WO2021191108A1 - Treatment or prevention of acute organ damage induced by viral infection with a nk1 inhibitor and/or a gabapentinoid - Google Patents
Treatment or prevention of acute organ damage induced by viral infection with a nk1 inhibitor and/or a gabapentinoid Download PDFInfo
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- WO2021191108A1 WO2021191108A1 PCT/EP2021/057190 EP2021057190W WO2021191108A1 WO 2021191108 A1 WO2021191108 A1 WO 2021191108A1 EP 2021057190 W EP2021057190 W EP 2021057190W WO 2021191108 A1 WO2021191108 A1 WO 2021191108A1
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- Prior art keywords
- treatment
- inhibitor
- aprepitant
- gabapentinoid
- gabapentin
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the present invention relates to the treatment or prevention of acute organ damage and/or cytokine storm, particularly as induced by viral infection, using (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt of either thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof, wherein (a) and (b) may be administered alone or in combination.
- a NKi inhibitor which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt of either thereof
- a gabapentinoid which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof
- SARS severe Acute Respiratory Syndrome
- SARS severe Acute Respiratory Syndrome
- MERS Middle East respiratory Syndrome
- SARS and MERS are associated with virus infection, among which the coronavirus (CoV) family is particularly prominent (Stark and Atreya 2005), as well as the influenza virus family.
- Coronaviruses can be subdivided into three groups based on genetic and serological markers (Gonzalez et al. 2003) and have the ability to induce lung, kidney, and other organ damage that produces SARS. To date, more than 60 SARS -inducing coronavirus (SARS-CoV) genomic sequences have been analysed (He et al. 2004).
- SARS-CoV SARS -inducing coronavirus
- SARS and MERS in general cause high pathogenicity and mortality rates in human populations (Song et al. 2019), in some cases causing fatal Acute Lung Injury (ALI) (Yue et al. 2018).
- Newly-emerging coronavirus strains e.g. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- influenza virus strains e.g. H7N9
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- H7N9 influenza virus strains
- Macroscopic examination at autopsy indicates that lungs in deceased patients with fatal ALI (such as in SARS) are characterised by:
- Thrombus present at pulmonary artery 4.
- mice in deceased patients with fatal ALI are characterised by:
- Endothelial cells of small pulmonary veins swollen and shed.
- Oedema present in the walls of small veins and some veins showed fibrinoid necrosis with infiltration of monocytes, neutrophils, and lymphocytes.
- ACE2 angiotensin-converting enzyme 2
- ACE2 angiotensin-converting enzyme 2
- ACE2 is widely expressed on the epithelial cells of alveoli, trachea, bronchi, bronchial serous glands (Liu et al. 2011), and alveolar monocytes and macrophages (Kuba et al. 2005).
- the virus enters and replicates in these target cells.
- ACE2 is also diffusely localized on the endothelial cells of arteries and veins, the mucosal cells of the intestines, tubular epithelial cells of the kidneys, epithelial cells of the renal tubules, and cerebral neurons and immune cells, providing a variety of susceptible cells to SARS-CoV (Guo et al. 2008) (Gu and Korteweg 2007).
- CD209L is an alternative receptor with a much lower affinity (Jeffers et al.
- the primary receptor is a multifunctional cell surface protein, dipeptidyl peptidase 4 (DPP4, also known as CD26) (Meyerholz, Lambertz, and McCray 2016), which is widely expressed on epithelial cells in the kidney, lung alveoli, small intestine, liver, and prostate, and on activated leukocytes (Widagdo et al. 2016).
- DPP4 dipeptidyl peptidase 4
- CD26 dipeptidyl peptidase 4
- MERS-CoV can infect several human cell lines, including lower respiratory, kidney, intestinal, and liver cells, as well as histiocytes, as shown by a cell-line susceptibility study (Oboho et al. 2015), indicating that the range of MERS-CoV tissue tropism in vitro was broader than that of any other CoV. MERS-CoV causes acute, highly lethal pneumonia and renal dysfunction (Oboho et al. 2015).
- NKi neurokinin 1
- NKi inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting.
- Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer. The latter is discussed, for example, in EP 2 837 381 Al.
- Other NKi inhibitors are well known to those skilled in the art.
- Gabapentinoids also known as a2d ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter g-aminobutyric acid (GABA) (i.e., GABA analogues) which block a2d subunit-containing voltage-dependent calcium channels (VDCCs), sometimes referred to as the gabapentin receptor.
- GABA inhibitory neurotransmitter g-aminobutyric acid
- VDCCs voltage-dependent calcium channels
- Clinically-used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil.
- Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome.
- Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal.
- NKi inhibitors and/or gabapentinoids may be efficacious in the treatment or prevention of acute organ damage induced by viral infection.
- a NKi inhibitor and/or a gabapentinoid is effective at treating and/or preventing development of the macroscopic and microscopic characteristics of a model of SARS-type lung injury.
- administration of a NKi inhibitor and/or a gabapentinoid is effective at down-regulating expression of the molecular targets of SARS-inducing coronaviruses and coronavirus-like viruses, and MERS-inducing coronaviruses, on both lung and renal cells.
- the administration may also prevent development and progression of the underlying viral infections.
- the available clinical evidence in COVID-19 patients supports these findings.
- the present invention provides a pharmaceutical composition which comprises:
- a gabapentinoid for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection.
- the present invention also provides a NKI inhibitor for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a gapanetinoid.
