EP4171545A1 - Inhibiteurs de sphingomyélinase acide pour la prévention et le traitement de la maladie covid-19 - Google Patents

Inhibiteurs de sphingomyélinase acide pour la prévention et le traitement de la maladie covid-19

Info

Publication number
EP4171545A1
EP4171545A1 EP21735939.7A EP21735939A EP4171545A1 EP 4171545 A1 EP4171545 A1 EP 4171545A1 EP 21735939 A EP21735939 A EP 21735939A EP 4171545 A1 EP4171545 A1 EP 4171545A1
Authority
EP
European Patent Office
Prior art keywords
fiasma
agent
covid
patients
use according
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.)
Pending
Application number
EP21735939.7A
Other languages
German (de)
English (en)
Inventor
Nicolas HOERTEL
Frédéric LIMOSIN
Marina Lucia SANCHEZ RICO
Miriam ABELLÁN
Pedro DE LA MUELA
Erich Gulbins
Johannes Kornhuber
Alexander CARPINTEIRO
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.)
Assistance Publique Hopitaux de Paris APHP
Universite Paris Cite
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Universite Paris Cite
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
Priority claimed from EP20305698.1A external-priority patent/EP3928775A1/fr
Priority claimed from EP20306117.1A external-priority patent/EP3973961A1/fr
Priority claimed from US17/146,013 external-priority patent/US20220347127A1/en
Application filed by Assistance Publique Hopitaux de Paris APHP, Universite Paris Cite filed Critical Assistance Publique Hopitaux de Paris APHP
Publication of EP4171545A1 publication Critical patent/EP4171545A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • the present invention relates to the preventive and therapeutic uses of acid sphingomyelinase inhibitors (FIASMAs) such as psychotropic medications and non psychotropic compounds having FIASMA activity, for lowering the risk of death and/or intubation in patient suffering from a viral infection caused by at least one betacoronavirus, in particular by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) through reduced cell and blood concentration of ceramides.
  • FIASMAs acid sphingomyelinase inhibitors
  • SARS-CoV-2 belongs to the species Coronavirus , in the genus Betacoronavirus and family Coronaviridae .
  • Coronaviruses are enveloped viruses with a helically symmetrical capsid. They have a single-stranded, positive-sense RNA genome and are capable of infecting cells in birds and mammals.
  • the morphology of the virions is typical, with a halo of protein protuberances ('Spike') which gave them their name of 'crown virus'.
  • Betacoronavirus genus (b-CoVs or Beta- CoVs), comprising virus infecting animals and/or humans, is subdivided into four lineages designated as A, B, C and D: ⁇ Lineage A also designated as subgenus Embecovirus includes HCoV-OC43 and
  • Lineage B also designated as subgenus Sarbecovirus includes SARS-CoV-1, SARS-CoV-2, and Bat SL-CoV-WIVl;
  • Lineage C also designated as subgenus Merbecovirus includes Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4), Pipistrellus bat coronavirus HKU5 (BtCoV- HKU5), and MERS-CoV, able to infect notably camels and humans;
  • Lineage D also designated as subgenus Nobecovirus includes Rousettus bat coronavirus HKU9 (BtCoV-HKU9).
  • Betacoronaviruses of the greatest clinical importance concerning humans are:
  • coronavirus infections can cause respiratory pathologies associated with symptoms similar to the common cold, bronchiolitis and more serious diseases such as the Severe Acute Respiratory Syndrome caused by SARS-CoV-1, which generated an epidemic in 2003, and the Middle Eastern Respiratory Syndrome caused by MERS-CoV, which generated an epidemic in 2012.
  • SARS-CoV-2 is the betacoronavirus causing the coronavirus epidemic of 2019-2021, generating the form of pneumonia known as coronavirus disease 2019 or COVID-19.
  • Symptoms of infection with SARS-CoV-2 are roughly similar to those of seasonal influenza infections: they include fever, fatigue, dry cough, shortness of breath, difficult breathing, pneumonia, renal failure, and may lead to death in severe cases.
  • the present inventors have discovered that the use of some antidepressants and non-psychotropic compounds (in particular hydroxyzine), all of which being able to inhibit the acid sphingomyelinase (ASM) / ceramide system (FIASMA agents), were significantly associated with reduced mortality in patients hospitalized for COVID-19 (see examples 1-3 below).
  • ASM acid sphingomyelinase
  • FIASMA agents acid sphingomyelinase
  • Betacoronavirus designates any virus belonging to the Betacoronavirus genus (b-CoVs or Beta-CoVs), in particular any betacoronavirus belonging to one of the four lineages designated as A, B, C and D. It designates a betacoronavirus infecting animals and/or humans. In particular, this designation includes the betacoronaviruses infecting human organisms chosen among OC43, HKU1, SARS- CoV-1, SARS-CoV-2 and MERS-CoV.
  • viral infection due to at least one betacoronavirus designates the fact that host cells of an organism have been infected by at least one betacoronavirus, the whole organism being said to have a viral infection.
  • a betacoronavirus infection in humans is usually diagnosed by a healthcare professional, based on observation of the infected patient's symptoms. Additional biological tests may be required to confirm the diagnosis: blood and/or sputum and/or bronchoalveolar fluid tests.
  • Infection by a betacoronavirus can be established, for example, by molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • Conventional diagnostic methods comprise techniques of molecular biology such as PCR, which is well known to the person in the field.
  • the term "treatment” refers to fighting the betacoronavirus infection in a human or animal organism.
  • the symptoms associated with the betacoronovirus infection will be reduced, or the severity of the disease will decrease.
  • the treatment of the invention to prevent the worsening of the disease and also to prevent, in certain cases, the viral infection itself (i.e., the entry of the virus into the patient cells).
  • COVID-19 disease mean the disease linked to the infection with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) ⁇
  • a “symptomatic COVID-19 disease” is characterized by a patient who shows at least one symptom of the COVID-19 disease.
  • the most common symptoms of the COVID-19 disease are fever, muscle aches, headaches, fatigue, loss of taste and smell and respiratory symptoms such as a dry cough, difficulty breathing and a lack of oxygen.
  • a symptomatic disease is in contrast to an asymptomatic disease which is characterized by a patient who is a carrier for a disease or infection but experiences no symptoms.
  • betacoronavirus disease such as COVID-19
  • the following forms are usually observed: an “asymptomatic form” wherein the subject is a carrier of at least on betacoronavirus but shows no symptom.
  • a “mild CO ID form” wherein the subject shows the first symptoms (or signs) of a COVID disease, as listed above.
  • Mild COVID symptoms comprise e.g., mild dry cough, mild muscle pain, mild headache, mild fever, mild fatigue, loss of taste or smell.
  • a “strong COVID form” wherein the subject shows strong respiratory symptoms such as difficulty breathing, lack of oxygen; other stronger symptoms such as fever, dry cough, aches and pains, nasal congestion, strong headache, conjunctivitis, sore throat, skin rash, discoloration of fingers or feet, or any combination thereof; as well as a deterioration of the general state of health with frequent diarrhoea, but also liver or urinary disorders, dizziness or neuromuscular problems; some of these symptoms may require hospitalisation. Most patients have an abnormal chest X-ray or CT scan within the first few days of illness, even in the absence of respiratory signs.
  • a “severe COVID form” or “critical COVID form” or “aggressive COVID form” wherein the subject has life-threatening symptoms (or signs) of COVID comprising at least one selected from (but not limited to) : respiratory distress, lung disorders, liver disorders, kidney disorders, neuromuscular disorders, brain disorders, etc, that requires hospitalisation and/or intensive care (in intensive care units (ICU)).
  • ICU intensive care units
  • the “severe symptomatic COVID-19 disease” is characterized by severe symptoms of the COVID-19 disease, in particular respiratory symptoms. Severe symptoms are acute respiratory distress syndrome that requires hospitalization of the patient in any unit, and especially in the intensive care unit (ICU) in case of critical infection.
  • ICU intensive care unit
  • the abbreviation “ICU” refers to an intensive care unit, a special department of a hospital or health care facility that provides intensive treatment medicine.
  • COVID-19 patients are human patients infected with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2).
  • antidepressant agent an active agent that is capable to treat mood disorders, such as depression (including severe depression) and/or dysthymia, and/or anxiety disorders.
  • Antidepressant agents according to the invention include, without limitation, serotonin reuptake inhibitors (SRIs); tricyclic antidepressants (TCAs); monoamine oxidase inhibitors (MAOs).
  • Serotonin reuptake inhibitors designate a class of compounds that typically act by inhibiting the reuptake of the serotonin neurotransmitter into the presynaptic terminal, thereby increasing the serotonin extracellular level and thus serotoninergic transmission. Such compounds can act selectively or non-selectively on the neurotransmitter serotonin. SRIs can indeed also display various degrees of selectivity towards the other monoamine reuptake systems, in particular the transporters for norepinephrine and dopamine.
