Selective FIASMA treatment

Abstract

The present disclosure relates to methods for treating or preventing diseases treatable or preventable by functional inhibitors of acid sphingomyelinase (FIASMA) or by non-FIASMA treatments in subjects with atherosclerosis. The present disclosure also relates to methods for treating or preventing depression or anxiety disorders treatable or preventable by FIASMA or by non-FIASMA treatments in subjects with atherosclerosis. The present disclosure also relates to methods for treating or preventing myocardial ischemia or heart failure treatable or preventable by FIASMA or by non-FIASMA treatments in subjects with atherosclerosis.

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating or preventing diseases treatable or preventable by functional inhibitors of acid sphingomyelinase (FIASMA) or by non-FIASMA treatments in subjects with atherosclerosis. The present disclosure also relates to methods for treating or preventing depression or anxiety disorders treatable or preventable by FIASMA or by non-FIASMA treatments in subjects with atherosclerosis. The present disclosure also relates to methods for treating or preventing myocardial ischemia or heart failure treatable or preventable by FIASMA or by non-FIASMA treatments in subjects with atherosclerosis.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 482,827, filed February 2, 2023, the contents of which are incorporated herein by reference. [Background technology]

[0003] Acid sphingomyelinase (ASMase, encoded by the SMPD1 gene) hydrolyzes sphingomyelin, resulting in the production of ceramide and phosphorylcholine. Ceramide plays an important role in signal transduction during programmed cell death (apoptosis), the cell cycle, cell differentiation, and senescence. Excess ceramide is a contributing factor to many diseases, including depression and cancer.

[0004] A broad group of compounds has shown high potential to inhibit ASMase without direct inhibition (1). These compounds are called functional inhibitors of acid sphingomyelinase (FIASMA) and are proposed to act through an alternative mechanism. By defining these FIASMAs as those with the ability to reduce ASMase activity by 50% at a concentration of 10 μM, Kornhuber et al. were able to identify 72 different compounds that act as FIASMAs (2). Examples of FIASMAs include common antidepressants, antihistamines, and calcium channel blockers, among several other drug classes. Summary of the Invention [Means for solving the problem]

[0005] In a first aspect, there is provided a method of treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA in a subject with atherosclerosis, the method comprising selectively administering a FIASMA to the subject for the treatment or prevention of the disease, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease.

[0006] The inventors have found that patients with some degree of atherosclerosis (e.g., at least 50 years old and / or diagnosed with atherosclerosis / coronary artery disease) have a lower risk of death and a lower risk of major adverse cardiac events when administered a FIASMA instead of a non-FIASMA to treat their disease. This finding advantageously means that if the patient has atherosclerosis, a FIASMA can be administered selectively to the disease, thereby reducing the patient's risk of death and major adverse cardiac events.

[0007] In a second aspect, there is provided a method for treating or preventing a depression or anxiety disorder treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA in a subject with atherosclerosis, the method comprising selectively administering a FIASMA to the subject for the treatment or prevention of the depression or anxiety disorder, and not administering a non-FIASMA to the subject for the treatment or prevention of the depression or anxiety disorder.

[0008] The inventors have advantageously demonstrated that treating a depression / anxiety disorder with a FIASMA, but not a non-FIASMA, reduces the patient's risk of death if the patient has atherosclerosis (e.g., is at least 50 years old and / or has been diagnosed with atherosclerosis or coronary artery disease). This finding advantageously means that a FIASMA can be selectively administered to treat or prevent a depression or anxiety disorder if the patient has atherosclerosis, thereby reducing the patient's risk of death.

[0009] In a third aspect, there is provided a method for treating or preventing atherosclerosis in a subject, wherein the disease is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA, and the subject has been administered the non-FIASMA for the treatment or prevention of the disease. The method comprises discontinuing the administration of the non-FIASMA for the treatment or prevention of the disease, selectively administering to the subject a FIASMA for the treatment or prevention of the disease, and not administering to the subject the non-FIASMA for the treatment or prevention of the disease.

[0010] In a fourth aspect, there is provided a method of treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA in a subject with atherosclerosis, the method comprising determining that a patient is at high risk of MACE, selectively administering a FIASMA to the subject to treat or prevent the disease and reduce the risk of MACE, and not administering a non-FIASMA to the subject to treat or prevent the disease.

[0011] In a fifth aspect, there is provided a method of treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA in a subject with atherosclerosis, the method comprising selectively administering a FIASMA to the subject for the treatment or prevention of the disease to reduce the risk of MACE or avoid an increased risk of MACE, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease.

[0012] In a sixth aspect, there is provided a method for reducing the risk of MACE in a subject who has atherosclerosis and is being treated for a secondary disease other than atherosclerosis, the method comprising determining that the subject is at high risk of MACE, selectively administering a FIASMA to treat or prevent the secondary disease and to reduce the risk of MACE, and not administering a non-FIASMA to the subject to treat or prevent the secondary disease.

[0013] The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings. [Brief explanation of the drawings]

[0014] [Figure 1A] Covariate balance plots in Cohort A (patients with presumed diagnosed atherosclerosis) are shown. [Figure 1B] Propensity score density in Cohort A (patients with presumed diagnosed atherosclerosis) is shown. [Figure 2A] Kaplan-Meier survival curves for time to all-cause mortality in patients with presumed diagnosed atherosclerosis (Cohort A) with FIASMA SSRIs versus non-FIASMA SSRIs, based on survival assumption 1. [Figure 2B] Kaplan-Meier survival curves for time to all-cause mortality in patients with presumed diagnosed atherosclerosis (Cohort A) with FIASMA SSRIs versus non-FIASMA SSRIs, based on survival assumption 2. [Figure 3A] Kaplan-Meier survival curves for time to major adverse cardiac events (MACE) with FIASMA SSRIs versus non-FIASMA SSRIs in patients with presumed diagnosed atherosclerosis (Cohort A). Survival curves based on survival assumption 1 are shown. [Figure 3B] Kaplan-Meier survival curves for time to major adverse cardiac events (MACE) with FIASMA SSRIs versus non-FIASMA SSRIs in patients with presumed diagnosed atherosclerosis (Cohort A). Survival curves based on survival assumption 2 are shown. [Figure 4A] Covariate balance plots in Cohort B (patients with confirmed atherosclerosis) are shown. [Figure 4B] Propensity score density in Cohort B (patients with confirmed atherosclerosis) is shown. [Figure 5A] Kaplan-Meier survival curves for time to all-cause mortality in patients with confirmed atherosclerosis / CAD (Cohort B) using FIASMA SSRIs versus non-FIASMA SSRIs, based on survival assumption 1. [Figure 5B]Kaplan-Meier survival curves for time to all-cause mortality in patients with confirmed atherosclerosis / CAD (Cohort B) using FIASMA SSRIs versus non-FIASMA SSRIs, based on survival assumption 2. [Figure 6A] Kaplan-Meier survival curves for time to major adverse cardiac events (MACE) with FIASMA SSRIs versus non-FIASMA SSRIs in patients with confirmed atherosclerosis / CAD (Cohort B). Survival curves based on survival assumption 1 are shown. [Figure 6B] Kaplan-Meier survival curves for time to major adverse cardiac events (MACE) with FIASMA SSRIs versus non-FIASMA SSRIs in patients with confirmed atherosclerosis / CAD (Cohort B). Survival curves based on survival assumption 2 are shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] I. Abbreviations ASMase: acid sphingomyelinase CACS: Coronary Artery Calcium Score CAD: Coronary artery disease FIASMA: a functional inhibitor of acid sphingomyelinase IMT: intima-media thickness MACE: Major Adverse Cardiac Event MI: Myocardial infarction SSRI: selective serotonin reuptake inhibitors