- the present invention also provides a gabapentinoid for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally whrerein the method comprises co-administration with a NKI inhibitor.
- the present invention also provides a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, which method comprises administering to said patient (a) aNKl inhibitor and/or (b) a gabapentinoid, optionally wherein (a) and (b) are co-administered.
- the present invention also provides a product comprising (a) a NK1 inhibitor and/or (b) gabapentinoid, optionally wherein (a) and (b) are provided as a combined preparation for simultaneous, concurrent, separate or sequential use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection.
- the present invention also provides use of a NK1 inhibitor in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a gabapentinoid.
- the present invention also provides use of a gabapentinoid in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a NK1 inhibitor.
- the present invention also provides a pharmaceutical composition which comprises:
- the present invention also provides a kit which comprises:
- NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention.
- the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017 (otherwise referred to as tradipitant), L-733,060, L-732,138, L -703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760 735, CP-122721, L-758 298, L-741 671, L-742 694, CP-99994 or T-2328, or a pharmaceutically acceptable salt of any thereof.
- the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, tradipitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.
- the NKI inhibitor is aprepitant, fosaprepitant, or netupitant, maropitant, tradipitant, or a pharmaceutically acceptable salt of any thereof.
- the NKI inhibitor is aprepitant or its prodrug fosaprepitant, or a pharmaceutically acceptable salt of either thereof.
- a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
- Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
- Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
- NKi inhibitor is aprepitant.
- Fosaprepitant is prodrug of aprepitant and has the following structure:
- Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:
- the NKi inhibitor is fosaprepitant dimeglumine.
- compositions comprising fosaprepitant are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.
- aqueous solvent such as saline
- Fosaprepitant is converted in vivo to aprepitant.
- fosaprepitant is converted to aprepitant.
- NK1R inhibitors are beneficial in treating or preventing acute organ damage and/or cytokine storm, particularly as induced by viral infection, by two possible mechanisms.
- NK1R antagonists inhibit Substance P signalling via NK1R and thus reduce both initiation and development of inflammatory processes, particularly in the lung, thereby having an anti-inflammatory effect and preventing / reducing the acute organ damage and/or cytokine storm that may otherwise ensue in viral infections.
- NK1R antagonists may inhibit the expression of ACE2 and CD290L (particularly in the lung) thereby reducing the ability of SARS-inducing coronaviruses and coronavirus-like viruses to bind to and enter cells.
- NK1R inhibitors have shown promising results, particularly in treating acute lung inflammation associated with severe or critical COVID-19 infection.
- the effects may be complementary to antiviral treatments for COVID-19.
- Another trial was a study of aprepitant - see ClinicalTrials.gov Identifier: NCT0446864.
- the study is a randomized controlled trial to investigate the efficacy and safety aprepitant 80 mg orally given daily to treat cytokine storm causing inflammatory lung injury and respiratory failure associated with severe or critical COVID-19 infection.
- Participants are randomized to treatment with either aprepitant or placebo, in addition to dexamethasone (6mg orally given daily) as a standard treatment given to both groups for Covid-19 infection as per the protocol at the treating hospital. An analysis of 41 participants has been published.
- Gabapentinoids are a well-known class of drug that are derivatives of the inhibitory neurotransmitter g-aminobutyric acid (GABA), that is they are GABA derivatives or GABA analogues. These terms may be used interchangeably herein.
- Gabapentinoids block a2d subunit-containing voltage-dependent calcium channels (VDCCs). Any suitable gabapentinoid can be used in the present invention. Typically, the gabapentinoid is gabapentin, pregabalin, mirogabalin, or a gabapentin prodrug, such as gabapentin enacarbil.
- the gabapentinoid is gabapentin or pregabalin.
- the gabapentinoid is a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof: wherein
- Ri is a Ci- 6 alkyl, phenyl, or C3-6 cycloalkyl group
- R2 is a hydrogen or methyl group
- Ri and R 2 together form a C 3-6 cycloalkyl group
- R 3 is a hydrogen, methyl, or carboxyl group.
- Ci - 6 alkyl group may be a straight-chain or branched-chain alkyl group.
- Ci- 6 alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
- a C3-6 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- Ri is a Ci- 6 alkyl, phenyl, or C 3-6 cycloalkyl group
- R 2 is a hydrogen or methyl group
- R 3 is a hydrogen, methyl, or carboxyl group.
- Ri is a Ci- 6 alkyl group, more preferably a -(CH 2 )o- 2 -iC 4 H 9 group and most preferably an -1C 4 H 9 group (i.e., an isobutyl group).
- R 2 is hydrogen.
- R 3 is hydrogen
- a particularly preferred compound of formula (I) is one in which Ri is an -1C4H9 group and R 2 and R 3 are both hydrogen.
- Compounds of formula (I) can contain one or several asymmetric carbon atoms.
- the invention includes the individual diastereomers or enantiomers, and the mixtures thereof.
- the individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
- a particularly preferred compound of formula (I) is pregabalin, i.e. (3S)-3- (aminomethyl)-5-methylhexanoic acid.
- a particularly preferred gabapentinoid is pregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
- Pregabalin has the following structure:
- Another preferred compound of formula (I) is 4-methylpregabalin.
- another particularly preferred gabapentinoid is 4-methylpregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
- Ri and R2 together form a C3-6 cycloalkyl group; and R3 is a hydrogen, methyl, or carboxyl group.