  • SRIs typically include selective serotonin reuptake inhibitors (SSRIs), serotonine and norepinephrine reuptake inhibitors (SNRIs) and serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRIs).
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs serotonine and norepinephrine reuptake inhibitors
  • SNDRIs serotonin-norepinephrine-dopamine reuptake inhibitor
  • SSRIs selective serotonin reuptake inhibitors
  • SSRIs include, without limitation, fluoxetine, citalopram, escitalopram, sertraline, norsertraline, paroxetine, fluvoxamine, vortioxetine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine, zimelidine, dapoxetine, and etoperidone.
  • they are chosen among citalopram, escitalopram, sertraline, norsertraline, paroxetine, fluvoxamine, vortioxetine, femoxetine, indalpine, alaproclate, cericlamine, ifoxetine and zimelidine.
  • active SSRIs metabolites include, without limitation, desmethylcitalopram, didesmethylcitalopram, and seproxetine (i.e. (S)-norfluoxetine).
  • serotonine and norepinephrine reuptake inhibitors include, without limitation, duloxetine, venlafaxine, desvenlafaxine, milnacipran, levominalcipran and sibutramine.
  • serotonin-norepinephrine-dopamine reuptake inhibitor examples include, without limitation, bicifadine, brasofensine, tesofensine and nomifensine.
  • TCAs tricyclic antidepressants
  • clomipramine amoxapine
  • nortriptyline maprotiline
  • trimipramine imipramine
  • desipramine desipramine and protriptyline.
  • monoamine oxidase inhibitors include, without limitation, iproniazide, phenelzine, tranylcipromine, moclobemide, selegiline and rasagiline.
  • Suitable antidepressant agents are for example: anpirtoline hydrochloride, CGS- 12066A, CGS 12066B dimaleate, oxymetazoline, 5-carboxamidotryptamine, CP-93129 and salts thereof (such as CP-93129 dihydrochloride), CP-94253 and salts thereof (such as CP-94253 hydrochloride), CP-122,288, CP-135,807, RU-24969 and salts thereof (such as RU-24969 hemi succinate), ziprasidone, asenapine, 5-nonyloxytryptamine oxalate, pindolol and (S)-(-)-pindolol and the like.
  • Antidepressant agent can act by blocking presynaptic alpha-2 adrenergic receptors.
  • blockers include, among others, mirtazapine, aptazapine, esmirtazapine, setiptiline and S32212 (also known as N-[4-methoxy-3-(4-methylpiperazin-l-yl)phenyl]-l,2-dihydro- 3 H-b enzo [e] indol e-3 -carb oxami de) .
  • Antidepressant agent can also be atypical antidepressant (defined as such as they do not belong to any of the foregoing classes of antidepressants), for example, without limitation, tianeptine, agomelatine, nefazodone, trazodone, buspirone, tandospirone, and ketamine.
  • Antidepressant agent can also be a 5 HT2 R stimulating or blocking agent, such as agomelatine or Saint John’s wort.
  • the Acid SphingoMyelinase enzyme (ASM, EC 3.1.4.12) is a lysosomal glycoprotein that catalyses the hydrolysis of sphingomyelin into ceramide and phosphorylcholine. Ceramide consecutively leads to membrane reorganization involving membrane rafts and downstream signalling that may result in apoptosis.
  • ASM Acid SphingoMyelinase enzyme
  • at least three other sphingomyelinases have been described in mammalian cells that vary in their pH optimum, cofactor dependency and subcellular localization.
  • ceramide generation activation of ASM is critical for at least some cellular responses, such as apoptosis induced by reactive nitrogen species, radiation, and CD95 ([5]).
  • the activity of acid sphingomyelinase on the cell surface results in the formation of ceramide in the outer leaflet of the cell membrane.
  • the generation of ceramide molecules within the outer leaflet alters the biophysical properties of the plasma membrane because the very hydrophobic ceramide molecules spontaneously associate with each other to form small ceramide-enriched membrane domains that fuse and form large, highly hydrophobic, tightly packed, gel-like ceramide-enriched membrane domains ([4]).
  • the formation of these ceramide-enriched domains seems to be responsible of the entry of the SARS-CoV-2 virus in the epithelial cells.
  • FIASMA agent or “agent having a FIASMA activity”, because it can effectively inhibit the ASM enzyme (the acid sphingomyelinase enzyme), directly or indirectly (the term “FIASMA” stands for Functional Inhibitor of Acid SphingoMyelinAse) and lead to decreased concentration of ceramide in the blood and in the cells.
  • FIASMA Functional Inhibitor of Acid SphingoMyelinAse
  • said term also encompass any agent that can lower the ceramide level at the surface of epithelial cells and in the blood by other means. In particular, it designates all agents that can in vitro lower the ASM activity and/or the ceramide surface level in epithelial cells by at least 50%, whatever the duration of incubation time.
  • Determination of the ASM activity in these cells can be performed by conventional techniques, as disclosed in [4] For example, 14 C sphingomyelin can be used and contacted with Vero or Caco-2 cells in presence or absence of the agent of the invention. The release of 14 C phosphorylcholine can then be monitored.
  • the Ceramide amount can be determined at the cell surface as disclosed in [4], e.g., by flow cytometry using anti-ceramide antibodies, or in the blood as measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) consisting of an Acquity UPLC instrument (Waters Associates, Milford, MA, USA) coupled to a triple quadrupole (TQS Micro, Waters) mass spectrometer as detailed in Marin-Corral et al, 2021 ([57]).
  • LC-MS/MS tandem mass spectrometry
  • the terms “medication of the invention”, “treatment of the invention” or “agent of the invention” designate any compound that is able to efficiently inhibit the ASM enzyme (FIASMA agents) or to reduce the ceramide level at the surface of epithelial cells and thus to reduce the level of ceramides in the blood.
  • the agent of the invention can also reduce the activity of other sphingomyelinase enzymes, so as to reduce the levels of ceramide in epithelial cells and thus in the blood. Also, it can indirectly inhibit the activity of the sphingomyelinase enzymes by displacing them from lysosomal membranes, in particular intralysosomal vesicles, thereby releasing them into the lysosomal lumen and causing their partial degradation. Finally, it can also neutralize surficial ceramide by interacting with same or reducing the formation of same without inhibiting the ASM (for example diazepam). All these inhibitory activities ultimately lower the infection of epithelial cells with the SARS-CoV-2 virus.
  • ASM for example diazepam
  • This agent can be any agent whose FIASMA activity is demonstrated, including all the agents whose FIASMA activity has not been described yet, and will be discovered in the future.
  • agent of the invention also designates any derivative, analog, isomer, metabolite, salt, solvate, clathrate, polymorph, and co-crystal of the compounds mentioned below, provided that it has the inhibitory activities described above.
  • derivative it is meant herein a compound that is directly derived from a chemical compound of interest and is structurally similar though non-identical to said compound, and which retains the same biological activity and/or physico-chemical properties.
  • analog or “functional analog”, it is meant herein a compound that is not directly derived from a chemical compound of interest and is thus structurally different, but exhibits the same biological activity and/or physico-chemical properties, such as isosters.
  • isomer it is meant herein a compound having the same chemical formula as a compound of interest, but a different chemical structure. This term encompasses structural isomers and stereoisomers. Should the isomer of the invention be a stereoisomer, the individual stereoisomers (enantiomers and diastereoisomers) and mixtures thereof are included within the scope of the invention. Some of the compounds according to the invention may exist in tautomeric forms (a type of structural isomer), which are also included within the scope of the invention.
  • metabolite as used herein, it is meant any compound that is an intermediate and/or a product of metabolism.
  • a metabolite from a chemical compound is usually formed as part of the natural biochemical process of degrading and eliminating the compound of interest in a subject to which it is administered.
  • solvate should be understood as meaning any form of the active agent in accordance with the invention (FIASMA agent), in which said compound is linked through non-covalent interactions to another molecule (normally a polar solvent), including especially hydrates and alcoholates, such as methanolate. Methods of solvation are well-known in the art.
  • clathrate it is meant herein a chemical substance consisting of a lattice or cage that entraps or contains a second type of molecule/compound of interest, and which can be used to increase the stability and solubility in water of the molecule/compound of interest.
  • Clathrates are typically polymeric.
  • polymorphs means herein different crystalline forms of a compound of interest in which molecules have different arrangements and/or different molecular conformation. It includes crystalline liquid form or crystalline solid form of a compound of interest. Hydrates and clathrates can be polymorphs.
  • co-crystal it is meant herein a crystalline structure composed of at least two components, where the components may be atoms, ions or molecules. Solvates and clathrates may be co-crystals in certain conditions.
  • pharmaceutically acceptable salt is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • the pharmaceutically acceptable salts comprise:
  • acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl -L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the agent of the invention is preferably contained in a pharmaceutical composition.