[0016] II. Terminology and Methods Unless otherwise specified, technical terms are used according to conventional usage. For definitions of common terms in molecular biology, see Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-854287-9), Kendrew et al. (eds), The Encyclopaedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9), and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

[0017] In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided.

[0018] Administration and Selective Administration: As used herein, administering an agent (e.g., FIASMA or non-FIASMA) to a subject means giving, applying, or contacting the agent to the subject. Administration can be by any of a number of routes depending on the agent being administered, including, for example, oral, topical, intranasal, inhalation, intravenous, intramuscular, intravitreal, intraconjunctival, intracorneal, intraocular, ophthalmic, subcutaneous, intravaginal, rectal, and intraperitoneal. "Selectively administering" means choosing to administer a first agent (e.g., FIASMA) instead of administering a second agent (e.g., non-FIASMA) for the treatment or prevention of a disease.

[0019] Atherosclerosis: thickening or hardening of arteries caused by the buildup of plaque in the lining of the arteries.

[0020] Coronary Artery Disease (CAD): A disease caused by the buildup of plaque in the walls of the coronary arteries over time, narrowing them and restricting or completely blocking blood flow to the heart (i.e., coronary atherosclerosis).

[0021] Functional inhibitor of acid sphingomyelinase (FIASMA): A compound that has the ability to reduce the activity of acid sphingomyelinase (ASMase) by 50% at a concentration of 10 μM. Many known FIASMAs are described in detail in Kornhuber et al. (Functional inhibitors of acid sphingomyelinase (FIASMAs). Handb Exp Pharmacol. 2013; (215): 169-186. doi: 10.1007 / 978-3-7091-1368-4_9), which is incorporated herein by reference in its entirety. Measurement of enzyme inhibition rate is routine in the art. Methods for determining ASMase inhibition are described in Kornhuber et al. (Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One. 2011;6(8):e23852. doi:10.1371 / journal.pone.0023852), which is incorporated herein by reference in its entirety. Briefly, ASMase activity was measured in whole cell lysates. After adding the agent to growth medium at a final concentration of 10 μM, cells were incubated at 37°C in a humidified atmosphere of 8.5% CO2 for 30 minutes (DMEM: pH 7.5). Residual ASM activity was normalized to control cells treated with solvent alone. Non-FIASMAs include compounds that do not have the ability to reduce ASMase activity by 50% at a concentration of 10 μM. In some embodiments, non-FIASMAs are compounds that reduce ASMase activity by less than 50% at a concentration of 10 μM. In some embodiments, the non-FIASMA is a compound that reduces ASMase activity by 1-49% at a concentration of 10 μM. In some embodiments, the non-FIASMA is a compound that reduces ASMase activity by 10-45% at a concentration of 10 μM.

[0022] MACE: Major adverse cardiac events, a composite clinical endpoint important in assessing efficacy and safety outcomes for patients. Examples of MACE include myocardial infarction, stroke, unstable angina, heart failure, hospitalization for heart failure, acute coronary syndrome, ischemic heart disease, revascularization, cardiovascular death, and all-cause mortality.

[0023] Pharmaceutically acceptable: The term "pharmaceutically acceptable" refers to a non-toxic material that does not interfere with the effectiveness of the active pharmaceutical ingredient(s).

[0024] Pharmaceutically acceptable salts: Salts prepared by methods known to those skilled in the art from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, or sulfuric acid, and / or organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, or tartaric acid.

[0025] Subject: As used herein, the terms "subject" and "patient" are used interchangeably and refer to an animal that is identified or treated in the methods described herein. In many embodiments, the subject is a mammal, particularly a primate, and preferably a human.

[0026] Therapeutically effective amount: A dose sufficient to provide a therapeutic benefit in the treatment or prevention of a disease, or to slow, minimize, or reduce the progression of one or more symptoms associated with a disease, or to cause regression of the disease.

[0027] Treating or preventing a disease: Treating a disease in a subject means that one or more symptoms of the disease are ameliorated, i.e., are less severe than before treatment, and / or the progression of the disease is prevented (i.e., the disease does not progress and remains stable) or slowed (i.e., the disease does not progress to the next stage as quickly). This does not necessarily mean that symptoms of the disease are completely cured or no longer present in the subject, although this may be the case in some methods. Preventing a disease in a subject means that the treatment is prophylactic in that the disease or one or more symptoms thereof are prevented, either completely or partially.

[0028] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. "Comprising A or B" means including A, including B, or including both A and B. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of any conflict, the present description, including explanations of terms, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0029] III. Method Overview A. Diseases treatable or preventable by FIAMSA or non-FIASMA Described herein are methods for treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA in a subject with atherosclerosis, the methods comprising selectively administering a FIASMA to the subject for the treatment or prevention of the disease, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease.

[0030] The disease can be any disease treatable or preventable by a FIASMA or a non-FIASMA. In other words, there are at least two therapies that can be administered to treat or prevent the disease, including a FIASMA and a non-FIASMA, and thus there is a choice between administering a FIASMA or a non-FIASMA to the subject. The method includes selectively administering a FIASMA to the subject for the treatment or prevention of the disease, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease. In other words, a choice has been made to administer a FIASMA to treat or prevent the disease, instead of administering a non-FIASMA to treat or prevent the disease.

[0031] Typically, selectively administering a FIASMA to a subject involves administering a therapeutically effective amount of a FIASMA to the subject.