- Ri and R2 together form a cyclopentyl or cyclohexyl group, more preferably a cyclohexyl group.
- R3 is hydrogen.
- another particularly preferred compound of formula (I) is one in which Ri and R2 together form a cyclohexyl group and R3 represents hydrogen.
- This compound is gabapentin.
- a particularly preferred gabapentinoid is gabapentin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
- An example of a prodrug of gabapentin is gabapentin enacarbil.
- Gabapentin has the following structure:
- a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
- Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, hydrosulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, mandelic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
- Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
- a prodrug of a compound of formula (I) is a structural analogue of a compound of formula (I) which is transformed in the body into a compound of formula (I) or a species which mimics the biological activity of the compound of formula (I).
- a prodrug of pregabalin is a structural analogue of pregabalin which is transformed in the body into pregabalin itself or a species which mimics the biological activity of pregabalin.
- a prodrug of gabapentin is a structural analogue of gabapentin which is transformed in the body into gabapentin itself or a species which mimics the biological activity of gabapentin.
- in the body is meant within the human or animal body following administration of the prodrug to the human or animal.
- the compound of formula (I) is not typically formulated as a prodrug.
- the gabapentinoid used in the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example pregabalin or gabapentin or a pharmaceutically acceptable salt thereof. More preferably, the gabapentinoid used in the present invention is a compound of formula (I), for instance pregabalin or gabapentin.
- the patient to be treated is a mammal.
- the patient is a human.
- the patient may have a confirmed or suspected viral infection, which may be a coronavirus infection or an influenza infection.
- the coronavirus may be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), or any related or similar virus.
- SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
- SARS-CoV-1 severe acute respiratory syndrome coronavirus 1
- MERS-CoV Middle East respiratory syndrome-related coronavirus
- the patient may not (yet) exhibit overt symptoms of viral infection, but will typically exhibit one or more symptoms of a disease associated with viral infection, particularly symptoms affecting the respiratory system.
- the patient may be exhibiting one or more symptoms of the coronavirus disease COVID-19.
- Symptoms may include fever, cough, shortness of breath or difficulty breathing, loss of smell and/or taste, tiredness, aches, runny nose, sore throat.
- Confirmation of a viral infection may be made by any suitable assay.
- rRT-PCR real-time reverse-transcription polymerase chain reaction
- Treatment is preferably administered to the patient prior to any respiratory symptom becoming severe.
- Patients who are particularly likely to develop severe symptoms are older people, people with suppressed immunity, and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer. Treatment is particularly suitable for such patients.
- Treatment is preferably administered to prevent, arrest or reverse acute lung injury (ALI) in the patient.
- ALI may be characterised by alveolar-capillary membrane injury, inflammation, and/or increased permeability pulmonary edema.
- the present invention involves the use of (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or gabapentin, or a pharmaceutically acceptable salt of either thereof, alone or in any combination.
- a NKi inhibitor which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof
- a gabapentinoid which is preferably pregabalin and/or gabapentin, or a pharmaceutically acceptable salt of either thereof, alone or in any combination.
- active ingredients herein referred to as “active ingredients”.
- the present invention provides a pharmaceutical composition that comprises: (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; including for use in the treatment or prevention of acute organ damage, particularly when induced by viral infection.
- Pharmaceutical compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.
- the present invention extends to situations where the active ingredients discussed above are co-administered. More than one NKi inhibitor and/or more than one gabapentinoid may be co-administered.
- the active ingredients can be present either in a single pharmaceutical composition or in separate pharmaceutical compositions, including in separate pharmaceutical compositions optimized for administration either by the same mode or a different mode.
- the active ingredients may both be administered intravenously, orally, or by inhalation, either in a single pharmaceutical composition or, more preferably, in separate pharmaceutical compositions.
- the product comprising (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; as a combined preparation for simultaneous, concurrent, separate or sequential use, the product may comprise either a single pharmaceutical composition that comprises both (a) and (b) (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a) and a second (i.e., separate) pharmaceutical composition that comprises (b).
- the product may comprise either a single pharmaceutical composition that comprises both (a) and each of the gabapentinoids (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a), a second (i.e., separate) pharmaceutical composition that comprises the first gabapentinoid, e.g. pregablin, and a third (i.e., separate) pharmaceutical composition that comprises the second gabapentinoid, e.g. gabapentin, and so on for any further gabapentinoid.
- Co-administration of the active ingredients according to the present invention includes simultaneous, separate and sequential administration.
- administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.).
- aprepitant is preferably delivered orally, whereas fosaprepitant is preferably administered intravenously.
- Pregabalin and gabapentin are both typically delivered orally.
- the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate).
- binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium glyco
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
- the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
- the pharmaceutical compositions typically take the form of an aqueous injectable solution.
- suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
- the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler.
- the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant.
- Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydro fluoroalkanes.
- compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art.
- compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
- additional active ingredients such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
- the compositions of the invention do not contain any further active ingredients (i.e. the pharmaceutical compositions contain only (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof.
- Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations.
- Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.
- NKi inhibitors such as aprepitant and fosaprepitant, and pharmaceutically acceptable salts thereof, are currently approved for use in treating nausea and vomiting in patients, including those suffering from cancer who may also be suffering from nausea and vomiting as a result of chemotherapy and/or surgery . It is thus preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating nausea and vomiting, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
- Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome.
- gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. It is thus preferred in the present invention that the gabapentinoid is not prescribed and/or administered to the patient for the purpose of treating any of these indications, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
- SARS is characterized by haemorrhagic fluid in pleural cavity, localized haemorrhage under pleura, pleural adhesions and focal sub-pleural haemorrhage, thrombus present at pulmonary artery, lung bilateral consolidation (focal or extensive), red-coloured haemorrhagic infarct present at cut surface of lung and focal haemorrhage in mucosa, blood-stained purulent or pale red fluid in lumen, congestion and focal haemorrhage in mucosa at the level of trachea.
- the present inventors have observed that these characteristics are mirrored in ALI induced in rabbits by inhalation of sodium hypochlorite solution. This inhalation model is therefore used as a surrogate for ALI induced by viral infection.
- New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a group of 3 rabbits (Group 1) was administered an oral dose of aprepitant at 10 mg/kg body weight per day, another group of 3 rabbits (Group 2) was administered an oral dose of 40 mg/kg body weight per day, a third group (Group 3) was administered an oral dose of 80 mg/kg body weight per day and a fourth group (Group 4) was administered an oral dose of lOOmg/kg body weight per day.
- aprepitant was administered as an aerosol by inhalation, also from days 3 to 7, to a group of 3 rabbits (Group 5) at a dose of 0.05 mg/kg body weight per day, to another group of three rabbits (Group 6) at a dose of 0.1 mg/kg body weight per day, to another group of three rabbits (Group 7) at a dose of 0.2 mg/kg body weight per day and to another group of three rabbits (Group 8) at a dose of 0.4 mg/kg body weight per day.
- a placebo consisting only of aerosol with no drug added administered from days 3 to 7 to a group of 3 rabbits (Placebo Group; Group 9).
- 3 rabbits were kept under identical conditions but were not administered any treatment nor the aforementioned sodium hypochlorite solution (Control Group; Group 10).
- Aerosol was administered by means of a paediatric inhalation mask connected to a nebulising system with an air compressor with the following characteristics: particle size of 0.5 to 10 micrometres, average particle size 4 micrometres, compressor pressure range 30 to 36 psi (210 to 250 KPa/2.1 to 2.5 bar), operating pressure range 8 to 16 psi (50 to 100 kPa/0.5 to 1.0 bar), flow rate 6 to 8 litres/min.
- NK1 receptors were incubated in the presence of anti-NKl antibodies (S8305, Sigma-Aldrich) diluted 1:1000 at 4 °C overnight. After this time they were washed in 0.05M Tris buffer at room temperature. Subsequently, Envision System-HRP (Dako) reagents were added for 30 min at room temperature.
- the total number of cells and the number of cells displaying immunostaining were counted in each one of the fields in order to subsequently determine the percentage of cells displaying said immunostaining.
- the sections (slides) stained with hematoxylin/eosin the area occupied by fibrosis was assessed.
- NK1R antagonists prevents and avoids SARS-type lung damage induced at the level of macroscopic autopsy findings.
- This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with NK1 receptor antagonists compared to the control group (untreated), and shows that Aprepitant, induces an improvement thereof when is administered orally or by inhalation.
- the use of non-peptide NK1 receptor antagonists prevents the development and progression of SARS-type ALI.
- NK1R antagonists prevents and avoids SARS-type lung damage induced at the level of microscopic findings.
- This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with NK1 receptor antagonists compared to the control group (untreated), and shows that Aprepitant induces an improvement thereof when is administered orally or by inhalation.
- the use of non-peptide NK1 receptor antagonists prevents the development and progression of progression of SARS-type ALI.
- NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
- NK1 receptor antagonists may prevent the binding of SARS-inducing viruses to lung cells.
- Table 7 Immunohistochemical expression in cases treated with the inhaled Aprepitant drug versus placebo cases in lung.
- the results shown in Table 6 show a reduction of the molecular targets to which SARS- inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group.
- the results shown in Table 7 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group.
- the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as SARS- type ALI.
- NK1R antagonists inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
- results shown in Table 8 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group.
- results shown in Table 9 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group.
- the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
- NK1R antagonists inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
- NK1 receptor antagonists may prevent the binding of MERS-inducing viruses to lung cells.
- results shown in Table 10 show a reduction of the molecular targets to which MERS- inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group.
- results shown in Table 11 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group.
- the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS- type ALI.
- NK1R antagonists inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
- Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with NK1 receptor antagonists. The results obtained show that the NK1 receptor agonist, Aprepitant, induces a reduction thereof when administered as treatment.
- the use of non-peptide NK1 receptor antagonists may prevent the binding of SARS-inducing viruses to renal cells.
- results shown in Table 12 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group.
- results shown in Table 13 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group.
- the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
- NKi inhibitor is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells.
- New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a group of 3 rabbits (Group 11) was administered an oral dose of Pregabalin of 1 mg/kg body weight per day
- another group of 3 rabbits (Group 12) was administered an oral dose of 3 mg/kg body weight per day
- a third group (Group 13) was administered an oral dose of Pregabalin of 5 mg/kg body weight per day
- a fourth group (Group 14) was administered an oral dose of Pregabalin of 7mg/kg body weight per day.