  • This pharmaceutical composition herein also called the “pharmaceutical composition of the invention”, therefore comprises the medication of the invention and a pharmaceutically acceptable carrier, which can be as defined above.
  • the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • a “pharmaceutically acceptable carrier” or “excipient” refers to a non-toxic solid, semi solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the present invention relates to the use of functional inhibitors of the acid sphingomyelinase enzyme (or FIASMA agents), for treating a viral infection due to at least one betacoronavirus in a patient in need thereof or to prepare a medicament intended to treat patients that have been diagnosed to be infected with at least one betacoronavirus.
  • Said patient suffers for example from a symptomatic COVID-19 disease, more particularly from a strong or severe symptomatic COVID-19 disease.
  • These agents can be used in particular for preventing and/or treating acute respiratory distress syndrome associated to said viral infection, or for lowering the risk of intubation or for increasing the survival rate of patients infected by said betacoronavirus.
  • antidepressant agents having a FIASMA activity Treatment with antidepressant agents having a FIASMA activity
  • psychotropic medications including certain antidepressants (i.e., amitriptyline, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, lofepramine, maprotiline, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine) have been shown to in vitro inhibit acid sphingomyelinase with varying degrees [4, 5, 12, 13] Yet, in these studies, there are discrepancies whether citalopram, venlafaxine and mirtazapine do have in vitro FIASMA effect, which may be the case for longer incubation times.
  • the present invention relates to the use of antidepressant agents having FIASMA activity, preferably 5 HT R-stimulating or blocking agents (in particular 5 HTIR-stimulating or blocking agents or 5HT2R-stimulating or blocking agents) having FIASMA activity, to prepare a medicament intended to treat patients that have been diagnosed to be infected with at least one betacoronavirus.
  • antidepressant agents having FIASMA activity preferably 5 HT R-stimulating or blocking agents (in particular 5 HTIR-stimulating or blocking agents or 5HT2R-stimulating or blocking agents) having FIASMA activity
  • the present invention also discloses a method for preventing and/or treating any subject that has been diagnosed to be infected with at least one betacoronavirus, said method comprising administering to said subject an effective amount of an antidepressant agent having FIASMA activity, for example a 5 HTR-stimulating or blocking agent (in particular 5 HTIR-stimulating or blocking agents or 5HT2R-stimulating or blocking agents) having FIASMA activity.
  • the method of the invention can comprise a diagnosis step as preliminary step.
  • the said infection can be diagnosed or detected by any conventional means, such as molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • the antidepressant agent of the invention having FIASMA activity, is used for preventing and/or treating patients infected by a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS-CoV-2.
  • SARS-CoV Severe Acute Respiratory Syndrome-related coronavirus
  • the agents of the invention are intended to treat patients suffering from a symptomatic COVID-19 disease, and more particularly from a strong or severe symptomatic COVID-19 disease, as defined above.
  • the treatment of the invention is administered to subjects (animals or humans) that experience for example difficulty in breathing and/or a lack of oxygen.
  • the antidepressant agents of the invention are capable of preventing and/or treating acute respiratory distress syndrome associated to said viral infection, of lowering the risk of intubation and / or of increasing the survival rate of patients infected by said betacoronavirus, as described in the examples below.
  • said subject is a human patient.
  • Said patient can be older than 75 years old, between 65 and 74 years old, between 18 and 65 years old, or below 18 years old.
  • said human patient is older than 50 years old, even more preferably older than 70 years old.
  • said subject is an animal chosen in the group consisting of: bats, hedgehog, camels, mice, humans, pigs, cats, among others. Any other animal that can be infected with a betacoronavirus could also benefit from the treatment of the invention.
  • the pharmaceutical composition of the invention can contain any antidepressant agent having FIASMA activity that can lower the risk of intubation and/or death of a COVID patient.
  • said agent can be a 5-HT R-stimulating or blocking agent having FIASMA activity, including escitalopram, citalopram, sertraline, fluoxetine, paroxetine, mirtazapine, venlafaxine, duloxetine, or clomipramine ([4]).
  • said antidepressant agent having FIASMA activity is selected in the group consisting of: Amitriptyline, Sertraline, Protriptyline, Fluoxetine, Nortriptyline, Maprotiline, Trimipramine, Desipramine, Lofepramine, Clomipramine, Duloxetine, Paroxetine, Imipramine, Fluvoxamine, Doxepin, Escitalopram, Citalopram, venlafaxine and mirtazapine.
  • said antidepressant agent having FIASMA activity is selected in the group consisting of: Amitriptyline, Sertraline, Protriptyline, Fluoxetine, Nortriptyline, Maprotiline, Trimipramine, Desipramine, Lofepramine, Clomipramine, Duloxetine, Paroxetine, Imipramine, Fluvoxamine, Doxepin, Escitalopram and Citalopram.
  • said antidepressant agent having FIASMA activity is selected in the group consisting of: Sertraline, Fluoxetine, Clomipramine, Duloxetine, Paroxetine, Fluvoxamine, Escitalopram, Citalopram, venlafaxine and mirtazapine.
  • the antidepressant agent used in the composition of the invention is chosen in the group consisting of: escitalopram, venlafaxine, citalopram, sertraline, fluoxetine, paroxetine, duloxetine, mirtazapine, or clomipramine.
  • the antidepressant agent used in the composition of the invention is chosen in the group consisting of: escitalopram, venlafaxine, paroxetine, fluoxetine, and mirtazapine.
  • the antidepressant used in the composition of the invention is chosen in the group consisting of: Dosulepin, Vortioxetine, and Milnacipran.
  • the antidepressant used in the composition of the invention is Diazepam.
  • the antidepressant agent used in the composition of the invention is a SSRI having a FIASMA activity, such as Fluoxetine or Fluvoxamine.
  • the composition of the invention can contain a combination of at least two antidepressant agents having FIASMA activity as defined above.
  • the total FIASMA dose received calculated as the sum of the doses of each FIASMA medication that is received by the patient, multiplicated by the degree of in vitro inhibition of ASM of each of these FIASMA medications, is hypothesized to be correlated with mortality reduction in COVID-19. Therefore, the higher this total dose is, the lower the mortality will be.
  • the daily dose of the antidepressant agent(s) to be administered to the infected subject is preferably the conventional dose used in the art for antidepressant purposes. Importantly, this could not have been predicted from any prior art study, even from those suggesting that some antidepressant molecules may have an effect on the endocytic virus entry.
  • the present invention shows for the first time that using conventional non-toxic doses (no need of higher doses) is enough to efficiently impair virus infection and reduce the mortality of the COVID disease.
  • This dose is for example comprised between about 5 mg/day and about 60 mg/day for fluoxetine-equivalent dose, said dose being as defined in [50]
  • low to moderate doses of 10 mg/day to 40 mg/day are used in the context of the invention among adults aged more than 70 years old of age, so as to minimize side effects.
  • low and moderate doses of antidepressants are generally well tolerated, especially when they are used on a short period, including in older adults who are the most prone to develop severe Covid-19 infection.
  • said antidepressant agent can be administered to the subject at an effective Fluoxetine-equivalent dose comprised between about 20 mg/day and about 60 mg/day, preferably between about 30 mg/day and about 60 mg/ day, more preferably between about 40 mg/day and about 60 mg/day for parenteral or oral administration.
  • the dose to be administered can be comprised between about 20 mg/day and about 60 mg/day, preferably between about 30 mg/day and about 60 mg/ day, more preferably between about 40 mg/day and about 60 mg/day for parenteral or oral administration.
  • the dose to be administered can be comprised between about 150 mg/day and about 300 mg/day, preferably between about 200 mg/day and about 300 mg/ day, more preferably between about 250 mg/day and about 300 mg/day for parenteral or oral administration.
  • the dose of antidepressant contained in the composition of the invention is such that, when converted into dose-equivalent to fluoxetine-equivalent dose as explained in Hayasaka Y ([50]), it is comprised in the above-mentioned ranges.
  • said antidepressant agent can be administered to the subject at an effective Fluoxetine-equivalent dose orally or by intravenous perfusion comprised between 5 mg and 60 mg per day, and preferably between 10 mg and 50 mg in older adults aged 70 years and over, and between 30 mg and 60 mg in younger adults aged 18 to 69 years old of age. It is within the skill of the person in the art to determine the desired therapeutic amount of antidepressant agent to deliver by routine methods in the art.
  • composition of the invention may preferably be in a form suitable for the purposes of the invention.
  • said composition may be in a form suitable for parenteral or oral administration, such as a liquid suspension, or a solid dosage form (granules, pills, capsules or tablets).
  • parenteral as used herein includes subcutaneous injection, intravenous, or intramuscular, injection.
  • the agent of the invention is administered to the patient once it is diagnosed from severe COVID disease, and until the patient displays at least one symptom of the COVID disease.
