A method of treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which leads to COVID-19 disease is described whereby the patient is repeatedly treated with fenfluramine and the treatment continued to obtain a desired end point not previously recognized.
The free base of fenfluramine is an amphetamine derivative having the structure:
As used herein, the term “fenfluramine” refers to both the free base depicted in Structure 1 and its pharmaceutically acceptable salts thereof.
Fenfluramine was first marketed in the US in 1973 and had been administered in combination with phentermine to prevent and treat obesity. However, in 1997, it was withdrawn from the US market as its use was associated with the onset of cardiac valvular fibrosis and pulmonary hypertension. Subsequently, the drug was withdrawn from sale globally and is no longer indicated for use in any therapeutic area anywhere in the world.
Despite the health concerns surrounding fenfluramine, attempts have been made to identify further therapeutic uses for that product. Aicardi and Gastaut (New England Journal of Medicine (1985), 313:1419 and Archives of Neurology (1988) 45:923-925) reported four cases of self-induced photosensitive seizures that responded to treatment with fenfluramine. Clemens, in Epilepsy Research (1988) 2:340-343 reported a study on a boy suffering pattern sensitivity-induced seizure that were resistant to anticonvulsive treatment. Fenfluramine reportedly successfully terminated these self-induced seizures and the author concluded that this was because fenfluramine blocked the photosensitive triggering mechanism.
Provided is a method of treating a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising: determining the patient has been infected with SARS-CoV-2; and administering to the patient a therapeutically effective dose of fenfluramine.
In an aspect of the invention, the fenfluramine is the sole therapeutic agent administered to the patient.
In another aspect of the invention, the fenfluramine is adjunctive therapy and is co-administered with a second, or a second and third, or a second, third and fourth, therapeutic agent. Any second, or any combination of second and third, or any combination of second, third and fourth therapeutic agents of interest may be utilized. In some cases, the second, or a second and third, or a second, third and fourth, therapeutic agent is selected from the group consisting of: Remdesivir, a monoclonal antibody, convalescent plasma from a subject who had previously been infected with SARS-CoV-2 and which comprises antibodies for SARS-CoV-2, a viricide, amantadine, rimantadine, and a nucleoside analog. Exemplary nucleoside analogs include acyclovir and zidovudine (AZT). In some cases, the co-therapeutic agent is zinc.
In another aspect of the invention, the treatment continues in amounts and over a period of time so as to reduce the need by the patient for antiviral medication by 25% or more, 50% or more, 75% or more, or completely eliminate the need for antiviral medication.
In another aspect of the invention, the treatment is continued in amounts and over a period of time so as to reduce the patient's hospitalization visits by 25% or more, 50% or more, 75% or more, or completely eliminate hospitalization visits due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which leads to COVID-19 disease.
Another aspect of the invention comprises administering a liquid fenfluramine formulation by the use of an oral syringe which is graduated for precise measurement of the liquid formulation. The formulation may include flavoring and coloring agents or may be completely devoid of any excipient materials beyond those necessary to dissolve the fenfluramine in the liquid which may be water.
In some cases, the fenfluramine can be administered directly to a lung of the patient. For instance, an aqueous composition comprising fenfluramine can be aerosolized to generate an aerosol, and the aerosol can be directed into a lung of the patient. In some cases, the aerosol comprises liquid droplets of the aqueous fenfluramine composition having a dimension (e.g. a diameter) of 10 μm or less, such as 1 μm or less or 0.1 μm or less. In some cases the administering comprises directing an aerosol comprising fenfluramine into a lung of the patient.
In some cases, the administering includes delivering the dose of fenfluramine to the patient as an aerosol. In other words, an aqueous fenfluramine solution is aerosolized and then directed to the nose or lungs of the subject.
Before the present methods of treatment are described, it is to be understood that this invention is not limited to particular method described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a step of administering” includes a plurality of such steps and reference to “the symptom” includes reference to one or more symptoms and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Definitions
The term “fenfluramine” refers to both the free base depicted in Structure 1 and its pharmaceutically acceptable salts thereof. Pharmaceutically acceptable acid addition salts are those formed from acids which form non-toxic acid anions such as, for example, the hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts.