- a group of 3 rabbits (Group 15) was administered an oral dose of 1 mg/kg body weight per day of Pregabalin combined with lOmg/Kg body weight of Aprepitant
- another group of 3 rabbits (Group 16) was administered an oral dose of 3 mg/kg body weight per day of Pregabalin combined with lOmg/Kg body weight of Aprepitant
- a third group (Group 17) was administered an oral dose of 5 mg/kg body weight of Pregabalin per day combined with lOmg/Kg body weight of Aprepitant
- a fourth group (Group 18) was administered an oral dose of Pregabalin of 7mg/kg body weight combined with lOmg/Kg body weight of Aprepitant per day.
- Pregabalin prevents and avoids SARS-type lung damage induced at the level of macroscopic autopsy findings.
- This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with Pregabalin compared to the control group (untreated), and shows that Pregabalin induces an improvement thereof.
- the use of Pregabalin prevents the development and progression of SARS-type ALI.
- the results shown in Table 14 show a reduction of all the macroscopic findings in autopsy in the samples derived from the groups treated with Pregabalin compared to the control group (untreated) and that Pregabalin reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
- Pregabalin prevents and avoids SARS-type lung damage induced at the level of microscopic findings.
- This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with Pregabalin compared to the control group (untreated), and shows that Pregabalin induces an improvement thereof when is administered.
- the use of Pregabalin prevents the development and progression of SARS-type ALL
- the results shown in Table 15 show a reduction of all the microscopic findings in autopsy in the samples derived from the groups treated with Pregabalin compared to the control group (untreated) and that Pregabalin reduces the presence of all unfavourable pathological microscopic findings in autopsy.
- Table 15 Microscopic autopsy findings in cases treated with Pregabalin versus control cases.
- Pregabalin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
- Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of SARS-inducing viruses to lung cells.
- Table 16 Immunohistochemical expression in cases treated with Pregabalin versus control cases in lung.
- Results 2.4 Treatment with Pregabalin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses. Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of SARS-inducing viruses to renal cells.
- SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group.
- Pregabalin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
- results shown in Table 18 show a reduction of the molecular targets to which MERS- inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group.
- Pregabalin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS-type ALI. Results 2.6
- Pregabalin inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
- Pregabalin is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells.
- Example 1 Materials and Methods Conducted in parallel with Example 1. 24 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
- a group of 3 rabbits (Group 19) was administered an oral dose of Gabapentin of 3 mg/kg body weight per day
- another group of 3 rabbits (Group 20) was administered an oral dose of 6 mg/kg body weight of Gabapentin per day
- a third group (Group 21) was administered an oral dose of Gabapentin of 9 mg/kg body weight per day
- a fourth group (Group 22) was administered an oral dose of Gabapentin of 12 mg/kg body weight per day.
- a group of 3 rabbits (Group 23) was administered an oral dose of 1 mg/kg body weight per day of Gabapentin combined with lOmg/Kg body weight of Aprepitant
- another group of 3 rabbits (Group 24) was administered an oral dose of 3 mg/kg body weight per day of Gabapentin combined with lOmg/Kg body weight of Aprepitant
- a third group (Group 25) was administered an oral dose of 5 mg/kg body weight of Gabapentin per day combined with lOmg/Kg body weight of Aprepitant
- a fourth group (Group 26) was administered an oral dose of Gabapentin of 7mg/kg body weight combined with lOmg/Kg body weight of Aprepitant per day.
- This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with Gabapentin compared to the control group (untreated), and shows that Gabapentin induces an improvement thereof.
- the use of Gabapentin prevents the development and progression of SARS-type ALI.
- the results shown in Table 20 show a reduction of all the macroscopic findings in autopsy in the samples derived from the groups treated with Gabapentin compared to the control group (untreated) and that Gabapentin reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
- Table 20 Macroscopic autopsy findings in cases treated with the drug Gabapentin versus control. Results 3.2
- This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with Gabapentin compared to the control group (untreated), and shows that Gabapentin induces an improvement thereof when is administered.
- the use of Gabapentin prevents the development and progression of SARS-type ALI.
- the results shown in Table 21 show a reduction of all the microscopic findings in autopsy in the samples derived from the groups treated with Gabapentin compared to the control group (untreated) and that Gabapentin reduces the presence of all unfavourable pathological microscopic findings in autopsy.
- Table 21 Microscopic autopsy findings in cases treated with Gabapentin versus control cases.
- Treatment with Gabapentin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
- SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group.
- Gabapentin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as SARS-type ALI.
- MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group.
- Gabapentin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS-type ALI.
- MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group.
- Gabapentin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
- Gabapentin is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells. The same may be expected of other gabapentinoids (see Example 2).
- Example 4 assessment of the groups treated with a combination of Aprepitant and Pregabalin (from Example 2)
- Treatment with Aprepitant and Pregabalin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses
- Aprepitant and Pregabalin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
- the use of Aprepitant and Pregabalin reduces the expression of the molecule targets of SARS-inducing coronavirus and coronavirus-like viruses. Reduction is greater than with either drug used separately (compare to Results 1.4 and 2.4). Results 4.5
- Treatment with Aprepitant and Pregabalin inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
- MERS-inducing coronavirus Reduction is greater than with either drug used separately (compare to Results 1.5 and 2.5).
- MERS-inducing coronavirus Reduction is greater than with either drug used separately
- Example 5 assessment of the groups treated with a combination of Aprepitant and
- MERS-inducing coronavirus Reduction is greater than with either drug used separately (compare to Results 1.5 and 3.5).
- MERS-inducing coronavirus Reduction is greater than with either drug used separately (compare to Results 1.6 and 3.6).