  • the treatment preferably ceases when the infection is over. Such short-term treatments are well tolerated and do not induce any side-effect or dependency in the treated patients.
  • Trifluoperazine Thioridazin, Sertindole, Fluphenazine, Flupenthixol, Perphenazine, Aripiprazole, Penfluridol, Chlorprothixene, Pimozide, Promazine, Chlorpromazine), medications of the nervous system (cinnarizine, flunarizine), certain antihistaminic medications (astemizole, clemastine, cyproheptadine, desloratadine, loratadine, mebhydrolin, pimethixene, promethazine, terfenadine), certain anticholinergic antiparkinson medications (benztropine, biperidene, profenamine), antiprotozoal medications (emetine, quinacrine), calcium channel blockers (amlodipine, bepridil, fendiline, mibefradil, perhexiline), beta blocking agents (carvedilol), antiarrhythmics (amiodarone,
  • FIASMA non-psychotropic
  • Study baseline was defined as the date of hospital admission for COVID-19 and the primary endpoint was a composite of intubation or death.
  • This endpoint was compared between patients who received a (non-psychotropic) FIASMA medication (e.g., loperamide, amlodipine, amiodarone, aripiprazole, chlorpromazine, and desloratadine) and those who did not, in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidity. It was observed that FIASMA medication use at baseline was significantly associated with a 42% reduction of risk of intubation or death among adult patients hospitalized for severe COVID-19.
  • a FIASMA medication e.g., loperamide, amlodipine, amiodarone, aripiprazole, chlorpromazine, and desloratadine
  • the present inventors performed a large (7,345 adult inpatients with COVID-19, including 138 (1.9%) patients receiving hydroxyzine during the hospitalization) multicenter observational retrospective study, and examined the association between hydroxyzine use with the risk of death, ascertained by death certificates, among male and female adult patients (aged 18 to 103 years old of age) who have been admitted to these medical centers with COVID-19, ascertained by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) test from analysis of nasopharyngeal or oropharyngeal swab specimens.
  • RT-PCR positive reverse-transcriptase-polymerase-chain-reaction
  • hydroxyzine prescribed for others indications (including urticaria, allergic rhinitis, hay fever, conjunctivitis, pruritis) and for its tranquilizer and sedative properties, are significantly and substantially associated with reduced risk of death in hospitalized adult patients with Covid-19, independently of patients’ characteristics, disease’s severity and use of other psychotropic medications (figure 6).
  • the present invention therefore relates to the use of non psychotropic agents having FIASMA activity, to prepare a medicament intended to treat patients that have been diagnosed to be infected with at least one betacoronavirus.
  • non-psychotropic FIASMA agents can be, for example:
  • - antipsychotic agents such as Triflupromazine, Trifluoperazine, Thioridazin, Sertindole, Fluphenazine, Flupenthixol, Perphenazine, Aripiprazole, Penfluridol Chlorprothixene, Pimozide, Promazine, Chlorpromazine,
  • - medications of the nervous system such as cinnarizine and flunarizine
  • antihistaminic medications such as astemizole, clemastine, cyproheptadine, desloratadine, loratadine, mebhydrolin, pimethixene, promethazine, and terfenadine,
  • anticholinergic antiparkinson medications such as benztropine, biperidene, profenamine,
  • calcium channel blockers such as amlodipine, bepridil, fendiline, mibefradil, and perhexiline,
  • - beta blocking agents such as carvedilol
  • - antiarrhythmics such as amiodarone and aprindine
  • antivertigo medications such as cinnarizine and flunarizine
  • vasodilators such as dilazep and suloctidil
  • - cough suppressants such as cloperastine
  • - antidiarrheal medications such as loperamide, - antimycobacterials such as clofazimine,
  • - endocrine therapy medications such as tamoxifen
  • - muscle relaxants such as cyclobenzaprine.
  • composition of the invention can contain a combination of at least two non psychotropic agents or a combination of psychotropic and non-psychotropic agents having FIASMA activity as defined above. It is preferred to combine at least one psychotropic agent and at least one non-psychotropic agent, among those defined above.
  • the total FIASMA dose received calculated as the sum of the doses of each FIASMA medication that is received by the patient, multiplicated by the degree of in vitro inhibition of ASM of each of these FIASMA medications, is hypothesized to be correlated with mortality reduction in COVID-19. Therefore, the higher this total dose is, the lower the mortality will be.
  • the present invention therefore proposes to use any of these non-psychotropic FIASMA agents for preventing severe forms of the COVID19 disease to occur, or to treat patients that have been diagnosed to be infected with at least one betacoronavirus.
  • the use of any of these compounds or any combination of these compounds is encompassed within the present invention.
  • the present invention proposes to use antipsychotic agents such as Triflupromazine, Trifluoperazine, Thioridazin, Sertindole, Fluphenazine, Flupenthixol, Perphenazine, Aripiprazole, Penfluridol Chlorprothixene, Pimozide, Promazine, Chlorpromazine for preventing or treating a viral infection due to at least one betacoronavirus such as SARS-CoV-2, in a patient in need thereof.
  • Said patient suffers for example from a symptomatic COVID-19 disease, more particularly from a strong or severe symptomatic COVID-19 disease.
  • These agents can be used in particular for preventing and/or treating acute respiratory distress syndrome associated to said viral infection, or for lowering the risk of intubation or for increasing the survival rate of patients infected by said betacoronavirus.
  • the present invention proposes to use any other non psychotropic FIASMA agents as disclosed above, for example cinnarizine, flunarizine, benztropine, biperidene, profenamine, emetine, quinacrine, amlodipine, bepridil, fendiline, mibefradil, perhexiline, carvedilol, amiodarone, aprindine, alverine, camylofm, dicycloverine, mebeverine, cinnarizine, flunarizine, conessine, solasodine, tomatidine, dilazep, suloctidil, cloperastine, loperamide, clofazimine, tamoxifen, or cyclobenzaprine, for preventing or treating a viral infection due to at least one betacoronavirus such as SARS-CoV-2, in a patient in need thereof. Said patient suffers for example from a betacoronavirus
  • FIASMA activity such as ambroxol or natural products such as Tomatidine, Conessine or Solasodine, can also be used in this respect.
  • the present invention proposes to use a non-psychotropic FIASMA agent chosen in the group consisting of: Triflupromazine, Trifluoperazine, Thioridazin, Sertindole, Fluphenazine, Flupenthixol, Perphenazine, Aripiprazole, Penfluridol Chlorprothixene, Pimozide, Promazine, Chlorpromazine, cinnarizine, flunarizine, benztropine, biperidene, profenamine, emetine, quinacrine, amlodipine, bepridil, fendiline, mibefradil, perhexiline, carvedilol, amiodarone, aprindine, alverine, camylofm, dicycloverine, mebeverine, cinnarizine, flunarizine, conessine, solasodine, tomatidine, dilazep, sulocti
  • the present invention proposes to use a non-psychotropic FIASMA agent chosen in the group consisting of: astemizole, clemastine, cyproheptadine, desloratadine, loratadine, promethazine, and terfenadine.
  • a non-psychotropic FIASMA agent chosen in the group consisting of: astemizole, clemastine, cyproheptadine, desloratadine, loratadine, promethazine, and terfenadine.
  • mebhydrolin, or pimethixene chosen in the group consisting of: astemizole, clemastine, cyproheptadine, desloratadine, loratadine, promethazine, and terfenadine.
  • mebhydrolin, or pimethixene chosen in the group consisting of: astemizole, clemastine, cyprohepta
  • the present invention proposes to use loperamide, amlodipine, amiodarone, aripiprazole, chlorpromazine, or desroratadine for preventing or treating a viral infection due to at least one betacoronavirus such as SARS-CoV-2, in a patient in need thereof.
  • Said patient suffers for example from a symptomatic COVID-19 disease, more particularly from a strong or severe symptomatic COVID-19 disease.
  • non-psychotropic agents can be used in particular for preventing and/or treating acute respiratory distress syndrome associated to said viral infection, or for lowering the risk of intubation or for increasing the survival rate of patients infected by said betacoronavirus.
  • these agents are capable of preventing and/or treating acute respiratory distress syndrome associated to said viral infection, of lowering the risk of intubation and / or of increasing the survival rate of patients infected by said betacoronavirus, as described in the examples below.
  • these non-psychotropic FIASMA medications can be prescribed at their usual doses for their other indications (cf. Vidal for example).
  • said subject is a human patient.
  • Said patient can be older than 75 years old, between 65 and 74 years old, between 18 and 65 years old, or below 18 years old.
  • said human patient is older than 50 years old, even more preferably older than 70 years old.
  • said subject is an animal chosen in the group consisting of: bats, hedgehog, camels, mice, humans, pigs, cats, among others. Any other animal that can be infected with a betacoronavirus could also benefit from the treatment of the invention.
  • the pharmaceutical composition of the invention containing these non-psychotropic FIASMA agents may preferably be in a form that is suitable for the purposes of the invention.