Fenfluramine was first approved in 1976 as an anoretic agent. The mechanism of action of fenfluramine in promoting weight loss during the 1970's and 1980's was unclear, but thought to be related to brain levels (or turnover rates) of serotonin or to increased glucose utilization. The anti-appetite effects of fenfluramine have been shown to be suppressed by serotonin-blocking drugs and by drugs that lower brain levels of this amine neurotransmitter. Furthermore, decreased serotonin levels produced by selective brain lesions have been shown to suppress the action of fenfluramine. Fenfluramine was approved for use in the treatment of Dravet Syndrome, a childhood epileptic encephalopathy, in June 2020 Additional research done on the mechanism of action of fenfluramine has demonstrated interference with serotonin synaptic reuptake and triggering the release of serotonin in the brain due to disruption of its vesicular storage.
The effects of dexfenfluramine (d-Fen, the d-enantiomer component of racemic fenfluramine) on lymphocytes in HIV+ and HIV-comparators. It was found that dexfenfluramine increased the amount of the cytokine IL-2 produced by CD4+ and CD8+ lymphocytes from HIV+ patients. d-FEN increased the number of CD4+ and CD8+ lymphocytes that produced IFN-gamma from either HIV+ or HIV-patients and increased the number of HIV+ patient's CD8+ lymphocytes that produce TNF-alpha [Int J Immunopharmacol.; 20(12):751-63 (December 1998)].
Data from even more recent studies provide evidence that fenfluramine is a positive allosteric modulator of the sigma-1 receptor. [P. Martin, et al., Poster 2.032; 71st Annual Meeting of the American Epilepsy Society, Dec. 1-5, 2017, Washington, D.C.]. The Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator, is involved in restoring homeostasis and modulation of many biological mechanism associated with neurodegeneration. Thus sigma-1 agonists are useful in providing neuroprotection and restoration and maintenance of neuronal signaling pathways. Methods of using fenfluramine in a method for improving cognition and slowing or halting cognitive decline have been disclosed in WO2020105005. Studies combining low doses of fenfluramine or (+)-fenfluramine and PRE-084 (a sigma-1 agonist) followed by calculation of combination indexes (Maurice, 2016) showed that most combinations led to synergistic effects in several animal models. Racemic fenfluramine, as well as its active isomer (+)-fenfluramine, behaved in vitro and in vivo as Sig1R positive modulators. [Maurine, T., et al., Soc. Neurosci. Abstr. 692]
US201916360375 to Fekete and Vannay describes the use of sigma-1 ligands in methods of lessening or preventing tissue scarring including lung fibrosis. Sigma-1 receptor plays an important role in the functioning of tissues associated with the endocrine, immune and nervous systems.
The terms “cytokine release syndrome” (CRS) and “cytokine storm” are used interchangeably herein to describe exaggerated, excessive synthesis of certain cytokines such as IL-6 in response to any type of stress/trauma including infection with a pathogen, chemical exposure and physical trauma. The term is used to refer to the result of infection known to be capable of producing CRS. The stress may be a stress induced by viral infection and more particularly viral infection caused by infection with any virus, including COVID-19 which can produce CRS. The cytokine level is exaggerated or excessive when it reaches a level which is no longer beneficial. Such a level may generate a systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic, lympho-histiocytosis. These responses can result in a range of undesirable results including organ failure and death.
Two viral entry points were identified in April 2020 after researchers demonstrated that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. [Hoffmann, M., et al., Cell; 181(2):271-280. (2020.] More recently, in vitro infectivity assays in Vero 6 cells have highlighted sigma receptors land 2 in the endoplasmic reticulum as two (among several other receptor targets) as potential candidates for drug development to combat SARS-CoV-2 after demonstrating that sigma 1 and sigma 2 receptors are “hijacked” by SARS-CoV-2 proteins, Nsp6 and ORF9c, respectively. [Nature Biotechnology Vol. 38 p. 655-664 (June 2020)]. The sigma 1 receptor, which carries out Ca2+ signaling in the endoplasmic reticulum's mitochondria-associated membrane, is known to promote cell survival, activate the unfolded protein response, mediate lipid remodeling and influence autophagosome-lysosome fusion. Three generic drugs, hydroxy-chloroquine, haloperidol and clemastine were tested and shown to inhibit SARS-CoV-2 in vitro through this mechanism.