[0032] In some embodiments, the disorder is selected from the group consisting of depression, anxiety disorders, allergies, cardiac arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome. In particular embodiments, the disorder is depression or an anxiety disorder. Further information regarding these embodiments is provided in subsection B below.

[0033] In some embodiments, the disease is not atherosclerosis or a disease caused by atherosclerosis, such as myocardial infarction, heart failure, stroke, aneurysm, blood clot, angina, coronary artery disease, peripheral artery disease, carotid artery disease, or chronic kidney disease.

[0034] The FIASMA may be any suitable FIASMA used in the treatment or prevention of a particular disease. For example, if the disease is depression, the FIASMA may be a FIASMA used in the treatment or prevention of depression. As a further example, if the disease is heart failure, the FIASMA may be a FIASMA used in the treatment or prevention of heart failure. Various FIASMAs are known and are reported in Table 1 of Kornhuber et al. (Functional inhibitors of acid sphingomyelinase (FIASMAs). Handb Exp Pharmacol. 2013;(215):169-186. doi:10.1007 / 978-3-7091-1368-4_9), which is incorporated herein by reference in its entirety.

[0035] In some embodiments, the FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupepine ... In some embodiments, the antihistamine is selected from the group consisting of phenthixol, fluphenazine, fluvoxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

[0036] In various embodiments, the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine. In some embodiments, the FIASMA is a tricyclic antidepressant (e.g., amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine). In some embodiments, the FIASMA is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the FIASMA is paroxetine or fluoxetine. In various embodiments, the FIASMA is fluoxetine.

[0037] It should be noted that citalopram and escitalopram have been incorrectly listed as FIASMAs in certain prior art documents, including Hoertel et al. (Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study. 2021. Clin. Pharmacol. Ther., 110:1498-1511). However, these drugs are not considered FIASMAs within the scope of this application because they do not have the ability to reduce acid sphingomyelinase (ASMase) activity by 50% at a concentration of 10 μM.

[0038] In some embodiments, the non-FIASMA agent that is not administered is a non-FIASMA SSRI (e.g., citalopram, escitalopram, vilazodone, vortioxetine) or a non-FIASMA serotonin-norepinephrine reuptake inhibitor (SNRI) (e.g., duloxetine, venlafaxine, desvenlafaxine) or a non-FIASMA monoamine oxidase inhibitor (MAOI).

[0039] In some embodiments, the non-FIASMA that is not administered is a non-FIASMA calcium channel antagonist (eg, nifedipine, diltiazem, verapamil).

[0040] In some embodiments, the non-FIASMA that is not administered is a non-FIASMA antihistamine (e.g., diphenhydramine, acrivastine, cetirizine, fexofenadine).

[0041] Atherosclerosis is the thickening or hardening of arteries caused by the buildup of plaque in the inner lining of the arteries. Atherosclerosis can affect any artery in the body. For example, atherosclerosis can affect the arteries of the heart (causing coronary artery disease), the arteries of the legs, arms, or pelvis (causing peripheral artery disease), the arteries of the neck (causing carotid artery disease), the arteries supplying blood to the kidneys (causing renal artery stenosis), the arteries supplying blood to the brain (causing vertebral artery disease), and / or the arteries supplying blood to the intestines (causing mesenteric artery ischemia). In various embodiments, the subject has coronary artery disease. Coronary artery disease occurs when plaque builds up in the walls of the coronary arteries over time, narrowing the arteries and restricting or completely blocking blood flow to the heart (i.e., coronary atherosclerosis).

[0042] A subject is considered to have atherosclerosis if the subject has been diagnosed with atherosclerosis (i.e., definitively diagnosed atherosclerosis), and / or is suspected to have atherosclerosis if the subject meets certain criteria (i.e., presumably diagnosed atherosclerosis).

[0043] A subject can be diagnosed with atherosclerosis using one or more diagnostic methods, including blood tests (such as blood glucose and cholesterol levels), electrocardiograms, ultrasound imaging (such as 2D and 3D vascular ultrasound), ankle-brachial index, cardiac angiography, computed tomography, magnetic resonance angiography, and positron emission tomography.

[0044] If a subject meets certain criteria, it can be assumed that the subject has atherosclerosis. In various embodiments, a subject has atherosclerosis if the subject is at least 50 years old. In certain embodiments, a subject has atherosclerosis if the subject is at least 55 years old. In some embodiments, a subject has atherosclerosis if the subject is at least 60 years old. In some embodiments, a subject has atherosclerosis if the subject has previously suffered a myocardial infarction. Typically, a subject has atherosclerosis if the subject is at least 50 years old or older.

[0045] In some embodiments, the subject has a family history of myocardial infarction. In certain embodiments, the subject has previously suffered a myocardial infarction. In some embodiments, the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

[0046] The subject can be any subject. For example, the subject can be a human or a non-human animal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a non-human animal selected from the group consisting of a primate, a horse, a sheep, a pig, a cow, a mouse, a rat, a rabbit, a dog, and a cat.

[0047] In some embodiments, the method does not involve administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder. In other words, in some embodiments, the method does not involve administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder. Thus, the subject can be defined as a subject who has not been administered a non-FIASMA.

[0048] B. Depression or anxiety disorder Described herein are methods for treating or preventing a depression or anxiety disorder treatable or preventable by a FIASMA or a non-FIASMA in a subject with atherosclerosis, the methods comprising selectively administering a FIASMA to the subject for the treatment or prevention of the depression or anxiety disorder, and not administering a non-FIASMA to the subject for the treatment or prevention of the depression or anxiety.

[0049] In some embodiments, the method is for treating or preventing depression. Depression is a common mental illness with multiple subtypes. The depression may be of any type / category, provided that the depression is treatable or preventable with FIASMA or non-FIASMA. The depression may be selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder.

[0050] In some embodiments, the disorder is an anxiety disorder. Anxiety disorders are common mental illnesses with multiple subtypes. The anxiety disorder may be any type / category of anxiety, provided that the anxiety disorder is FIASMA or non-FIASMA treatable or preventable. The anxiety disorder may be selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

[0051] The FIASMA may be any FIASMA used to treat or prevent a specific disease. For example, if the disease is depression, the FIASMA is a FIASMA used to treat or prevent depression. Various FIASMAs are known and are reported in Table 1 of Kornhuber et al. (Functional inhibitors of acid sphingomyelinase (FIASMAs). Handb Exp Pharmacol. 2013;(215):169-186. doi:10.1007 / 978-3-7091-1368-4_9).