  • said composition may be in a form suitable for parenteral or oral administration, such as a liquid suspension, or a solid dosage form (granules, pills, capsules or tablets).
  • parenteral as used herein includes subcutaneous injection, intravenous, or intramuscular, injection.
  • the present invention relates to non-psychotropic FIASMA agents for use for treating a viral infection due to a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS-CoV-2, in a patient in need thereof. It also relates to said non-psychotropic FIASMA agent, for its use for treating patients suffering from a symptomatic COVID-19 disease, advantageously from a strong or severe symptomatic COVID-19 disease. It also relates to said non-psychotropic FIASMA agent, for its use for preventing and/or treating acute respiratory distress syndrome associated to said viral infection.
  • SARS-CoV Severe Acute Respiratory Syndrome-related coronavirus
  • non-psychotropic FIASMA agent for its use for lowering the risk of intubation and/or for lowering the risk of hospitalization and/or for increasing the survival rate of patients (i.e., decreasing risk of death) infected by said coronavirus.
  • the present invention relates to the use of a non-psychotropic FIASMA agent as described above, for the preparation of a medicament that is intended to treat a symptomatic COVID-19 disease, advantageously from a strong or severe symptomatic COVID-19 disease; or an acute respiratory distress syndrome associated to said viral infection.
  • the present invention also discloses a method for treating a viral infection due to a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS- CoV-2, in a patient in need thereof, said method comprising administering in said patient a significant amount of non-psychotropic FIASMA agents.
  • SARS-CoV Severe Acute Respiratory Syndrome-related coronavirus
  • It also discloses a method for treating patients suffering from a symptomatic COVID-19 disease, a method for preventing and/or treating acute respiratory distress syndrome associated to said viral infection, and a method for lowering the risk of intubation and/or for increasing the survival rate (i.e., decreasing risk of death) of patients infected by said coronavirus, said methods comprising administering in said patients a significant amount of non psychotropic FIASMA agents.
  • the daily dose of the non-psychotropic agent(s) to be administered to the infected subject is preferably the conventional non-toxic dose used in the art for the indications for which they were accepted by FDA or EMEA. Importantly, this could not have been predicted from any prior art study.
  • the present invention shows for the first time that using conventional non-toxic doses of these agents (no need of higher doses) is enough to efficiently impair virus infection and reduce the mortality of the COVID disease.
  • the non-psychotropic agents can be administered at their conventional doses for which they have been approved by at least one competent national or regional health authority (e.g., FDA or EMEA).
  • at least one competent national or regional health authority e.g., FDA or EMEA.
  • the non-psychotropic FIASMA agent of the invention is preferably incorporated in a pharmaceutical composition, said composition containing, apart from said agent, a pharmaceutically acceptable excipient as defined above.
  • the pharmaceutical composition of the invention may preferably be in a form suitable for the purposes of the invention.
  • said composition may be in a form suitable for parenteral or oral administration, such as a liquid suspension, or a solid dosage form (granules, pills, capsules or tablets).
  • parenteral as used herein includes subcutaneous injection, intravenous, or intramuscular, injection.
  • the pharmaceutical composition of the invention is more preferably administered orally.
  • the non-psychotropic agent of the invention is administered to the patient once it is diagnosed from severe COVID disease, and until the patient displays at least one symptom of the COVID disease.
  • the treatment preferably ceases when the infection is over.
  • Such short-term treatments are well tolerated and do not induce any side-effect or dependency in the treated patients.
  • the non-psychotropic agent of the invention is an inhibitor of the histamine HI -receptor (hereafter “inhibitor of the invention” or “HI inhibitor”).
  • the present invention proposes to use inhibitors of peripheral Histamine receptors having FIASMA activity for treating a viral infection due to a Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV), in particular SARS-CoV-2, in a patient in need thereof.
  • SARS-CoV Severe Acute Respiratory Syndrome-related coronavirus
  • Said inhibitors can also be efficient for treating patients suffering from a symptomatic COVID-19 disease, advantageously from a strong or severe symptomatic COVID-19 disease.
  • said inhibitors can prevent and/or treat acute respiratory distress syndrome associated to said viral infection ; and/or lower the risk of intubation and/or lower the risk of hospitalization and/or eventually increase the survival rate of patients infected by said coronavirus.
  • histamine receptors which bind histamine as their primary endogenous ligand (namely the HI receptor, H2 receptor, H3 receptor, and H4 receptor). Although the inventors have gathered data involving anti-Hl compounds, the three other histamine receptors are likely to be involved in the regulation of the COVID-related mortality as well, because of the well-known cross regulation occurring between all these histamine receptors, provided that they also have a FIASMA activity.
  • the present invention relates to the use of inhibitors of peripheral H2 receptors, of peripheral H3 receptors, or of peripheral H4 receptors, wherein said inhibitors have a FIASMA activity.
  • inhibitors are preferably chosen in the group consisting of: astemizole, clemastine, cyproheptadine, desloratadine, loratadine, mebhydrolin, pimethixene, promethazine, hydroxyzine and terfenadine, and preferably astemizole, clemastine, cyproheptadine, desloratadine, loratadine, promethazine, hydroxyzine and terfenadine, or a pharmaceutical salt or solvate thereof. Stereoisomers and conformers thereof are also herein encompassed.
  • the present invention more precisely relates to the use of any of these anti-histaminic inhibitors for treating a viral infection due to a Severe Acute Respiratory Syndrome- related coronavirus (SARS-CoV), in particular SARS-CoV-2, in a patient in need thereof.
  • SARS-CoV Severe Acute Respiratory Syndrome- related coronavirus
  • Said inhibitors can also be efficient for treating patients suffering from a symptomatic COVID-19 disease, advantageously from a strong or severe symptomatic COVID-19 disease.
  • said inhibitors can prevent and/or treat acute respiratory distress syndrome associated to said viral infection ; and/or lower the risk of intubation and/or lower the risk of hospitalization and/or eventually increase the survival rate of patients infected by said coronavirus.
  • the histamine HI -receptor is a member of the superfamily of G-protein-coupled receptors (GPCRs). Histamine cross links sites on transmembrane domains III and V to stabilize the receptor in its active conformation, thus causing the equilibrium to switch to the position “on”.
  • GPCRs G-protein-coupled receptors
  • HI antihistamine which are not structurally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor, to produce the opposite effect.
  • HI -antihistamines are not receptor antagonists, but inverse agonists of the HI receptor.
  • the HI inhibitor of the invention inhibits the activity of the HI receptor by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% (i.e., complete loss of activity) relative to a control.
  • the inhibitor of the invention is capable of binding to an allosteric site of the histamine HI receptor.
  • the inhibitor of the invention has an IC50 of less than or equal to 500nM, less than or equal to 250nM, less than or equal to lOOnM, less than or equal to 50nM, less than or equal to lOnM, less than or equal to InM, less than or equal to 0,lnM, less than or equal to 0,01nM, less than or equal to O,OOIhM.
  • Said inhibitory effect can be tested by conventional means, such as those disclosed in Diaz Nebreda et al ([58]).
  • the HI inhibitor of the invention is hydroxyzine or a pharmaceutical salt or solvate thereof. Stereoisomers and conformers thereof are also herein encompassed.
  • Hydroxyzine is a member of the diphenylmethylpiperazine class of antihistamines. It is sold under the brand names Atarax and many others (Vistaril, Equipose, Masmoran, Paxistil, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, Tranquizine, etc.). Its CAS number is 68-88-2. It is also known as hydroxizine, or hydroxycine. Its chemical formula is 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-l-yl]ethoxy]ethanol:
  • any salt thereof can be used in the invention.
  • said salt can be a pamoate (CAS 10246-75-0) or a hydrochloride or a di-hydrochloride salt (CAS2192-693-1).
  • These salts are commercially available and therefore very easy to acquire and use: Vistaril, Equipose, Masmoran, and Paxistil are preparations of the pamoate salt, while Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, and Tranquizine are of the hydrochloride salt.
  • hydroxyzine is one of the most prescribed in France. Beyond its antihistamine activity, hydroxyzine is also prescribed as a psychotropic medication for its tranquilizer and sedative properties, as it weakly acts as an antagonist of the serotonin 5-HT2A-receptor, the dopamine D2 receptor, and the al- adrenergic receptor. Because prior research supports that severe COVID-19 is characterized by an overexuberant inflammatory response and that viral load has been associated with the worsening of symptoms it was hypothesized that the antihistamine compound hydroxyzine could be potentially effective in reducing the risk of death in patients with COVID-19.
  • hydroxyzine prescribed for others indications (including urticaria, allergic rhinitis, hay fever, conjunctivitis, pruritis) and for its tranquilizer and sedative properties, are significantly and substantially associated with reduced risk of death in hospitalized adult patients with Covid-19, independently of patients’ characteristics, disease’s severity and use of other psychotropic medications.