Haloperidol binds in the low nM range to both sigma-1 and sigma-2 receptors. Chloroquine, which is currently in clinical trials for COVID-19 has mid-nM activity at the Sigma1 receptor, and low uM activity against the Sigma2 receptor. Fenfluramine has been reported to have a Ki of 266 nM in a non-selective sigma binding assay. [Martin, P., et al., Epilepsy & Behavior 105 (2020) 106989; //doi.org/10.1016/j.yebeh.2020.106989]
Additionally, reduction of the level of Sigma-1 receptors in human cells has recently been shown to slow or prevent SARS-CoV-2 viral replication in human cells and sigma-2 receptor (also referred to as TMEM97; https://www.uniprot.org/uniprot/Q5BJF2), has also be implicated in SARS-CoV-2 infection and is an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter NPC1 [Alon, A., et al., Proc. Natl. Acad. Sci. U.S.A. 114:7160-7165 (2017)]
The term “ZX008” refers to fenfluramine hydrochloride formulated as an oral solution.
The term “reduction from baseline” is used throughout in order to refer to a reduction relative to the same or similar patient prior to administration of fenfluramine. During the baseline period, the patient is treated with other therapeutic agents, except for fenfluramine. Treatment with the same other therapeutic agents is substantially maintained during the treatment with fenfluramine. The comparison is made relative to the observations, measurements or tests made during the baseline period.
The term metered-dose inhaler (MDI) is a device that delivers a specific amount of medication such as a formulation of fenfluramine to the lungs, in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The fenfluramine medication could be administered via a metered dose inhaler along with a bronchodilator, corticosteroid or a combination of both.
A metered-dose inhaler consists of three major components; the canister which is produced in aluminum or stainless steel by means of deep drawing, where the formulation resides; the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and an actuator (or mouthpiece) which allows the patient to operate the device and directs the aerosol into the patient's lungs. The formulation itself is made up of the fenfluramine drug, a liquefied gas propellant and, in many cases, stabilizing excipients. The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination.
To use the inhaler the patient presses down on the top of the canister, with their thumb supporting the lower portion of the actuator. Actuation of the device releases a single metered dose of the formulation which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled.
An inhaler (also known as a puffer, pump or allergy spray) is a medical device used for delivering formulations of fenfluramine into the lungs through the work of a person's breathing. This allows formulations of fenfluramine to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with asthma and chronic obstructive pulmonary disease (COPD) being among the most notable.
Some of the common types of inhalers include meter-dosed inhalers, dry powder inhalers, soft mist inhalers, and nebulizers. Each device has advantages and disadvantages and can be selected based on specific patient needs, as well as age, coordination, and lung function. Proper education on inhaler use is important to ensure that inhaled medication takes its proper effects in the lungs.
Meter-Dosed Inhalers (MDI)
The most common type of inhaler is the pressurized metered-dose inhaler (MDI) which is made up of 3 standard components—a metal canister, plastic actuator, and a metering valve. The medication is typically stored in solution in a pressurized canister that contains a propellant or suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in aerosol form through the actuator and into a patient's lungs. These devices require significant coordination as a person must discharge the medication at or near the same time that they inhale in order for the medication to be effective.
Different Types of Dry Powder Inhalers
Dry Powder Inhalers (DPI)
Dry powder inhalers release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. This device usually contains a chamber in which the powdered medication is deposited prior to each dosage. The powder can then be inhaled with a quick breath. This allows for medication to be delivered to the lungs without the need for use of propellant/suspension.
Soft mist inhalers release a light mist containing medication without the need for a propellant/suspension. Upon pressing a button, the inhaler creates a mist of medication, allowing for inhalation into the lungs. SMIs suspend inhaled medications for roughly 1.2 seconds, which is longer than the average MDI inhaler suspension time period. This requires less coordination when using and may be helpful for young patients or patients that find the MDI inhalers difficult to use.