[0052] In various embodiments, the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine. In some embodiments, the FIASMA is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the FIASMA is paroxetine or fluoxetine. In various embodiments, the FIASMA is fluoxetine.

[0053] In some embodiments, the method does not involve administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder. In other words, in some embodiments, the method does not involve administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder.

[0054] In certain embodiments, methods are provided for treating or preventing a depression or anxiety disorder treatable or preventable by a FIASMA SSRI (e.g., fluoxetine and / or paroxetine) or by a non-FIASMA SSRI (e.g., escitalopram and / or citalopram) in a subject with atherosclerosis, the method comprising selectively administering to the subject a FIASMA SSRI for the treatment or prevention of the depression or anxiety disorder, and not administering to the subject a non-FIASMA SSRI for the treatment or prevention of the depression or anxiety disorder.

[0055] The above descriptions relating to methods of treating or preventing a disease in a subject are equally applicable to these methods of treating or preventing a depression or anxiety disorder in a subject.

[0056] C. Secondary Medical Uses Also described herein is a functional inhibitor of acid sphingomyelinase (FIASMA) for use in treating or preventing a disease in a subject with atherosclerosis, where the disease is treatable or preventable by FIASMA or a non-FIASMA, and the non-FIASMA is not administered to the subject for the treatment or prevention of the disease. The above description of methods for treating or preventing a disease in a subject can be applied to these second medical use embodiments as well. In particular, in some embodiments, the disease is not atherosclerosis or a disease caused by atherosclerosis. In some embodiments, the method includes not administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder.

[0057] Also described herein is a functional inhibitor of acid sphingomyelinase (FIASMA) for use in treating or preventing a depression or anxiety disorder in a subject with atherosclerosis, wherein the depression or anxiety disorder is treatable or preventable by a FIASMA or a non-FIASMA, and the non-FIASMA is not administered to the subject for the treatment or prevention of the depression or anxiety disorder. The above descriptions regarding methods for treating or preventing a disease in a subject and methods for treating or preventing a depression or anxiety disorder in a subject can be applied to these second medical use embodiments as well. In particular, in some embodiments, the method comprises not administering a non-FIASMA to the subject for the treatment or prevention of any disease or disorder.

[0058] D. Further Methods Also described herein are methods for treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA in a subject with atherosclerosis, wherein the subject is being administered a non-FIASMA for the treatment or prevention of the disease. The method comprises discontinuing administration of the non-FIASMA for the treatment or prevention of the disease, selectively administering to the subject a FIASMA for the treatment or prevention of the disease, and not administering to the subject a non-FIASMA for the treatment or prevention of the disease. The above discussion regarding methods for treating or preventing a disease in a subject is equally applicable to these embodiments.

[0059] Also described herein are methods for treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA in a subject with atherosclerosis. The methods include determining that a patient is at high risk for MACE, selectively administering a FIASMA to the subject to treat or prevent the disease and to reduce the risk of MACE, and not administering a non-FIASMA to the subject to treat or prevent the disease. In some embodiments, the term "high risk" refers to risk above a threshold level. In some embodiments, the term "high risk" refers to a patient at higher risk of developing MACE compared to a control group. In various embodiments, the control group is a cohort of healthy patients or the general population, or a cohort of patients with atherosclerosis. "High risk" or "high risk" refers to a statistically higher risk compared to the control group. In some embodiments, the methods include determining that the patient is at high risk for MACE over the next six months or the next two years. The above discussion regarding methods for treating or preventing disease in a subject is equally applicable to these embodiments.

[0060] In some embodiments, determining that the patient is at increased risk of MACE comprises determining a risk score, hi some embodiments, determining that the patient is at increased risk of MACE comprises measuring one or more biomarkers associated with MACE, and / or calculating a genetic risk score, and / or imaging the patient, and / or calculating a risk score using a machine learning risk model, and / or calculating a clinical risk score.

[0061] The one or more biomarkers associated with MACE may be any biomarker known to be predictive, prognostic, or associated with MACE. Various biomarkers are known in the art; see, for example, Wang J et al. ("Biomarker-based risk model to predict cardiovascular events in patients with acute coronary syndromes - Results from BIPass registry" The Lancet Regional Health-Western Pacific 2022;25:100479), which is incorporated herein by reference in its entirety. In some embodiments, the one or more biomarkers are selected from the group consisting of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor 15 (GDF-15). In various embodiments, measuring the one or more biomarkers further includes identifying the one or more biomarkers as statistically different compared to a control. In some embodiments, measuring the one or more biomarkers further includes calculating a biomarker risk score (e.g., a BIPass risk score). Typically, the presence or amount of a biomarker is determined by isolating a biological sample from a subject and detecting and / or quantifying nucleic acid encoding the biomarker and / or detecting and / or quantifying the amount of the biomarker in the sample.

[0062] In various embodiments, an increased risk of MACE can be determined by calculating a genetic risk score for MACE based on sequencing of a subject's biological sample. Calculation of the genetic risk score is further described, for example, in Ramirez J et al. ("Prediction of Coronary Artery Disease and Major Adverse Cardiovascular Events Using Clinical and Genetic Risk Scores for Cardiovascular Risk Factors", Circulation: Genomic and Precision Medicine. 15(5):444-452), which is incorporated herein by reference in its entirety.

[0063] Imaging techniques are also used to assess MACE risk. See, e.g., Marcos-Garces V et al. ("Risk score for early risk prediction by cardiac magnetic resonance after acute myocardial infarction". Int J Cardiol. 2022 Feb 15;349:150-154), which is incorporated herein by reference in its entirety. In some embodiments, imaging the patient includes imaging the patient with cardiac magnetic resonance imaging. In some embodiments, imaging the patient further includes calculating an imaging risk score.

[0064] The risk score can also be calculated using a machine learning risk model. See, e.g., Wang J et al. ("Risk Prediction of Major Adverse Cardiovascular Events Occurrence Within 6 Months After Coronary Revascularization: Machine Learning Study" JMIR Med Inform 2022;10(4):e33395), which is incorporated herein by reference in its entirety.

[0065] High MACE risk can also be determined using a clinical risk score for MACE. An example of a method for identifying high MACE risk is the QRISK3 risk score (https: / / www.qrisk.org / three / ). In some embodiments, calculating the clinical risk score includes calculating the QRISK3 risk score. In various aspects, the subject exhibits a QRISK3 score greater than 10.