  • hydroxyzine will be preferably administered orally or via intramuscular injection.
  • the daily dose of the HI inhibitors of the invention to be administered to the infected subject is preferably the conventional dose used in the art and approved for said HI antihistamine compounds. This dose is for example comprised between about 12.5 mg/day and about 400 mg/day for hydroxyzine dose, when hydroxyzine is administered orally or through intramuscular injection.
  • the HI inhibitor of the invention is hydroxyzine which is administered orally at an effective dose comprised between about 12.5 mg/day and about 400 mg/day, preferably between about 25 mg/day and about 200 mg/day, preferably between about 50 mg/day and about 100 mg/day.
  • low to moderate doses are used in the context of the invention, so as to minimize side effects of the antihistamine compound.
  • low and moderate doses of antihistamine compound are generally well tolerated, especially when they are used on a short period, including in older adults who are the most prone to develop severe Covid-19 infection.
  • the HI inhibitors of the invention in a general manner are administered to the subject at a dose comprised between about 1 mg/day and about 400 mg/day, preferably between about 5 mg/day and about 300 mg/day, preferably 12.5 mg/day and about 400 mg/day, preferably between about 25 mg/day and about 300 mg/day, more preferably between about 50 mg/day and about 200 mg/day and most preferably between about 50 mg/day and about 100 mg/day (in particular if said inhibitor is administered orally).
  • the HI inhibitors of the invention are administered to the subject orally or by intramuscular perfusion at an effective dose comprised between about 1 mg/day and about 400 mg/day, preferably between about 5 mg/day and about 300 mg/day, preferably between about 12.5 mg and 400 mg per day, and preferably between 12.5 mg and 100 mg in older adults aged 70 years and over, and between 50 mg and 400 mg in younger adults aged 18 to 69 years old of age.
  • effective doses have to be divided by 2 to 4 folds if the patient furthermore suffers from renal impairment ( ⁇ 50mL/min) or liver failure.
  • the amount of the medication of the invention is determined by quantifying the level of circulating ceramides in a biological sample of the patient, prior to the treatment, or after initiating the treatment in order to adapt the dose of the treatment, in a personalized-medicine perspective.
  • Ceramides are bioactive lipids involved in inflammation, apoptosis, obesity, and insulin resistance, and are biomarkers of cardiovascular diseases. Circulating ceramides are for example long chain ceramides such as C18:0, 06:0 and C24:l or hexosylceramides.
  • the ceramide level can be determined at the cell surface of blood cells, e.g., by flow cytometry using anti-ceramide antibodies, or by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on plasma or serum samples.
  • LC-MS/MS tandem mass spectrometry
  • the treating method of the invention may also contain a first step of detecting the level of ceramide in a biological sample of the patient by appropriate means.
  • Said biological sample is preferably a blood, plasma or serum sample obtained from the patient.
  • the virus will not easily enter into the target cells and the patient may have a good prognosis, with or without treatment. It can therefore be said that the lower the total circulating ceramide level is, the more benign the COVID disease will be (provided that the ceramide level remains at such a low level). For example, the COVID disease shall remain asymptomatic or at a mild stage, at defined above.
  • the prognosis of the disease is bad and the patient is at risk of experiencing a strong form of the COVID disease.
  • the efficiency of the treatment s) can then be assessed by controlling the level of total circulating ceramide in the blood samples of the patient, at different time points after the treatment has been administered, until it has sufficiently decreased (i.e., has reached a level ⁇ 500 pmol/l).
  • the level of circulating long ceramides such as C18:0, C16:0 and C24:l can therefore advantageously serve as a prognostic marker, for example in a prognosis score, alone or in combination with other parameters (e.g., the total ceramide plasma level, the plasma levels of C18:0, C16:0 and C24: 1, the ratio of hexosylceramides/ceramides, etc.) to assess the severity of the COVID disease and help optimize the treatment in terms of dose and number of treatments.
  • other parameters e.g., the total ceramide plasma level, the plasma levels of C18:0, C16:0 and C24: 1, the ratio of hexosylceramides/ceramides, etc.
  • This marker can also be helpful to screen the efficacity of new medications, whose FIASMA activity is yet unknown, for their ability to prevent or treat strong forms of the COVID disease.
  • FIASMA medications include a wide range of medications from different pharmaceutical classes. The present results can suggest that any of these FIASMA medications may be useful in other diseases associated with observed increased acid sphingomyelinase activity thanks to its anti-apoptotic and neuroprotective effects. These other diseases include (cf.
  • brain ischemia stroke, ethanol-induced neuronal cell death, Alzheimer’s dementia, Parkinson’s disease, Wilson’s disease, Chorea Huntington, spinal cord injury, seizure disorder, glaucoma, major depression, inflammatory bowel disease, acute and chronic lung injury, and other infections associated with increased acid sphingomyelinase activity such as endotoxic shock syndrome, severe sepsis, infection by Neisseria gonorrhoeae .
  • FIASMA agents could also be used to protect against neurodegeneration occurring in multiple sclerosis, the radiation and chemotherapy-induced lethal gastrointestinal syndrome, and morphine anti -nociceptive tolerance.
  • the present invention relates to the use of the FIASMA agents of the invention, for preventing and/or treating any of the following diseases: brain ischemia, stroke, ethanol -induced neuronal cell death, Alzheimer’s dementia, Parkinson’s disease, Wilson’s disease, Chorea Huntington, spinal cord injury, seizure disorder, glaucoma, major depression, inflammatory bowel disease, acute and chronic lung injury, and other infections associated with increased acid sphingomyelinase activity such as endotoxic shock syndrome, severe sepsis, infection by Neisseria gonorrhoeae or Ebola virus, multiple sclerosis, radiation and chemotherapy-induced lethal gastrointestinal syndrome, and morphine anti -nociceptive tolerance.
  • diseases brain ischemia, stroke, ethanol -induced neuronal cell death, Alzheimer’s dementia, Parkinson’s disease, Wilson’s disease, Chorea Huntington, spinal cord injury, seizure disorder, glaucoma, major depression, inflammatory bowel disease, acute and chronic lung injury, and other
  • FIASMA medications can be psychotropic or non-psychotropic. They are for example antidepressants, antipsychotics, anti-histaminiques agents having FIASMA activity, as detailed above. Other compounds having FIASMA activity, for example natural products such as Tomatidine, Conessine or Solasodine, can also be used in this respect.
  • any FIASMA agent as described above could be used to improve the prognosis of any of the following diseases: brain ischemia, stroke, ethanol -induced neuronal cell death, Alzheimer’s dementia, Parkinson’s disease, Wilson’s disease, Chorea Huntington, spinal cord injury, seizure disorder, glaucoma, major depression, inflammatory bowel disease, acute and chronic lung injury, and other infections associated with increased acid sphingomyelinase activity such as endotoxic shock syndrome, severe sepsis, infection by Neisseria gonorrhoeae or Ebola virus, multiple sclerosis, radiation and chemotherapy-induced lethal gastrointestinal syndrome, and morphine anti -nociceptive tolerance.
  • FIGURE LEGENDS Figure 1 describes the characteristics of the studied cohort of EXAMPLE 1.
  • the shaded areas represent pointwise 95% confidence intervals.
  • Risk tables are displayed for the full sample crude analysis in A, for the full sample with the inverse-probability-weighting weights in B and for the matched analytic sample using a 1 : 1 ratio in C.
  • Figure 3 describes the characteristics of the studied cohort of EXAMPLE 2.
  • the shaded areas represent pointwise 95% confidence intervals.
  • Figure 5 describes the main characteristics of the Study cohort.
  • the shaded areas represent pointwise 95% confidence intervals.
  • COVID-19 was ascertained by a positive reverse- transcriptase-polymerase-chain-reaction (RT-PCR) test from analysis of nasopharyngeal or oropharyngeal swab specimens.
  • Severe COVID-19 was defined as having at least one of the following criteria at baseline [19-21]: respiratory rate >24 breaths/min or ⁇ 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air ⁇ 90%, temperature >40°C, systolic blood pressure ⁇ 100 mm Hg, lactate levels >2 mmol/L, or admission to an intensive care unit (ICU) within the first 24 hours form hospital admission.
  • ICU intensive care unit
  • AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n° 1980120 from National Commission for Information Technology and Civil Liberties (CNIL). All procedures related to this work adhered to the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
  • CNIL National Commission for Information Technology and Civil Liberties
  • FIASMA psychotropic medications were defined as psychotropic medications showing a substantial in vitro functional inhibition effect on ASM (i.e., a residual ASM activity lower than 50%), as described in detail elsewhere [4, 5, 12, 13]
  • FIASMA psychotropic medication use was defined as receiving at least one psychotropic FIASMA medication at study baseline, i.e. within the first 24 hours of hospital admission, and before the end of the index hospitalization, intubation or death.