Nebulizers
Nebulizers are designed to deliver medications over an extended period of time over multiple breaths through a mouthpiece or face mask. They generate a continuous mist with aerosolized medication, allowing a patient to breath normally and receive medications. They are commonly used in infants and toddlers requiring inhaled medications or in patients in the hospital who require inhaled medications.
An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart.
Echocardiography uses standard two-dimensional, three-dimensional, and Doppler ultrasound to create images of the heart.
Echocardiography has become routinely used in the diagnosis, management, and follow-up of patients with any suspected or known heart diseases. It is one of the most widely used diagnostic tests in cardiology. It can provide a wealth of helpful information, including the size and shape of the heart (internal chamber size quantification), pumping capacity, and the location and extent of any tissue damage. An echocardiogram can also give physicians other estimates of heart function, such as a calculation of the cardiac output, ejection fraction, and diastolic function (how well the heart relaxes), and further allows a determination of pulmonary artery blood pressure. An echocardiogram can determine if a patient has certain heart value irregularities that would place the patient in a group that fenfluramine should not be administered to. An echocardiogram can also assess pulmonary arterial hypertension which may be related to the respiratory dysfunction brought about the COVID-19 infection. Administration of fenfluramine via any of the pulmonary inhalation technologies described herein can reduce first pass hepatic metabolism of fenfluramine to the metabolite fenfluramine and thus lessen or prevent the side effects of cardiac valvulopathies and/or pulmonary arterial hypertension in a patient receiving fenfluramine inhalation therapy.
Echocardiography is an important tool in assessing wall motion abnormality in patients with suspected cardiac disease. It is a tool which helps in reaching an early diagnosis of myocardial infarction showing regional wall motion abnormality of the heart. Also, it is important in treatment and follow-up in patients with heart failure, by assessing ejection fraction. Patient given formulations of fenfluramine should have a follow-up echocardiogram to confirm that the patient is not developing heart value problems that could be related to the formulations of fenfluramine
Echocardiography can help detect pulmonary arterial hypertension (PAH), cardiomyopathies, such as hypertrophic cardiomyopathy, dilated cardiomyopathy, and many others. The use of stress echocardiography may also help determine whether any chest pain or associated symptoms are related to heart disease. The biggest advantage to echocardiography is that it is not invasive (does not involve breaking the skin or entering body cavities) and has no known risks or side effects.
Specific Aspects of the Invention
Provided is a method of treating a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising: determining the patient has been infected with SARS-CoV-2; and administering to the patient a therapeutically effective dose of fenfluramine.
In one aspect, the administration of fenfluramine via oral, parenteral or inhalation routes prevents or interferes with SARS-CoV-2 replication.
In another aspect, the administration of fenfluramine via oral, parenteral or inhalation routes prevents or lessens scarring in the lungs. In an embodiment, the administration of fenfluramine is via inhalation into the lungs.
In yet another aspect, the administration of fenfluramine is administered prophylactically via oral, parenteral or inhalation routes. In an embodiment, the prophylactic administration is via inhalation into the lungs. In another embodiment, the prophylactic administration is via an oral solid or liquid dosage form.
In still another aspect, the administration of fenfluramine via oral, parenteral or inhalation routes promotes an immune response to SARS-CoV-2 infection.
In some cases, the administering is performed for 5 days or more, such as 10 days or more or 15 days or more.
In some cases, the method further includes administering a co-therapeutic agent. The term “co-therapeutic agent” refers to a compound other than fenfluramine that has a therapeutic effect on a patient who is administered the co-therapeutic agent. In some cases the co-therapeutic agent is selected from the group consisting of: an anti-viral agent, zinc, and an immunomodulatory agent.
The co-therapeutic agent can be an anti-viral agent. In some cases the anti-viral agent is selected from the group consisting of: Remdesivir (a nucleotide analog that acts against SARS-CoV-2 by inhibiting RNA polymerase), a monoclonal antibody, convalescent plasma from a subject who had previously been infected with SARS-CoV-2 and which comprises antibodies for SARS-CoV-2, a viricide, amantadine, rimantadine, and a nucleoside analog. Exemplary nucleoside analogs include acyclovir and zidovudine (AZT). In some cases, the co-therapeutic agent is zinc.