- Aprepitant and Gabapentin are shown to be more effective than either drug alone as a treatment for the types of lung damage experienced in S ARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells. The same may be expected of other combinations of NKi inhibitor and gabapentinoids (see Example 4).
- CD209L (L-SIGN) Is a Receptor for Severe Acute Respiratory Syndrome Coronavirus.” Proceedings of the National Academy of Sciences of the United States of America 101 (44): 15748-53. https://doi.org/10.1073/pnas.0403812101.
- a phase III, single center, two-arm, open-label, randomized, controlled study has been designed to evaluate the efficacy and safety of aprepitant plus standard care compared with standard care alone in patients hospitalised with COVID-19. Patients will be randomized in a 1:1 ratio. Patients in all groups will receive the standard care (medications, therapies and interventions per standard hospital treatment protocols) during the study.
- the patients in control group will receive only the standard care whereas the patients in experimental groups will receive aprepitant plus standard care.
- aprepitant treatment will be given for 14 days.
- patients will receive the standard approved dose of aprepitant as a regimen of 125 mg capsule on first day and 80 mg capsule once daily on second to fourteenth days. This dose regimen is based on the recommended dose of aprepitant approved for treatment of chemotherapy induced vomiting and nausea.
- the study will consist of a screening visit of up to 3 days and will continue with the baseline visit at day 0. Screening and baseline visit can occur at the same day, if the participant has met all study inclusion and exclusion criteria. Primary evaluation period will be 21 days, and a final assessment will be performed at day 21 or the day of patient discharged. The table below summarises the study timetable.
- the study has the following primary objectives:
- the study has the following secondary objectives:
- NK1R antagonists inhibit Substance P signalling via NK1R and thus reduce both initiation and development of inflammatory processes, particularly in the lung, thereby having an anti-inflammatory effect and preventing / reducing acute organ damage and/or cytokine storm.
- NK1R antagonists may inhibit the expression of ACE2 and CD290L (particularly in the lung) thereby reducing the ability of SARS-inducing coronaviruses and coronavirus-like viruses to bind to and enter cells.
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Abstract
The present invention relates to the treatment or prevention of acute organ damage and/or cytokine storm, particularly as induced by viral infection, using (a) a NK1 inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt of either thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof, wherein (a) and (b) may be administered alone or in combination.
Description
TREATMENT OR PREVENTION OF ACUTE ORGAN DAMAGE INDUCED BY VIRAL INFECTION WITH A NK1 INHIBITOR AND/OR A GABAPENTINOID
FIELD OF THE INVENTION The present invention relates to the treatment or prevention of acute organ damage and/or cytokine storm, particularly as induced by viral infection, using (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt of either thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof, wherein (a) and (b) may be administered alone or in combination.
BACKGROUND TO THE INVENTION
The clinical symptoms of SARS (Severe Acute Respiratory Syndrome) are accompanied by damage to the lungs (Ding et al. 2003) and acute renal impairment (Chu et al. 2005). SARS is an emerging infectious virus-induced disease characterized by severe clinical manifestations of the lower respiratory tract, known since at least 2003 (Tsang et al. 2003). It can result in diffuse alveolar damage (Song et al. 2019) and renal failure (Chu et al. 2005). Middle East respiratory Syndrome (MERS) is a similar syndrome to SARS. Both SARS and MERS are associated with virus infection, among which the coronavirus (CoV) family is particularly prominent (Stark and Atreya 2005), as well as the influenza virus family. Coronaviruses can be subdivided into three groups based on genetic and serological markers (Gonzalez et al. 2003) and have the ability to induce lung, kidney, and other organ damage that produces SARS. To date, more than 60 SARS -inducing coronavirus (SARS-CoV) genomic sequences have been analysed (He et al. 2004).
SARS and MERS in general cause high pathogenicity and mortality rates in human populations (Song et al. 2019), in some cases causing fatal Acute Lung Injury (ALI) (Yue et al. 2018). Newly-emerging coronavirus strains (e.g. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) and influenza virus strains (e.g. H7N9) can be particularly problematic.
Macroscopic examination at autopsy (Ding et al. 2003) indicates that lungs in deceased patients with fatal ALI (such as in SARS) are characterised by:
1. Haemorrhagic fluid in pleural cavity
2. Localized haemorrhage under pleura, pleural adhesions and focal sub-pleural haemorrhage
3. Thrombus present at pulmonary artery
4. Lung bilateral consolidation (focal or extensive)
5. Red-coloured haemorrhagic infarct present at cut surface of lung
6. Focal haemorrhage in mucosa, blood-stained purulent or pale red fluid in lumen, congestion and focal haemorrhage in mucosa at the level of trachea.
Microscopic examination at autopsy (Ding et al. 2003) indicates that lungs in deceased patients with fatal ALI (such as in SARS) are characterised by:
1. Extensive bilateral consolidation.
2. Severe pulmonary oedema.
3. Haemorrhagic infarction.
4. There was desquamative alveolitis and bronchitis, with proliferation and desquamation of alveolar epithelial cells.
5. Alveolar exudation of mononuclear cells, lymphocytes and plasma cells (CD68, LCA positive).
6. Alveolar oedema.
7. Desquamated epithelial cells enlarged and some had undergone fusion to form syncytia.
8. Extensive hyaline membranes in alveoli.
9. Focal necrosis with infiltration of neutrophils, monocytes, and lymphocytes.
10. Capillaries in interlobular septa and alveolar walls dilated and congested.
11. Alveolar exudates organized and fibrosed.
12. Endothelial cells of small pulmonary veins swollen and shed.
13. Oedema present in the walls of small veins and some veins showed fibrinoid necrosis with infiltration of monocytes, neutrophils, and lymphocytes.
