emulsions), and liposomes. See, e.g., Remington's: The Science and Practice of Pharmacy 20th ed., ed. Gennaro, Lippincott: Philadelphia, PA 2003, incorporated by reference herein.
  • other compounds may be included either in the hydrophobic carrier or the solution, e.g., to stabilize the formulation.
  • the compositions described herein may be formulated into oral dosage forms.
  • the composition may be in the form of a tablet or capsule prepared by conventional means with, for example, carriers such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc, or silica
  • disintegrants e.g., potato star
  • Such preparations may be in the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable carriers, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid).
  • suspending agents e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, ethy
  • compositions herein may be formulated for parenteral administration, such as bolus injection or continuous infusion.
  • parenteral administration such as bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules, or in multi- dose containers, with an added preservative.
  • the composition may be in the form of a suspension, solution, dispersion, or emulsion in oily or aqueous vehicles, and may contain a formulary agent, such as a suspending, stabilizing, and/or dispersing agent.
  • compositions herein may be formulated as depot preparations. Such formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compositions may be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.
  • at least one PKC activator or combination thereof is delivered in a vesicle, such as a micelle, liposome, or an artificial low-density lipoprotein (LDL) particle. See, e.g., U.S.
  • LDL low-density lipoprotein
  • At least one PKC activator or combination of PKC activators may be present in the pharmaceutical composition in an amount ranging from about 0.01% to about 100%, from about 0.1% to about 90%, from about 0.1% to about 60%, from about 0.1% to about 30% by weight, or from about 1% to about 10% by weight of the final formulation.
  • at least one PKC activator or combination of PKC activators may be present in the composition in an amount ranging from about 0.01% to about 100%, from about 0.1% to about 95%, from about 1% to about 90%, from about 5% to about 85%, from about 10% to about 80%, and from about 25% to about 75%.
  • kits that may be utilized for administering to a subject a PKC activator according to the present disclosure.
  • the kits may comprise devices for storage and/or administration.
  • the kits may comprise syringe(s), needle(s), needle-less injection device(s), sterile pad(s), swab(s), vial(s), ampoule(s), cartridge(s), bottle(s), and the like.
  • the storage and/or administration devices may be graduated to allow, for example, measuring volumes.
  • the kit comprises at least one PKC activator in a container separate from other components in the system.
  • the kits may also comprise one or more anesthetics, such as local anesthetics.
  • the anesthetics are in a ready-to-use formulation, for example, an injectable formulation (optionally in one or more pre-loaded syringes), or a formulation that may be applied topically.
  • Topical formulations of anesthetics may be in the form of an anesthetic applied to a pad, swab, towelette, disposable napkin, cloth, patch, bandage, gauze, cotton ball, Q-tipTM, ointment, cream, gel, paste, liquid, or any other topically applied formulation.
  • Anesthetics for use with the present disclosure may include, but are not limited to lidocaine, marcaine, cocaine, and xylocaine.
  • kits may also contain instructions relating to the use of at least one PKC activator or a combination thereof.
  • the kit may contain instructions relating to procedures for mixing, diluting, or preparing formulations of at least one PKC activator or a combination thereof.
  • the instructions may also contain directions for properly diluting a formulation of at least one PKC activator or a combination thereof in order to obtain a desired pH or range of pHs and/or a desired specific activity and/or protein concentration after mixing but prior to administration.
  • the instructions may also contain dosing information.
  • the instructions may also contain material directed to methods for selecting subjects for treatment with at least one PKC activator or a combination thereof.
  • the PKC activator can be formulated, alone in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. Pharmaceutical compositions may further comprise other therapeutically active compounds which are approved for the treatment or prevention of one or more symptoms associated with COVID or long COVID. [0098] All of the references, patents and printed publications mentioned in the instant disclosure are hereby incorporated by reference in their entirety into this application. [0099] While there have been shown and described what are at present considered the preferred embodiments of the invention, those skilled in the art may make various changes and modifications which remain within the scope of the invention defined by the appended claims.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medical Informatics (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Primary Health Care (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Data Mining & Analysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pathology (AREA)
  • Databases & Information Systems (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne une méthode de traitement ou de prévention du COVID long chez un sujet qui a contracté ou présente un risque de contracter le COVID, la méthode comprenant l'administration audit sujet d'une quantité pharmaceutiquement efficace d'un activateur de la PKC (par exemple, bryostatine, bryologue, AGPI, AGPI cyclopropané, AGPI époxydé, facteur de croissance ou composé d'activation de facteur de croissance) avant ou pendant la contraction initiale du COVID, le sujet pouvant avoir contracté le COVID ou présenté les premiers symptômes de COVID au moins un mois avant l'administration de l'activateur de la PKC au sujet. Dans certains cas, le sujet peut être atteint d'un COVID long et présente au moins un symptôme de COVID long choisi parmi la fatigue intermittente, l'absence d'énergie, les problèmes respiratoires, la douleur thoracique, la douleur articulaire, la douleur musculaire ou l'endolorissement, les problèmes vasculaires, les problèmes neurologiques et/ou les affections cutanées.
PCT/US2023/027864 2022-07-18 2023-07-17 Méthode permettant d'améliorer la récupération après un covid long WO2024019953A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263390035P 2022-07-18 2022-07-18
US63/390,035 2022-07-18