In some cases, the method further includes administering a immunomodulatory co-therapeutic agent. The co-therapeutic agent can be an immunosuppressive agent. Exemplary immunosuppressive agents suppress cytokine production or produce inhibition to regulate the immune response, such as, interleukin-1 (IL-1) inhibitors e.g., anakinra, and/or interleukin-6 (IL-6) inhibitors e.g., toxilizumab, sarilumab or siltuximab.
In some cases, the therapeutically effective dose ranges from 0.5 mg to 500 mg of fenfluramine per day, such as 1 mg to 250 mg, 5 mg to 100 mg, and 10 mg to 50 mg. In some cases, the dose is 250 mg or less per day, such as 100 mg or less, 100 mg or less, or 50 mg or less. In some cases, the dose is 5 mg or more of fenfluramine per day, such as 10 mg or more, or 25 mg or more. In some cases, the dose is part of an aqueous composition. In some cases the therapeutically effective dose is dissolved in water. In some cases the therapeutically effective dose is dispersed in water.
In some cases, the patient is diagnosed with a secondary bacterial infection, and the method further includes administering an antibiotic to the patient.
The dose of fenfluramine administered in the methods of the present invention can be formulated in any pharmaceutically acceptable dosage form including, but not limited to oral dosage forms such as tablets including orally disintegrating tablets, capsules, lozenges, oral solutions or syrups, oral emulsions, oral gels, oral films, buccal liquids, powder e.g. for suspension, and the like; injectable dosage forms; transdermal dosage forms such as transdermal patches, ointments, creams; inhaled dosage forms; and/or nasally, rectally, vaginally administered dosage forms. Such dosage forms can be formulated for once a day administration, or for multiple daily administrations (e.g. 2, 3 or 4 times a day administration).
The dosage form of fenfluramine employed in the methods of the present invention can be prepared by combining fenfluramine with one or more pharmaceutically acceptable diluents, carriers, adjuvants, and the like in a manner known to those skilled in the art of pharmaceutical formulation.
Examples of processes for synthesizing fenfluramine are provided in the following documents: GB1413070, GB1413078 and EP441160. An example of a fenfluramine drug product synthesis is provided in US20180148403 and issued U.S. Pat. Nos. 10,351,509; and 10,351,510 all incorporated herein by reference.
The dose of fenfluramine to be used in a method of the present invention can be provided in the form of a kit, including instructions for using the dose in one or more of the methods of the present invention. In certain embodiments, the kit can additionally comprise a dosage form comprising one or more co-therapeutic agents. The kit may also contain directions for initiating fenfluramine therapy in a patient, in some instances the direction may take into account co-administration with other interacting antiviral drugs and provide alternate dosing instructions when the patient also receives those drugs concomitantly.
In some cases, the fenfluramine is free base fenfluramine. In other cases, the fenfluramine is a pharmaceutically acceptable salt of fenfluramine, such as fenfluramine hydrochloride.
It is known the fenfluramine can have effects on the operation of the heart. Such effects were seen historically mainly in patients treated at daily doses of 60 mg/day or more for a period of months However, it is desirable to assess the risk of administering fenfluramine to the patient and weight these risks versus the potential advantages of administering fenfluramine for treating COVID-19. As such, in some cases the method further comprises performing an echocardiogram (ECHO) and/or an electrocardiogram (EKG) on the patient before the administering, wherein the patient was determined to have a heart healthy enough for administration of fenfluramine.
In some cases the patient is diagnosed with one or more conditions selected from the group consisting of: chronic kidney disease, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, a compromised immune system, a body mass index (BMI) of 30 or more, heart failure, coronary artery disease, cardiomyopathy, sickle cell anemia, and type 2 diabetes mellitus.
In some cases a medical professional has determined that the subject is at risk for experiencing a cytokine storm.