  • patients who received a FIASMA psychotropic medication 24 hours after hospital admission were excluded from the analyses.
  • Study baseline was defined as the date of hospital admission for COVID-19.
  • the primary endpoint was the time from study baseline to intubation or death.
  • the timing of the primary endpoint was defined as the time of intubation.
  • Patients without an end-point event had their data censored on May 1 st , 2020.
  • Sex, hospital, number of medical conditions, delirium or dementia, any other mental disorder, and the prescription of any antidepressant, any antipsychotic, and any mood stabilizer were significantly associated with the endpoint of intubation or death.
  • a backward stepwise Cox regression showed that a model including age, sex, hospital, obesity, and the number of medical conditions, was meaningful and associated with the lowest AIC value.
  • the distributions of patient characteristics included in the propensity and regression analyses according to FIASMA psychotropic medication use are shown in Table 1. In the full sample, FIASMA psychotropic medication use substantially differed according to age, sex, hospital, and number of medical conditions. After applying the propensity score weights, there were no differences (i.e. all SMEK0.1) in any characteristic. In the matched analytic sample using a 1:1 ratio, sex, and the number of medical conditions differed between groups (Table 1).
  • ICD-10 International Statistical Classification of Diseases and Related Health Problems
  • FIASMA antidepressant use was significantly associated with reduced risk of intubation or death across all analyses (not shown).
  • Hazard ratios were lower than 1 for most individual FIASMA molecules, but none of them reached statistical significance across all main and sensitivity analyses, except for hydroxyzine and escitalopram, possibly because of limited statistical power due to individual sample sizes ⁇ 42 patients.
  • FIASMA inhibition of viral replication of FIASMA medications might underlie this relationship, as suggested by a recent in-vitro study [4] for fluoxetine.
  • SSRIs selective serotonin reuptake inhibitors
  • FIASMA medications including paroxetine and escitalopram.
  • SIR Sigma-1 receptors
  • SSRIs have been suggested to have potential value in regulating inflammation by inhibiting cytokine production in COVID-19 [7, 32] Because most FIASMA psychotropic antidepressants are SIR agonists, this mechanism might have overlapped their inhibition effect on ASM.
  • Severe COVID-19 at admission was defined as having at least one of the following criteria: respiratory rate > 24 breaths/min or ⁇ 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air ⁇ 90% , temperature > 40°C, systolic blood pressure ⁇ 100 mm Hg or high lactate levels [19-21]
  • AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n°1980120 from National Commission for Information Technology and Civil Liberties (CNIL).
  • hydroxychloroquine azithromycin, remdesivir, tocilizumab, sarilumab, or dexamethasone.
  • ICD-10 diagnosis codes for neoplasms and diseases of the blood (C00-D89); mental disorders (F01-F99); diseases of the nervous system (G00-G99); cardiovascular disorders (100-199); respiratory disorders (J00-J99); digestive disorders (K00-K95); dermatological disorders (L00-L99); diseases of the musculoskeletal system (M00-M99); diseases of the genitourinary system (N00-N99); endocrine disorders (E00-E89); and eye- ear-nose-throat disorders (H00-H95).
  • FIASMA medications were defined as having a substantial in vitro functional inhibition effect on ASM (i.e., a residual ASM activity lower than 50%), as detailed elsewhere [4, 5, 12, 13], and included: FIASMA alimentary tract and metabolism medication (i.e. loperamide); FIASMA cardiovascular system medication, subdivided into calcium channel blockers (i.e. amlodipine) and other cardiovascular medications (i.e. amiodarone and carvedilol); FIASMA nervous system medication, subdivided into psychoanaleptic medications (i.e.
  • FIASMA medication use was defined as receiving at least one FIASMA medication at study baseline, i.e. within the first 24 hours of hospital admission, and before the end of the index hospitalization, intubation or death.
  • patients who received a FIASMA medication 24 hours after hospital admission were excluded from the analyses.
  • Study baseline was defined as the date of hospital admission for COVID-19.
  • the primary endpoint was the time from study baseline to intubation or death.
  • the timing of the primary endpoint was defined as the time of intubation.
  • Patients without an end-point event had their data censored on May 1 st , 2020.
  • a multivariable Cox regression model showed that sex, hospital, obesity, medication according to compassionate use or as part of a medical trial, other infectious diseases, neoplasms and diseases of the blood, cardiovascular disorders, respiratory disorders, and diseases of the genitourinary system were significantly and independently associated with the endpoint (Table 3).
  • Neoplasms and diseases of the blood e 0.150 0.055 0.050 Yes 46 (16.6%) 293 (11.4%) 41 (14.8%)
  • ICD-10 diagnosis codes for certain infectious and parasitic diseases (A00-B99).
  • ICD-10 diagnosis codes for neoplasms C00-D49
  • diseases of the blood and blood-forming organs and certain disorders involving the immun mechanism D50-D89
  • ICD-10 diagnosis codes for mental, behavioural and neurodevelopmental disorders F01-F99.
  • ICD-10 diagnosis codes for diseases of the respiratory system J00-J99.
  • j Assessed using ICD-10 diagnosis codes for diseases of the digestive system K00-K95.
  • k Assessed using ICD-10 diagnosis codes for diseases of the skin and subcutaneous tissue L00-L99.
  • ICD-10 diagnosis codes for diseases of the musculoskeletal system and connective tissue M00-M99.
  • ICD-10 diagnosis codes for endocrine, nutritional and metabolic diseases E00-E89.
  • FIASMA use substantially differed according to all patient characteristics, except for medication according to compassionate use or as part of a medical trial, and the direction of the associations indicated older age and a higher medical severity of patients receiving any FIASMA. There were no substantial differences in any characteristic after applying the propensity score weights and in the matched analytic sample (Table 4).
  • FIASMA nervous system medication use and specifically FIASMA psychoanaleptic medication use, was significantly associated with decreased risk of intubation or death across all analyses (not shown).
  • FIASMA cardiovascular system medication use and specifically FIASMA calcium channel blockers medication use, was significantly and negatively associated with the outcome in the primary IPW analysis, multivariable analysis, and IPW analysis adjusted for unbalanced covariates.
  • Hazard ratios were lower than 1 for most individual FIASMA molecules, but none of them reached statistical significance across all main and sensitivity analyses, except for hydroxyzine and escitalopram (Table 5).
  • FIASMA Alimentary 0.39 (0.10 - 0.25 (0.05 - 0.15 (0.02 - 0.24 (0.05 -
  • FIASMA cardiovascular 0.88 (0.61 - 0.70 (0.49 - 0.56 (0.39 - 0.68 (0.49 - 0.74 (0.48 - 0.75 (0.5
  • Amlodipine 38 / 97 (39.2) 97 / 194 (50.0) 1.27; 0.510) 0.98; 0.037*) 0.79; ⁇ 0.001*) 0.94; 0.020*) e 1.16; 0.190) 1.11; 0.14
  • Amiodarone 18 / 33 (54.5) NA NA 37 / 66 (56.1) 2.27; 0.007*) 1.70; 0.140) 1.58; 0.712) 1.48; 0.47
  • Amitriptyline 8 / 20 (40.0) NA 21 / 40 (52.5) 1.31; 0.229) 1.17; 0.120) 1.28; 0.188) 1.21; 0.134) 1.36; 0.22
  • Escitalopram 12 / 42 (28.6) 40 / 84 (47.6) 0.56; ⁇ 0.0 0.90; 0.021*) 0.78; 0.005*) 0.80; 0.006*) 1.00; 0.050) ° 0.80; 0.008*)
  • Paroxetine 16 / 41 (39.0) 42 / 82 (51.2) 1.33; 0.262) 1.13; 0.130) 0.98; 0.041*) 0.97; 0.036*) q 0.94; 0.030*) 0.89; 0.02
  • Aripiprazole 1 / 6 (16.7) NA NA NA NA NA NA 1.95; 0.197)
  • Chlorpromazine 3 / 7 (42.9) NA NA NA NA NA NA 2.52; 0.829)
  • b Adjusted for hospital, smoking, medication prescribed as part of a clinical trial or according to compassionate use, cardiovascular disorders, respiratory disorders an diseases of the genitourinary system.
  • c Adjusted for cardiovascular disorders and diseases of the genitourinary system and endocrine disorders.
  • d Adjusted for hospital, smoking, for diseases of the nervous system, respiratory disorders and diseases of the genitourinary system.
  • throat disorders 20 throat disorders. p Adjusted for age, sex, hospital, obesity, smoking, medication prescribed as part of a clinical trial or according to compassionate use, neoplasms and diseases of th blood, digestive disorders and diseases of the genitourinary system.
  • q Adjusted for age, hospital, obesity, other infectious diseases, mental disorders, diseases of the nervous system, digestive disorders, diseases of the musculoskeleta system, genitourinary system and endocrine disorders.