[0066] Also described herein are methods for treating or preventing a disease treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA in a subject with atherosclerosis. The methods include selectively administering a FIASMA to the subject for the treatment or prevention of the disease to reduce the risk of MACE or avoid an increased risk of MACE, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease. The above discussion regarding methods for treating or preventing a disease in a subject is equally applicable to these embodiments.

[0067] Also described herein is a method for reducing the risk of MACE in a subject, wherein the subject has atherosclerosis and is being treated for a secondary disease other than atherosclerosis. The method includes determining that the subject is at high risk for MACE, selectively administering a FIASMA to treat or prevent the secondary disease and to reduce the risk of MACE, and not administering a non-FIASMA to the subject for the treatment or prevention of the secondary disease. The above description regarding methods for treating or preventing disease in a subject is equally applicable to these embodiments. The above description related to determining that the patient is at high risk for MACE is equally applicable to these embodiments.

[0068] The following examples are provided to illustrate certain specific features and / or embodiments, and should not be construed as limiting the disclosure to the particular features or embodiments described. [Example]

[0069] The inventors have found that patients with some degree of atherosclerosis (e.g., at least 50 years old and / or diagnosed with atherosclerosis / coronary artery disease) are at lower risk of death and serious adverse cardiac events if treated for their disease instead of non-FIASMA.

[0070] As a non-limiting example, the inventors have demonstrated that patients with presumed diagnosed atherosclerosis (i.e., at least 50 years of age) receiving antidepressants have a lower risk of death and serious adverse cardiac events when receiving a FIASMA antidepressant compared to when receiving a non-FIASMA antidepressant.

[0071] As a further non-limiting example, the inventors have demonstrated that patients with established atherosclerosis (i.e., patients diagnosed with atherosclerosis or coronary artery disease) receiving antidepressants have a lower risk of death and serious adverse cardiac events when receiving a FIASMA antidepressant compared to when receiving a non-FIASMA antidepressant.

[0072] These findings are important because patients with atherosclerosis (e.g., those at least 50 years of age and / or diagnosed with atherosclerosis / CAD) may be selectively prescribed FIASMA over non-FIASMA drugs for the treatment of their illness (e.g., depression and anxiety disorders) to improve their chances of survival.

[0073] Example 1 The present inventors sought to determine whether there were any differences between treating patients with presumed atherosclerosis with FIASMA versus non-FIASMA drugs. As a non-limiting example, the present inventors selected depression / anxiety disorder as the disease and tested the effects of the FIASMA drugs paroxetine and fluoxetine versus the non-FIASMA drugs escitalopram and citalopram. Table 1 below shows the ASMase inhibition data for paroxetine and fluoxetine. This data is derived from Kornhuber J et al. (Functional inhibitors of acid sphingomyelinase (FIASMAs). Handb Exp Pharmacol. 2013;(215):169-86. doi:10.1007 / 978-3-7091-1368-4_9. PMID:23579455). [Table 1]

[0074] This analysis was performed using the Maccabi database, the largest electronic medical record (EMR) database from a health maintenance organization in Israel, covering approximately 26% of the entire Israeli population and spanning the period 2010-2020.

[0075] The patient cohort (Cohort A) was defined according to Table 2 below. We identified 13,878 patients from the Maccabi database who purchased escitalopram, citalopram, paroxetine, or fluoxetine between 2012 and 2015, but who had not purchased any of these four SSRIs within 2 years prior to the reference date (i.e., the date of their first purchase of escitalopram, citalopram, paroxetine, or fluoxetine SSRIs), had activity records in the database for at least 2 years prior to the reference date, had no history of myocardial infarction within 2 years prior to the reference date, and were over 50 years of age. These patients were screened based on availability of data for at least half of their laboratory and vital values ​​and matched by reference date and propensity score, resulting in a cohort of 10,363 patients with estimated atherosclerosis. Covariate balance plots and propensity score density plots are shown in Figure 1. [Table 2]

[0076] Cohort A was divided into patients who received a FIASMA SSRI (paroxetine or fluoxetine) and patients who received a non-FIASMA SSRI (escitalopram or citalopram). Demographic information and baseline vital values ​​for patients within the cohort are shown in Table 3 below. [Table 3]

[0077] Baseline comorbidities (assessed in the 2 years prior to the reference date) among patients within Cohort A are shown in Table 4 below. [Table 4]

[0078] Baseline laboratory values ​​(identified as the closest value within one year prior to the reference date) for patients within Cohort A are shown in Table 5 below. [Table 5]

[0079] Baseline medication utilization among patients within Cohort A is shown in Table 6 below. [Table 6]

[0080] Univariate Cox proportional hazards regression analysis was used to examine the association between subject survival and prior use of FIASMA SSRIs or non-FIASMA SSRIs. The Cox proportional hazards model is a semiparametric model that makes no assumptions about the distribution of the baseline hazard function. However, a key assumption is that the hazard functions across strata remain proportional over time. h(t)=h0(t)exp(B1x1+…+B p x p ) h0(t) is the baseline hazard rate

[0081] The following survival assumptions were made: Survival assumption 1 (no treatment period data) Outcomes other than death Coding of follow-up period (days): If the patient experienced an event: the period from the baseline date to the date of the event If the patient does not experience an event: If the patient dies during the follow-up period: the period from the baseline date to the date of death If the patient has not died during the follow-up period: the period from the baseline date to the maximum activity date (maximum activity date = the last date of a coded diagnosis / procedure or the date of death (before 2021)) Three patients were excluded because they had no events and their peak activity date was before the baseline date. Events occurring within 90 days of the baseline date were ignored.

[0082] Coding of event indicators: 1 if an event occurred during the follow-up period, 0 otherwise.

[0083] death from all causes Coding of follow-up period (days): If the patient experienced an event: the period from the reference date to the date of death If the patient has not experienced an event: the period from the baseline date to the maximum activity date (maximum activity date = the last coded diagnosis / procedure date (before 2021)) Three patients who did not experience any events and whose maximum activity date was before the reference date were excluded.

[0084] Events occurring within 90 days of the reference date were ignored.

[0085] Coding of event indicators: 1 if death occurred during follow-up, 0 otherwise.

[0086] Survival assumption 2 (treatment period data available) Outcomes other than death Coding of follow-up period (days): If the patient experienced an event: the period from the baseline date to the date of the event If the patient does not experience an event: If the patient dies during the follow-up period: the period from the baseline date to the earlier of 1) the end of treatment or 2) the date of death. If the patient did not die during the follow-up period: the period from the baseline date to the end of treatment Three patients were excluded if they had no events and their peak activity date was before the baseline date. Events occurring within 90 days of the baseline date were ignored.