Publications (1)

Publication Number Publication Date
WO2024019953A1 true WO2024019953A1 (fr) 2024-01-25

Family

ID=89618109

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/027864 WO2024019953A1 (fr) 2022-07-18 2023-07-17 Méthode permettant d'améliorer la récupération après un covid long

Country Status (1)

Country Link
WO (1) WO2024019953A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200345699A1 (en) * 2019-04-17 2020-11-05 Gilead Sciences, Inc. Hiv protease inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200345699A1 (en) * 2019-04-17 2020-11-05 Gilead Sciences, Inc. Hiv protease inhibitors

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ABRAMSON EFRAT; HARDMAN CLAYTON; SHIMIZU AKIRA J.; HWANG SOONMYUNG; HESTER LYNDA D.; SNYDER SOLOMON H.; WENDER PAUL A.; KIM PAUL M: "Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation", CELL CHEMICAL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 4, 19 January 2021 (2021-01-19), AMSTERDAM, NL , pages 537, XP086539019, ISSN: 2451-9456, DOI: 10.1016/j.chembiol.2020.12.015 *
AL-HORANI RAMI A., KAR SRABANI, ALITER KHOLOUD F.: "Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 15, pages 5224, XP055940462, DOI: 10.3390/ijms21155224 *
BORGO CHRISTIAN, D’AMORE CLAUDIO, SARNO STEFANIA, SALVI MAURO, RUZZENE MARIA: "Protein kinase CK2: a potential therapeutic target for diverse human diseases", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 6, no. 1, XP093055658, DOI: 10.1038/s41392-021-00567-7 *
HUANG CHANGBAI, FENG FEI, SHI YONGXIA, LI WENHUI, WANG ZIQIAO, ZHU YUNKAI, YUAN SHUAI, HU DANDAN, DAI JUN, JIANG QIQI, ZHANG RONG,: "Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells", MICROBIOLOGY SPECTRUM, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 10, no. 5, 26 October 2022 (2022-10-26), US , XP093134184, ISSN: 2165-0497, DOI: 10.1128/spectrum.01056-22 *
KHAZAAL SHAYMAA, HARB JULIEN, RIMA MOHAMAD, ANNWEILER CÉDRIC, WU YINGLIANG, CAO ZHIJIAN, ABI KHATTAR ZIAD, LEGROS CHRISTIAN, KOVAC: "The Pathophysiology of Long COVID throughout the Renin-Angiotensin System", MOLECULES, MDPI AG, CH, vol. 27, no. 9, 2 May 2022 (2022-05-02), CH , pages 2903, XP093133768, ISSN: 1420-3049, DOI: 10.3390/molecules27092903 *
SANTOPAOLO MARIANNA, GREGOROVA MICHAELA, HAMILTON FERGUS, ARNOLD DAVID, LONG ANNA, LACEY AURORA, OLIVER ELIZABETH, HALLIDAY ALICE,: "Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months", IMMUNOLOGY AND INFLAMMATION. ELIFE, 3 June 2023 (2023-06-03), XP093133771, [retrieved on 20240221] *

Similar Documents

Publication Publication Date Title
US11820745B2 (en) PKC-activating compounds for the treatment of neurodegenerative diseases
JP6336914B2 (ja) 脳卒中の治療のためのホルボールエステルの組成物および使用方法
US11826345B2 (en) Dosing regimens of PKC activators
KR20080097989A (ko) 근위축증 치료를 위한 의약의 니트록시 유도체의 용도
WO2022094370A1 (fr) Procédés de traitement et de prévention de maladies neurodégénératives avec des composés activateurs de hgf
WO2012105476A1 (fr) Médicament prophylactique ou thérapeutique pour neuropathie périphérique provoquée par un agent anticancéreux
US20230000943A1 (en) Method of inducing synaptogenesis by administering angiotensin and analogues thereof
WO2024019953A1 (fr) Méthode permettant d'améliorer la récupération après un covid long
US20240165075A1 (en) Treatment of optic nerve inflammation using pkc activators
WO2022170232A1 (fr) Traitement de la sclérose en plaques au moyen d'activateurs de pkc
US20220184028A1 (en) Treatment of amyotrophic lateral sclerosis using pkc activators
US20130165453A1 (en) Therapeutic effects of bryostatins, bryologs, and other related substances on ischemia/stroke-induced memory impairment and brain injury
US20180256537A1 (en) Methods for survival and rejuvenation of dermal fibroblasts using pkc activators

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: 23843578

Country of ref document: EP

Kind code of ref document: A1