  • r Adjusted for age, hospital, obesity, other infectious diseases, cardiovascular disorders, digestive disorders and endocrine disorders.
  • s Adjusted for age, sex, hospital, obesity, smoking, medication prescribed as part of a clinical trial or according to compassionate use, other infectious diseases , neoplasm 5 and diseases of the blood, mental disorders, diseases of the nervous system, digestive disorders, diseases of the musculoskeletal system, diseases of the genitourinar system, endocrine disorders and eye-ear-nose-throat disorders.
  • NA Abbreviation: NA, not applicable.
  • j Adjusted for age, sex, medication according to compassionate use or as part of a clinical trial, mental disorders, diseases of the nervous system and dermatologica disorders.
  • k Adjusted for age, sex, obesity, smoking, medication according to sexual use or as part of a clinical trial, other infectious diseases, neoplasms and diseases o the blood, mental disorders, diseases of the nervous system, cardiovascular disorders, digestive disorders, dermatological disorders, diseases of the genitourinary system 5 and endocrine disorders.
  • NA Abbreviation: NA, not applicable.
  • AP-HP which comprises 39 hospitals, 23 of which are acute, 20 adult and 3 pediatric hospitals. Were included all adults aged 18 years or over who have been admitted with COVID-19 to these medical centers from the beginning of the epidemic in France, i.e. January 24th, until April 1st. COVID-19 was ascertained by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) test from analysis of nasopharyngeal or oropharyngeal swab specimens.
  • RT-PCR reverse-transcriptase-polymerase-chain-reaction
  • the data from the AP-HP Health Data Warehouse (‘Entrepot de Donnees de Sante (EDS)’) were used. This anonymized warehouse contains all the clinical data available on all inpatient visits for COVID-19 to any of the 39 Greater Paris University hospitals.
  • the data obtained included patients’ demographic characteristics, vital signs, laboratory test and RT-PCR test results, medication administration data, current medication lists, current diagnoses, and death certificates.
  • sex The following data were assessed for each patient at the time of the hospitalization: sex; age, which was categorized based on the OpenSAFELY study results (i.e. 18-50, 51-70, 71-80, 81+); obesity, defined as having a body -mass index higher than 30 kg/m 2 or an International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis code for obesity (E66.0, E66.1, E66.2, E66.8, E66.9); self-reported current smoking status; any medical condition associated with increased COVID-19-related mortality based on ICD-10 diagnosis codes, including diabetes mellitus (El l), diseases of the circulatory system (100-199), diseases of the respiratory system (J00-J99), neoplasms (C00-D49), diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (D5-D8), delirium (F05, R41), and dementia (G30, G31, F01-F03); any
  • the endpoint was the time from study baseline to death. Patients without an end-point event had their data censored on May 20th, 2020.
  • the individual propensities for receiving hydroxyzine were estimated using a multivariable logistic regression model that included patients’ characteristics (sex, age, obesity, current smoking status, number of medical conditions associated with increased COVID-19- related mortality, the presence of current sleep or anxiety disorder, any medication prescribed according to compassionate use or as part of a clinical trial), disease’s severity at hospital admission (using markers of clinical and biological severity of COVID-19), and other psychotropic medications (any benzodiazepine or Z-drug, any selective serotonin reuptake inhibitors (SSRI) antidepressant, any non-SSRI antidepressant, any mood stabilizer, and any antipsychotic medication).
  • patients characteristics (sex, age, obesity, current smoking status, number of medical conditions associated with increased COVID-19- related mortality, the presence of current sleep or anxiety disorder, any medication prescribed according to compassionate use or as part of a clinical trial), disease’s severity at hospital admission (using markers of clinical and biological severity of COVID-19), and other psychotropic medications (any benzodiazepine or Z
  • the predicted probabilities from the propensity-score models were used to calculate the stabilized inverse-probability-weighting weights. Associations between hydroxyzine use and the endpoint were then estimated using a multivariable Cox regression model including the inverse-probability-weighting weights. Kaplan-Meier curves were performed using the inverse-probability-weighting weights, and their pointwise 95% confidence intervals were estimated using the nonparametric bootstrap method.
  • Two sensitivity analyses were conducted, including a multivariable Cox regression model comprising as covariates the same variables as the inverse-probability-weighted analyses, and an univariate Cox regression model in a matched analytic samples using a 1 : 1 ratio, based on the same variables used for both the inverse-probability-weighted and the multivariable Cox regression analyses.
  • Weighted Cox regression models were used when proportional hazards assumption was not met. To reduce the effects of confounding, optimal matching was used in order to obtain the smallest average absolute distance across all clinical characteristics between exposed patient and non-exposed matched controls.
  • Any medication prescribed as part of a clinical trial or according to compassionate use e.g., hydroxychloroquine, azithromycin, remdesivir, tocilizumab, sarilumab or dexamethasone
  • W Included lithium or antiepileptic medications with mood stabilizing properties.
  • m Defined as having at least one of the following criteria: respiratory rate > 24 breaths/min or ⁇ 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air ⁇ 90% temperature > 40°C, or systolic blood pressure ⁇ 100 mm Hg.
  • K Defined as having at least one of the following criteria: high neutrophil-to-lymphocyte ratio, low lymphocyte-io-C-reactive protein (both variables were dichotomized at th median of the values observed in the full sample), and plasma lactate levels higher than 2 niniol/L.
  • HR hazard ratio
  • SE standard error
  • VTF variance inflation factor
  • Any medication prescribed as part of a clinical trial or according to compassionate use e.g., hydroxychloroquine, azithromycin, remdesivir, tocilizumab, sarilumab or dexamethasone
  • W Included lithium or antiepileptic medications with mood stabilizing properties.
  • m Defined as having at least one of the following criteria: respiratory rate > 24 breaths/min or ⁇ 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air ⁇ 90% temperature > 40°C, or systolic blood pressure ⁇ 100 mm Hg.
  • K Defined as having at least one of the following criteria: high neutrophil-to-lymphocyte ratio, low lymphocyte-io-C-reactive protein (both variables were dichotomized at th median of the values observed in the full sample), and plasma lactate levels higher than 2 niniol/L.
  • HR hazard ratio
  • SE standard error
  • the present analyses adjusted for numerous potential confounders, including patients’ characteristics (sex, age, obesity, current smoking status, number of medical conditions associated with increased COVID-19-related mortality, any medication prescribed according to compassionate use or as part of a clinical trial, and the presence of current sleep or anxiety disorder), disease’ s severity at hospital admission (using markers of clinical and biological severity of COVID-19), and other psychotropic medications as prior work have suggested that they may influence disease prognosis (including any benzodiazepine or Z-drug, any selective serotonin reuptake inhibitors (SSRI) antidepressant, any non-SSRI antidepressant, any mood stabilizer, and any antipsychotic medication).
  • patients characteristics (sex, age, obesity, current smoking status, number of medical conditions associated with increased COVID-19-related mortality, any medication prescribed according to compassionate use or as part of a clinical trial, and the presence of current sleep or anxiety disorder), disease’ s severity at hospital admission (using markers of clinical and biological severity of COVID-19), and other psychotropic medications as prior work
  • Cipriani A Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Focus. 2018;16:420-429.
  • Li L Li F
  • Fortunati F Krystal JH. Association of a Prior Psychiatric Diagnosis With Mortality Among Hospitalized Patients With Coronavirus Disease 2019 (COVID- 19) Infection. JAMANetw Open. 2020;3:e2023282-e2023282.

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Abstract

La présente invention concerne les utilisations préventives et thérapeutiques d'inhibiteurs de sphingomyélinase acide (FIASMA) tels que des médicaments psychotropes et des composés non psychotropes ayant une activité FIASMA, pour abaisser le risque de mort et/ou d'intubation chez un patient atteint d'une infection virale provoquée par au moins un bêtacoronavirus, en particulier par le SARS-CoV-2 (coronavirus 2 du syndrome respiratoire aigu sévère).
EP21735939.7A 2020-06-24 2021-06-24 Inhibiteurs de sphingomyélinase acide pour la prévention et le traitement de la maladie covid-19 Pending EP4171545A1 (fr)

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EP20305698.1A EP3928775A1 (fr) 2020-06-24 2020-06-24 Utilisation d'agents antidépresseurs pour le traitement de la maladie covid-19
EP20306117.1A EP3973961A1 (fr) 2020-09-29 2020-09-29 Utilisation de l'hydroxyzine et des analogues d'antihistaminiques pour le traitement de la maladie covid-19
US17/146,013 US20220347127A1 (en) 2021-01-11 2021-01-11 Use of antidepressant agents for preventing and treating the covid-19 disease
EP21305188 2021-02-12
PCT/EP2021/067427 WO2021260152A1 (fr) 2020-06-24 2021-06-24 Inhibiteurs de sphingomyélinase acide pour la prévention et le traitement de la maladie covid-19

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