14. Mixed thrombi present in small veins and hyaline thrombi appeared in microvessels.
15. Overall, pulmonary features were of diffuse alveolar damage causing acute respiratory distress syndrome.
Microscopic examination of lungs in MERS animal models and induced- ALI models for other viruses such as H7N9 reveals similar observations to those in SARS, demonstrating infiltration of neutrophils and macrophages and alveolar oedema (Alagaili et al. 2014) (Huang et al. 2015).
Regarding the molecular mechanisms that facilitate the production of SARS in virus infection, it is known that:
1. Upon exposure of the host to the virus, the virus binds to cells expressing the virus receptors, of which the angiotensin-converting enzyme 2 (ACE2) (Song et al. 2019) is one of the main receptors. In the respiratory tract, ACE2 is widely expressed on the epithelial cells of alveoli, trachea, bronchi, bronchial serous glands (Liu et al. 2011), and alveolar monocytes and macrophages (Kuba et al. 2005). The virus enters and replicates in these target cells. The mature virions are then released from primary cells and infect new target cells (Qinfen et al. 2004). Furthermore, as a surface molecule, ACE2 is also diffusely localized on the endothelial cells of arteries and veins, the mucosal cells of the intestines, tubular epithelial cells of the kidneys, epithelial cells of the renal tubules, and cerebral neurons and immune cells, providing a variety of susceptible cells to SARS-CoV (Guo et al. 2008) (Gu and Korteweg 2007).
2. CD209L is an alternative receptor with a much lower affinity (Jeffers et al.
2004).
Regarding the molecular mechanisms that facilitate the production of MERS in virus infection, it is known that for MERS-CoV infection of humans, the primary receptor is a multifunctional cell surface protein, dipeptidyl peptidase 4 (DPP4, also known as CD26) (Meyerholz, Lambertz, and McCray 2016), which is widely expressed on epithelial cells in the kidney, lung alveoli, small intestine, liver, and prostate, and on activated leukocytes (Widagdo et al. 2016). Consistent with this, MERS-CoV can infect several human cell lines, including lower respiratory, kidney, intestinal, and liver cells, as well as histiocytes, as shown by a cell-line susceptibility study (Oboho et al. 2015), indicating that the range of MERS-CoV tissue tropism in vitro was broader than that of any other CoV. MERS-CoV causes acute, highly lethal pneumonia and renal dysfunction (Oboho et al. 2015).
Aprepitant and its prodrug fosaprepitant are neurokinin 1 (NKi) inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting. Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer. The latter is discussed, for example, in EP 2 837 381 Al. Other NKi inhibitors are well known to those skilled in the art.
Gabapentinoids, also known as a2d ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter g-aminobutyric acid (GABA) (i.e., GABA analogues) which block a2d subunit-containing voltage-dependent calcium channels (VDCCs), sometimes referred to as the gabapentin receptor. Clinically-used gabapentinoids include
gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil. Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal.
There has been no data published indicating that NKi inhibitors and/or gabapentinoids may be efficacious in the treatment or prevention of acute organ damage induced by viral infection. There is an urgent need to develop more effective, well- tolerated and affordable treatments to improve symptoms and survival rates for sufferers of disorders such as SARS and MERS.
SUMMARY OF THE INVENTION
It has now been found that administration of a NKi inhibitor and/or a gabapentinoid is effective at treating and/or preventing development of the macroscopic and microscopic characteristics of a model of SARS-type lung injury. Similarly, administration of a NKi inhibitor and/or a gabapentinoid is effective at down-regulating expression of the molecular targets of SARS-inducing coronaviruses and coronavirus-like viruses, and MERS-inducing coronaviruses, on both lung and renal cells. Thus, the administration may also prevent development and progression of the underlying viral infections. The available clinical evidence in COVID-19 patients supports these findings.
The present invention provides a pharmaceutical composition which comprises:
(a) a NKI inhibitor; and/or
(b) a gabapentinoid; for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection.
The present invention also provides a NKI inhibitor for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a gapanetinoid.
The present invention also provides a gabapentinoid for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally whrerein the method comprises co-administration with a NKI inhibitor.
The present invention also provides a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, which method comprises administering to said patient (a) aNKl inhibitor and/or (b) a gabapentinoid, optionally wherein (a) and (b) are co-administered.
The present invention also provides a product comprising (a) a NK1 inhibitor and/or (b) gabapentinoid, optionally wherein (a) and (b) are provided as a combined preparation for simultaneous, concurrent, separate or sequential use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection.
The present invention also provides use of a NK1 inhibitor in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a gabapentinoid.
The present invention also provides use of a gabapentinoid in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, optionally wherein the method comprises co-administration with a NK1 inhibitor.
The present invention also provides a pharmaceutical composition which comprises:
(a) a NK1 inhibitor; and
(b) a gabapentinoid.
The present invention also provides a kit which comprises:
(a) a pharmaceutical composition comprising a NK1 inhibitor; and
(b) a pharmaceutical composition comprising a gabapentinoid.