[0087] Coding of event indicators: 1 if the event occurred during SSRI use or within 1 year after discontinuing use, 0 otherwise.

[0088] death from all causes Coding of follow-up period (days): If the patient experienced an event: the period from the reference date to the date of death If the patient has not experienced an event: the period from the baseline date to the end of treatment Three patients were excluded because they had no events and their peak activity date was before the baseline date. Events occurring within 90 days of the baseline date were ignored.

[0089] Coding of event indicators: 1 if death occurred during SSRI use or within 1 year after discontinuation, 0 otherwise.

[0090] The results of the univariate Cox proportional hazards regression analysis are shown in Table 7 below. [Table 7]

[0091] The only factor that reached statistical significance under survival assumption 2 was all-cause mortality (hazard ratio = 0.71, 95% confidence interval = 0.61-0.83, p-value = 1.01E-05). This is also evident from the Kaplan-Meier survival curves shown in Figure 2B. Among patients with presumed atherosclerosis (i.e., age >50 years), use of FIASMA SSRIs was associated with a reduced risk of all-cause mortality compared with use of non-FIASMA SSRIs, and this effect persisted throughout the study period.

[0092] Furthermore, the only factor that reached statistical significance under survival assumption 2 was MACE (hazard ratio = 0.79, 95% confidence interval = 0.70-0.89, p-value = 6.33E-05). This is also evident from the Kaplan-Meier survival curves shown in Figure 3B. In patients with presumed diagnosed atherosclerosis (i.e., age >50 years), use of FIASMA SSRIs was associated with a reduced risk of major adverse cardiac events compared with use of non-FIASMA SSRIs, and this effect persisted throughout the study period.

[0093] Example 2 We determined whether there were any differences between patients with established atherosclerosis / coronary artery disease treated with FIASMA SSRIs and non-FIASMA SSRIs.

[0094] This analysis was conducted using the Maccabi database. A patient cohort (Cohort B) was defined according to Table 8 below. We identified 3,050 patients from the Maccabi database who had purchased escitalopram, citalopram, paroxetine, or fluoxetine between 2012 and 2015, but had not purchased any of these four SSRIs in the year prior to the reference date, had at least two years of database activity prior to the reference date, and had been diagnosed with coronary artery disease or atherosclerosis within 10 years of the reference date. These patients were screened based on availability of at least half of their laboratory and vital data, and matched by reference date and propensity score. This resulted in 2,486 patients with confirmed atherosclerosis / coronary artery disease. The covariate balance plot and propensity score density plot are shown in Figure 4. [Table 8]

[0095] Of the patients in Cohort B (with confirmed atherosclerosis / coronary artery disease), 74.5% were also present in Cohort A (with presumed atherosclerosis) in Example 1.

[0096] Cohort B was divided into patients who purchased FIASMA SSRIs (paroxetine or fluoxetine) and patients who purchased non-FIASMA SSRIs (escitalopram or citalopram). Demographic and vital information at baseline for patients in Cohort B is shown in Table 9 below. [Table 9]

[0097] Baseline comorbidities (assessed in the 2 years prior to index) for patients in Cohort B are shown in Table 10 below. [Table 10]

[0098] Baseline laboratory values ​​(identified as the closest value within one year prior to the reference date) for patients in Cohort B are shown in Table 11 below. [Table 11]

[0099] The baseline medication usage (assessed within one year prior to the reference date) of patients in Cohort B is shown in Table 12 below. [Table 12]

[0100] Univariate Cox proportional hazards regression analysis was used to examine the association between subject survival and prior FIASMA SSRI or non-FIASMA SSRI use, using survival assumptions 1 and 2 from Example 1. The results of this analysis are shown in Table 13 below. [Table 13]

[0101] The only factor that reached statistical significance under survival assumption 2 was all-cause mortality (hazard ratio (HR) = 0.60, 95%, confidence interval (CI) = 0.47-0.76, p = 4.32E-05). This result is also evident from the Kaplan-Meier survival curve shown in Figure 5B. In patients with confirmed atherosclerosis / CAD, use of FIASMA SSRIs was associated with a reduced risk of all-cause mortality compared with use of non-FIASMA SSRIs, and this effect persisted throughout the study period.

[0102] The factor that reached statistical significance under survival hypotheses 1 and 2 was MACE, a result also evident from the Kaplan-Meier survival curves shown in Figures 6A and 6B.

[0103] The results from Cohort B with confirmed atherosclerosis / CAD support the results from Cohort A with probable atherosclerosis in Example 1, demonstrating that FIASMA has a significant preventive effect on all-cause mortality and major adverse cardiac events compared to non-FIASMA.

[0104] In view of the numerous embodiments to which the principles of the disclosed invention may be applied, it is to be understood that the illustrated embodiments are merely preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

[0105] References 1.Kornhuber J,Tripal P,Gulbins E,Muehlbacher M.Functional inhibitors of acid sphingomyelinase (FIASMAs).Handb Exp Pharmacol.2013;(215):169-186.doi:10.1007 / 978-3-7091-1368-4_9 2.KornhuberJ,MuehlbacherM,TrappS,PechmannS,FriedlA,Muehle C,Terfloth L,Groemer TW,Spitzer GM,Liedl KR,Gulbins E,Tripal P.Identification of Novel Functional Inhibitors of Acid Sphingomyelinase.PLOS ONE 2011;6(8):e23852.https: / / doi.org / 10.1371 / journal.pone.0023852

Claims

1. 1. A method of treating or preventing atherosclerosis in a subject, wherein the disease is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA inhibitor, the method comprising: A method comprising selectively administering a FIASMA to said subject for the treatment or prevention of said disease, and not administering a non-FIASMA to said subject for the treatment or prevention of said disease.

2. 2. The method of claim 1, wherein the disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome.

3. 3. The method of claim 2, wherein the disorder is depression or an anxiety disorder.

4. 4. The method of claim 3, wherein the disorder is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

5. 5. The method of any one of claims 1 to 4, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

6. The method of any one of claims 1 to 5, wherein the subject has coronary artery disease.

7. 10. The method of any preceding claim, comprising not administering to said subject a non-FIASMA for the treatment or prevention of any disease or disorder.

8. 10. The method of any preceding claim, wherein the disease is not atherosclerosis or a disease caused by atherosclerosis.

9. The FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connesin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupentixol, fluphenazine ...

10. The method of any preceding claim, wherein the active ingredient is selected from the group consisting of ruboxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

10. 10. The method of claim 9, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

11. 10. The method of any of the preceding claims, wherein the FIASMA is a selective serotonin reuptake inhibitor.