Also provided is a kit comprising a container comprising fenfluramine and instructions directing a healthcare professional to administer the fenfluramine to the patient. In some cases, the fenfluramine is present in an aqueous fluid. In some cases, the kit contains information for the physician of the need to have an echocardiogram performed in order to determine if the patient can safely be treated with fenfluramine. In some cases, the kit contains informs the physician that fenfluramine stimulates an immune response in immunocompromised patients.
Mechanism of Action
Without intending to be limited by any particular mechanism of action, the following describes how fenfluramine aids in the treatment of a patient infected with SARS-CoV-2.
First, fenfluramine impedes the virus's ability to hijack the patient's cellular machinery. The Nsp6 protein of SARS-CoV-2 has been found to interact with sigma-1 and sigma-2 receptors (Gordon et al, Nature, 2020, doi: 10.1038/s41586-020-2286-9), which are proteins at the endoplasmic reticulum (ER). Gordon also reported that drugs which are predicted regulators of sigma-1 and sigma-2 receptors resulted in antiviral activity in several viral assays. Thus, by interfering with the interaction of Nsp6 with sigma-1 reduces the possibility of a SARS-CoV-2 infection.
Furthermore, fenfluramine is a positive modulator of sigma-1 receptors (Martin et al, Epilepsy & Behavior, 2020, doi: 10.1016/j.yebeh.2020.106989). Hence, administration of fenfluramine might inhibit SARS-CoV-2 infectivity by modulating the sigma-1 receptor and preventing it from being successfully used by the Nsp6 protein of SARS-CoV-2.
Second, fenfluramine increases the number and responsiveness of immune cells to SARS-CoV-2. D-fenfluramine has been shown to increase the local immune response to the opportunistic microbial pathogen of Candida albican (Mathews et al, Behavior Brain Research, 1996, doi: 10.1016/0166-4328(96)00117-9). Specifically, D-fenfluramine administration resulted in “marked increase in CD3+ and CD8+ lymphocytes [and] a modest increase in the numbers of NK1.1+ cells” (abstract). In addition, long term exposure to D-fenfluramine avoided the age-related decline in levels of natural killer and T cells (Clancy et al, Behavior Brain Research, 1996, doi: 10.1016/0166-4328(96)00114-3). Specifically, 15-month-old rats with long term fenfluramine administration had immune cell levels that were similar to 7-month-old rats that had not received fenfluramine. Hence, fenfluramine increases the number and responsiveness of immune cells.
Third, fenfluramine aids in preventing the body from mounting an overactive immune response, thereby avoiding the dangers of a cytokine storm. Patients with COVID-19 have been observed to have upregulation of pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF), TNF-alpha, and interferon-gamma. The highest levels of TNF-alpha, IL-6, and IL-10 have been associated with a more marked reduction in T-cell counts, both CD8+ and CD4+. In addition, it has been observed that fenfluramine administration has suppressed the production of pro-inflammatory cytokines interleukin-1beta and TNF-alpha in response to an in vivo lipopolysaccharide challenge (Connor et al, European Journal of Pharmacology, 2002, doi: 10.1016/S0014-2999(02)02588-8). Hence, fenfluramine administration downregulates some of the pro-inflammatory cytokines, thereby reducing the chance of a dangerous and potentially fatal cytokine storm.
Interleukin-6 (IL-6) is normally secreted transiently in response to injury or infections. However, unregulated synthesis and secretion of IL-6 has contributed to a host of pathological effects such as rheumatoid arthritis. Furthermore, IL-6 induces differentiation of B cells and naïve CD4+ T cells and inhibits TGF-beta differentiation, providing a crucial link between innate and acquired immune responses. These actions place IL-6 in a central role in mediating and amplifying cytokine release syndrome, commonly associated with Ebola and SARS-COV-2 infections, and other types of trauma and infections.
Elevated IL-6 was found to be significantly correlated with death in COVID-19 patients Originally developed for the treatment of arthritis, anti-IL-6R mAbs have been used to treat CRS as a complication of cancer therapy using adaptive T-cell therapies.
The severity of SARS-CoV-1 infection is associated with increased serum concentrations of IL-6 and as such the administration of fenfluramine decreases concentrations of IL-6 and treats adverse effects of SARS-CoV-1 infection.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.