12. 10. The method of any of the preceding claims, wherein the FIASMA is paroxetine or fluoxetine.

13. 10. The method of any preceding claim, wherein the subject is a non-human animal.

14. The method of any one of claims 1 to 12, wherein the subject is a human.

15. 1. A method for treating or preventing a depression or anxiety disorder in a subject with atherosclerosis, wherein the depression or anxiety disorder is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA; A method comprising selectively administering a FIASMA to said subject for the treatment or prevention of said depression or anxiety disorder, and not administering a non-FIASMA to said subject for the treatment or prevention of said depression or anxiety disorder.

16. 16. The method of claim 15, wherein the disorder is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

17. 17. The method of claim 15 or claim 16, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

18. The method of any one of claims 15 to 17, wherein the subject has coronary artery disease.

19. 19. The method of any one of claims 15 to 18, comprising not administering to said subject a non-FIASMA drug for the treatment or prevention of any disease or disorder.

20. 20. The method of any one of claims 15 to 19, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

21. The method of any one of claims 15 to 20, wherein the FIASMA is a selective serotonin reuptake inhibitor.

22. The method of any one of claims 15 to 21, wherein the FIASMA is paroxetine or fluoxetine.

23. The method of any one of claims 15 to 22, wherein the subject is a non-human animal.

24. The method of any one of claims 15 to 22, wherein the subject is a human.

25. A functional inhibitor of acid sphingomyelinase (FIASMA) for treating or preventing atherosclerosis in a subject, comprising: the disease is treatable or preventable by the FIASMA or by a non-FIASMA; A FIASMA wherein a non-FIASMA is not administered to said subject for the treatment or prevention of said disease.

26. FIASMA for use according to claim 25, wherein the disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infections and irritable bowel syndrome.

27. FIASMA for use according to claim 25 or claim 26, wherein the disease is depression or anxiety disorder.

28. FIASMA for use according to any one of claims 25 to 27, wherein the disease is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression and seasonal affective disorder, or the disease is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder and social phobia.

29. FIASMA for use according to any one of claims 25 to 28, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

30. 30. The method of claim 29, wherein the subject has coronary artery disease.

31. FIASMA for use according to any one of claims 25 to 30, wherein the subject is not administered a non-FIASMA for the treatment or prevention of any disease or disorder.

32. FIASMA for use according to any one of claims 25 to 31, wherein the disease is not atherosclerosis or a disease caused by atherosclerosis.

33. The FIASMA may be selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupenthixol, fluphenazine, and fluvoxamine. , hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

34. 34. A FIASMA for use according to any one of claims 25 to 33, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

35. FIASMA for use according to any one of claims 25 to 34, wherein said FIASMA is a selective serotonin reuptake inhibitor.

36. FIASMA for use according to any one of claims 25 to 35, wherein said FIASMA is paroxetine or fluoxetine.

37. FIASMA for use according to any one of claims 25 to 36, wherein the subject is a non-human animal.

38. FIASMA for use according to any one of claims 25 to 36, wherein the subject is a human.

39. 1. A functional inhibitor of acid sphingomyelinase (FIASMA) for use in treating or preventing depression or anxiety disorders in a subject with atherosclerosis, comprising: the depression or anxiety disorder is treatable or preventable by the FIASMA or by a non-FIASMA; The non-FIASMA is not administered to the subject for the treatment or prevention of the depression or anxiety disorder.

40. FIASMA for use according to claim 39, wherein the disease is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disease is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

41. FIASMA for use according to claim 39 or 40, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

42. FIASMA for use according to any one of claims 39 to 41, wherein the subject has coronary artery disease.

43. 43. The FIASMA for use according to any one of claims 39 to 42, wherein the subject is not administered a non-FIASMA for the treatment or prevention of any disease or disorder.

44. 44. A FIASMA for use according to any one of claims 39 to 43, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

45. FIASMA for use according to any one of claims 39 to 44, wherein said FIASMA is a selective serotonin reuptake inhibitor.

46. FIASMA for use according to any one of claims 39 to 45, wherein said FIASMA is paroxetine or fluoxetine.

47. FIASMA for use according to any one of claims 39 to 46, wherein the subject is a non-human animal.

48. FIASMA for use according to any one of claims 39 to 46, wherein the subject is a human.

49. 1. A method of treating or preventing atherosclerosis in a subject, wherein the disease is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or by a non-FIASMA, and the subject is being administered a non-FIASMA for the treatment or prevention of the disease, the method comprising: discontinuing administration of a non-FIASMA drug for the treatment or prevention of said disease; selectively administering a FIASMA to said subject for the treatment or prevention of said disease, and not administering a non-FIASMA to said subject for the treatment or prevention of said disease.

50. 50. The method of claim 49, wherein the disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome.

51. 51. The method of claim 49 or claim 50, wherein the disorder is depression or an anxiety disorder.

52. 52. The method of any one of claims 49 to 51, wherein the disorder is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

53. 53. The method of any one of claims 49 to 52, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

54. 54. The method of any one of claims 49 to 53, wherein the subject has coronary artery disease.

55. 55. The method of any one of claims 49 to 54, wherein said method comprises not administering to said subject a non-FIASMA drug for the treatment or said prevention of any disease or disorder.

56. 56. The method of any one of claims 49 to 55, wherein the disease is not atherosclerosis or a disease caused by atherosclerosis.

57. The FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupentixol, fluphenazine ...

57. The method of any one of claims 49 to 56, wherein the medicament is selected from the group consisting of voxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

58. 58. The method of any one of claims 49 to 57, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

59. 59. The method of any one of claims 49 to 58, wherein the FIASMA is a selective serotonin reuptake inhibitor.

60. 60. The method of any one of claims 49 to 59, wherein the FIASMA is paroxetine or fluoxetine.

61. 61. The method of any one of claims 49 to 60, wherein the subject is a non-human animal.

62. 61. The method of any one of claims 49 to 60, wherein the subject is a human.

63. 1. A method of treating or preventing atherosclerosis in a subject, wherein the disease is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA inhibitor, the method comprising: determining that the patient is at high risk for MACE; A method comprising selectively administering a FIASMA to the subject for the treatment or prevention of the disease and to reduce the risk of MACE, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease.

64. 64. The method of claim 63, wherein the disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome.

65. 65. The method of claim 63 or claim 64, wherein the disorder is depression or an anxiety disorder.

66. 66. The method of any one of claims 63 to 65, wherein the disorder is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

67. 67. The method of any one of claims 63 to 66, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

68. 68. The method of any one of claims 63 to 67, wherein the subject has coronary artery disease.

69. 69. The method of any one of claims 63-68, wherein said method comprises not administering to said subject a non-FIASMA drug for the treatment or prevention of any disease or disorder.

70. 70. The method of any one of claims 63 to 69, wherein the disease is not atherosclerosis or a disease caused by atherosclerosis.

71. The FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupentixol, fluphenazine ...

71. The method of any one of claims 63 to 70, wherein the active ingredient is selected from the group consisting of voxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

72. 72. The method of any one of claims 63-71, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

73. 73. The method of any one of claims 63 to 72, wherein the FIASMA is a selective serotonin reuptake inhibitor.

74. 74. The method of any one of claims 63 to 73, wherein the FIASMA is paroxetine or fluoxetine.

75. 75. The method of any one of claims 63 to 74, wherein the subject is a non-human animal.

76. 75. The method of any one of claims 63 to 74, wherein the subject is a human.

77. 1. A method of treating or preventing atherosclerosis in a subject, wherein the disease is treatable or preventable by a functional inhibitor of acid sphingomyelinase (FIASMA) or a non-FIASMA inhibitor, the method comprising: A method comprising selectively administering a FIASMA to the subject for the treatment or prevention of the disease and to reduce the risk of MACE or avoid an increased risk of MACE, and not administering a non-FIASMA to the subject for the treatment or prevention of the disease.

78. 78. The method of claim 77, wherein the disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome.

79. 79. The method of claim 77 or claim 78, wherein the disease is depression or an anxiety disorder.

80. 80. The method of any one of claims 77 to 79, wherein the disorder is depression, and the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, and the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

81. 81. The method of any one of claims 77 to 80, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

82. 82. The method of any one of claims 77 to 81, wherein the subject has coronary artery disease.

83. 83. The method of any one of claims 77-82, wherein said method comprises not administering to said subject a non-FIASMA drug for the treatment or prevention of any disease or disorder.

84. 84. The method of any one of claims 77 to 83, wherein the disease is not atherosclerosis or a disease caused by atherosclerosis.

85. The FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupentixol, fluphenazine ...

85. The method of any one of claims 77 to 84, wherein the active ingredient is selected from the group consisting of voxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

86. 86. The method of any one of claims 77-85, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

87. 87. The method of any one of claims 77 to 86, wherein the FIASMA is a selective serotonin reuptake inhibitor.

88. 88. The method of any one of claims 77 to 87, wherein the FIASMA is paroxetine or fluoxetine.

89. 89. The method of any one of claims 77 to 88, wherein the subject is a non-human animal.

90. 79. The method of any one of claims 77 to 78, wherein the subject is a human.

91. 1. A method for reducing the risk of MACE in a subject, comprising: the subject has atherosclerosis and is being treated for a secondary non-atherosclerotic disease, and the method comprises: determining that the subject is at high risk for MACE; The method comprises selectively administering a FIASMA to treat or prevent the secondary disease and to reduce the risk of MACE, and not administering a non-FIASMA to the subject to treat or prevent the secondary disease.

92. 92. The method of claim 91, wherein the secondary disease is selected from the group consisting of depression, anxiety disorders, allergies, arrhythmias, pain, angina, hypertension, psychosis, schizophrenia, mania, muscle spasms, pruritus, bulimia nervosa, premenstrual dysphoric disorder, alcohol abuse, cystic fibrosis, septic shock, microbial infection, and irritable bowel syndrome.

93. 93. The method of claim 91 or claim 92, wherein the secondary disorder is depression or an anxiety disorder.

94. 94. The method of any one of claims 91 to 93, wherein the secondary disorder is depression, wherein the depression is selected from the group consisting of clinical depression, depressive episode, recurrent depressive disorder, reactive depression, dysthymia, cyclothymia, manic depression, psychotic depression, prenatal depression, postnatal depression, and seasonal affective disorder, or the disorder is an anxiety disorder, wherein the anxiety disorder is selected from the group consisting of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia.

95. 95. The method of any one of claims 91 to 94, wherein the subject is at least 50 years old, and / or the subject has a family history of myocardial infarction, and / or the subject has previously suffered a myocardial infarction.

96. 96. The method of any one of claims 91 to 95, wherein the subject has coronary artery disease.

97. 97. The method of any one of claims 91 to 96, wherein the method comprises not administering to the subject a non-FIASMA drug for the treatment or prevention of any disease or disorder.

98. 98. The method of any one of claims 91 to 97, wherein the secondary disease is not atherosclerosis or a disease caused by atherosclerosis.

99. The FIASMA is selected from the group consisting of alverine, amiodarone, amitriptyline, amlodipine, aprindine, astemizole, AY-9944, benstropine, bepridil, biperiden, camylofine, carvedilol, cepharanthine, chlorpromazine, chlorprothixene, cinnarizine, clemastine, clofazimine, clomiphene, clomipramine, cloperastine, connexin, cyclobenzaprine, cyproheptadine, desipramine, desloratadine, dicyclomine, dilazep, dimebon, doxepin, drofenine, emetine, ethopropazine, fendiline, flunarizine, fluoxetine, flupentixol, fluphenazine ...

99. The method of any one of claims 91 to 98, wherein the medicament is selected from the group consisting of voxamine, hydroxyzine, imipramine, lofepramine, loperamide, loratadine, maprotiline, mebeverine, mebhydroline, mibefradil, norfluoxetine, nortriptyline, paroxetine, penfluridol, perhexiline, perphenazine, pimethixene, pimozide, promazine, promethazine, protriptyline, quinacrine, sertindole, sertraline, solasodine, suloctidil, tamoxifen, terfenadine, thioridazine, tomatidine, trifluoperazine, triflupromazine, trimipramine, zolantidine, and combinations thereof.

100. 100. The method of any one of claims 91-99, wherein the FIASMA is selected from the group consisting of amitriptyline, clomipramine, desipramine, doxepin, fluoxetine, flupenthixol, fluvoxamine, imipramine, lofepramine, maprotiline, norfluoxetine, nortriptyline, paroxetine, protriptyline, sertraline, and trimipramine.

101. 101. The method of any one of claims 91 to 100, wherein the FIASMA is a selective serotonin reuptake inhibitor.

102. The method of any one of claims 91 to 101, wherein the FIASMA is paroxetine or fluoxetine.

103. 103. The method of any one of claims 91 to 102, wherein the subject is a non-human animal.

104. The method of any one of claims 91 to 102, wherein the subject is a human.

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