Cell Preparation:
The cell line utilized for the infection was human lung epithelial (Calu-3) cells (ATCC® HTB-55™). These cells were grown from a frozen aliquot of a laboratory working cell line. Passage number is limited to no more than 30 passages from the original aliquot. Cells were grown in T150 flasks in 1×DMEM (ThermoFisher cat. no. 12500062) supplemented with 2 mM L-glutamine (Hyclone cat. no. H30034.01), non-essential amino acids (Hyclone cat. no. SH30238.01), 25 mM HEPES (HyClone cat. no. 16777-032) and 10% Fetal Bovine Serum (FBS) (Atlas Biologicals cat. no. EF-0500-A). Serum was heat-inactivated for infections.
On the day previous to executing the assay, Calu-3 cells were removed from T150 flasks by trypsinization (0.25% Trypsin, Corning cat. no. 25-053-C1) and measured for count and viability by Hemocytometer in trypan blue. Cells were resuspended to 1.3×105 cells/mL in 1×DMEM, and plated at 150 μl (0.15 mLs) per well for a density of 20,000 cells/well in 96 well plate. The plates were then incubated for approximately 24 hours to allow cell adherence at 37° C., 5% CO2. Cell passage used was 20.
Virus Stocks:
The virus strain used for the assay was the mNeonGreen SARS-CoV-2 provided by the World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch, Galveston, Tex. (Xie et al, 2020). This reporter virus was constructed from the virus strain (2019-nCoV/USA_WA1/2020) isolated from the first reported SARS-CoV-2 case in the US (Harcourt et al., 2020, Holshue et al., 2020). Virus stocks were amplified in Vero E6 cells to Passage 1 (P1) with a titer of 9.7×105 PFU/mL. Stocks were stored at −80° C. Virus infection of indicated wells were carried out with an MOI=0.5 and 0.1.
Assay Setup:
1. Fenfluramine was diluted to 50 μM in cell culture media which is described above.
2. Pre-treatment: Media was aspirated from the 96 wells, 100 μL of the compound dilution (and vehicle control) was added to cells as shown above in the plate map, and the plate(s) incubated at 37° C./5% CO2 for 1 hour.
3. After the pre-treatment, virus (MOI 0.5 or 0.1, see plate map) was added dropwise into the media, plates were sealed with Aeroseal and incubated for 72 hr at 37° C./5% CO2.
4. Cytotoxicity assays were conducted in parallel, for these no virus was added.
5. At 72 hr, supernatants were harvested and stored at −80 C. Infected cells were imaged using the Celigo imaging Cytometer (Nexcelom Bioscience).
a. Cell viability: was assessed by staining cells with the ViaStain™ Calcein AM/Hoechst/PI Viability Kit (Nexcelom, Cat #CS5-V006-1) per manufacturer's instructions and imaging with the Celígo Imaging Cytometer (Nexcelom). Briefly, live and metabolically active cells were detected using the Calcein AM stain (Ex/Em: 488/520). Dead cells were detected using the propidium iodide stain (PI, Ex/Em: 493/636). Total number of cells were detected using the Hoechst-nuclear stain (Ex/Em: 352/461). Thus, cell viability was assessed by comparing live cells counts (normalized to total cell count) across treatment groups, and cell cytotoxicity was assessed through comparison of dead cell counts (normalized to total cells) across treatment groups.
b. Viral replication: cells were infected with the mNeonGreen SARS-CoV-2 reporter virus (provided by The World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch, Galveston, Tex.). Following infection for 72 hr, media was aspirated from cells, and cells were washed with 1×PBS. Cells were then stained with Hoechst nuclear stain (Nexcelom, Cat #CS1-0128) according to manufacturer's instructions and imaged with the Celígo Imaging Cytometer (Nexcelom). SARS-CoV-2 replication was detected and quantified using the mNeonGreen reporter fluorescence (Ex/Em: 506/517 nm). The total number of cells were quantified using Hoechst-nuclear staining (Ex/Em: 352/461). Reporter expression values (fluorescence at 517 nm) were normalized to total cell count, and then compared among treatment groups.
Results:
It was found SARS-CoV-2 viral replication was statistically significantly (p<0.0001) lower in samples of Calu-3 cells that were administered 50 mM of fenfluramine compared control cells receiving only vehicle. In particular, the average viral replication for the control cells was approximately 7-103 whereas the average viral replication for the fenfluramine-contacted cells was about 2·103, as shown in
It is hypothesized that fenfluramine has the lysosomotropism property. Fenfluramine might act as a positive allosteric modulator of sigma-1. Vela, Jose Miguel (Frontiers in Pharmacology, 2020, 11:582310, “Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?”, doi: 10.3389/fphar.2020.582310), describes sigma-1 ligands and lysosomotropism.
Cell Preparation:
The cell line utilized for the infection and plaque assays is Vero E6 cells (ATCC® CRL-1586). These cells were grown from a frozen aliquot of a laboratory working cell line. Passage number is limited to no more than 50 passages from the original aliquot. Cells were grown in T150 flasks in 1×DMEM (ThermoFisher cat. no. 12500062) supplemented with 2 mM L-glutamine (Hyclone cat. no. H30034.01), non-essential amino acids (Hyclone cat. no. SH30238.01), and 10% heat inactivated Fetal Bovine Serum (FBS) (Atlas Biologicals cat. no. EF-0500-A).
On the day previous to executing the assay, Vero E6 cells were removed from T150 flasks by trypsinization (0.25% Trypsin, Corning cat. no. 25-053-C1) and measured for count and viability by Hemocytometer in trypan blue. Cells were resuspended to 2.3×105 cells per mL in 1×DMEM (supplemented as indicated above) and plated at 0.15 mLs per well (35,000 cells/well) in 96-well plates. The plates were then incubated for approximately 24 hours to allow cell adherence at 37° C., 5% CO2.
Virus Stocks:
The virus strain used for the assay was SARS-CoV2, USA WA 01/2020, CSU V2 03/17/202 passage 3. Virus stocks were obtained from BEI Resources and amplified in Vero E6 cells to Passage 3 (P3) with a titer of 5.5×105 PFU/mL. Stocks were stored at −80° C. Virus infection of indicated wells were carried out with an MOI=0.1.
3. Pre-treatment: Media was aspirated from the 96 wells, 100 □L of the compound dilutions (and controls) as shown above in the plate map were added, and the plate(s) incubated at 37° C./5% CO2 for 1 hr.
4. After the pre-treatment, virus (MOI 0.1) was added dropwise into the media, plates were sealed with Aeroseal and incubated for 72 hr at 37° C./5% CO2. For cytotoxicity assays, no virus was added.
5. At 72 hr, supernatants were harvested and stored at −80 C. Cytoprotection was measured using neutral red.
a. Neutral red (NR) solution (0.33% NRS, Sigma Aldrich cat. no. N2889) maintained at room temperature was diluted 1:24 in 10% 1×DMEM warmed to 37° C. Immediately after dilution the solution was centrifuged at 4000 rpm in a table top centrifuge for 30 min (to remove any NR crystals)
b. The diluted NR solution was added to the cells (150 □l/well)
c. The plate was incubated at 37° C., 5% CO2 for approximately 2 hours
d. NR solution was removed, and NR solubilization solution (1% glacial acetic acid in 50% ethanol) was added to each well at 150 μl/well. Plates were incubated at room temperature for 10 minutes, and solubilization solution mixed by pipetting
e. 130 μL from each well was transferred to a new plate
f. Absorbance was read on a plate reader at 540 nm.
Results:
The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art and are to be construed as being without limitation to such specifically recited examples and conditions.
Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
This application claims priority to U.S. Provisional Applications 63/053,162, filed Jul. 17, 2020; 63/054,397, filed Jul. 21, 2020; and 63/058,334, filed Jul. 29, 2020, which are incorporated herein by reference.
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20220016053 A1 | Jan 2022 | US |
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63058334 | Jul 2020 | US | |
63054397 | Jul 2020 | US | |
63053162 | Jul 2020 | US |