DETAILED DESCRIPTION
NKi inhibitors
NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention.
Typically, the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017 (otherwise referred to as tradipitant), L-733,060, L-732,138, L -703,606, WIN 62,577, CP-122721, TAK-637,
R673, CP-100263, WIN 51708, CP-96345, L-760 735, CP-122721, L-758 298, L-741 671, L-742 694, CP-99994 or T-2328, or a pharmaceutically acceptable salt of any thereof.
Preferably, the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, tradipitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.
More preferably, the NKI inhibitor is aprepitant, fosaprepitant, or netupitant, maropitant, tradipitant, or a pharmaceutically acceptable salt of any thereof.
Most preferably, the NKI inhibitor is aprepitant or its prodrug fosaprepitant, or a pharmaceutically acceptable salt of either thereof. As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
Aprepitant is not typically formulated in the form of a pharmaceutically acceptable salt. Thus, in a preferred aspect of the invention the NKi inhibitor is aprepitant. Fosaprepitant is prodrug of aprepitant and has the following structure:
Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:
Thus, in a preferred aspect of the invention, the NKi inhibitor is fosaprepitant dimeglumine.
Pharmaceutically acceptable salts of fosaprepitant, such as fosaprepitant dimeglumine, are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.
Fosaprepitant is converted in vivo to aprepitant. Thus, when administered to a patient, typically intravenously, fosaprepitant is converted to aprepitant.
NK1R inhibitors (also referred to as antagonists) are beneficial in treating or preventing acute organ damage and/or cytokine storm, particularly as induced by viral infection, by two possible mechanisms. NK1R antagonists inhibit Substance P signalling via NK1R and thus reduce both initiation and development of inflammatory processes, particularly in the lung, thereby having an anti-inflammatory effect and preventing / reducing the acute organ damage and/or cytokine storm that may otherwise ensue in viral infections. In addition, NK1R antagonists may inhibit the expression of ACE2 and
CD290L (particularly in the lung) thereby reducing the ability of SARS-inducing coronaviruses and coronavirus-like viruses to bind to and enter cells.
Clinical trials of NK1R inhibitors have shown promising results, particularly in treating acute lung inflammation associated with severe or critical COVID-19 infection. The effects may be complementary to antiviral treatments for COVID-19.
One such trial was a study of tradipitant (LY-686017) - see ClinicalTrials.gov Identifier: NCT04326426 (also referred to as ODYSSEY). The study is a randomized, double-blind placebo-controlled trial to investigate the efficacy and safety of tradipitant 85 mg orally given twice daily to treat inflammatory lung injury associated with severe or critical COVID-19 infection. Participants are randomized 1:1 to treatment with either tradipitant or placebo in addition to standard of care for COVID-19 infection as per the protocol at the treating hospital. Interim analysis of the first 60 enrolled patients was published online in August 2020. Clinical status was assessed on a 7 point scale ranging from death, to mechanical ventilation, various levels of oxygen requirements, to hospital discharge. Clinical improvement was defined as at least a 2 point improvement in the 7 point scale. A comparable proportion of patients improved between the two treatment arms, 57% for tradipitant and 50% for placebo. Mortality rate was also comparable: 14.2% for tradipitant and 16.6% for placebo. However, tradipitant provided benefit in time to improvement. After 7 days of treatment, tradipitant patients recovered sooner than placebo patients (statistically significant difference (HR=2.55, p=0.0375)). The benefit was generally consistent among patients of varying degree of severity at baseline. Tradipitant showed numerical benefit over placebo with an earlier median time to recovery (HR=1.55, p=0.2254) with median time to improvement 10 days for tradipitant versus 28 days for placebo. The results suggest that tradipitant may accelerate clinical improvement for patients with COVID-19 pneumonia. This could be of significant clinical benefit for patients and public health by decreasing health care costs/resources for patients with COVID-19 pneumonia.
Another trial was a study of aprepitant - see ClinicalTrials.gov Identifier: NCT0446864. The study is a randomized controlled trial to investigate the efficacy and safety aprepitant 80 mg orally given daily to treat cytokine storm causing inflammatory lung injury and respiratory failure associated with severe or critical COVID-19 infection. Participants are randomized to treatment with either aprepitant or placebo, in addition to dexamethasone (6mg orally given daily) as a standard treatment given to both groups for Covid-19 infection as per the protocol at the treating hospital. An analysis of 41
participants has been published. See “Aprepitant as a combinant with Dexamethasone reduces the inflammation via Neurokinin 1 Receptor Antagonism in severe to critical Covid-19 patients and potentiates respiratory recovery: A novel therapeutic approach”; Riffat Mehboob, et al. 2020. medRxiv 2020.08.01.20166678; doi: https://doi.Org/10.l 101/2020.08.01.20166678). The results suggest that patients receiving aprepitant had reduced levels of the inflammatory marker CRP relative to patients receiving placebo, consistent with an anti-inflammatory effect.
Gabapentinoids Gabapentinoids are a well-known class of drug that are derivatives of the inhibitory neurotransmitter g-aminobutyric acid (GABA), that is they are GABA derivatives or GABA analogues. These terms may be used interchangeably herein. Gabapentinoids block a2d subunit-containing voltage-dependent calcium channels (VDCCs). Any suitable gabapentinoid can be used in the present invention. Typically, the gabapentinoid is gabapentin, pregabalin, mirogabalin, or a gabapentin prodrug, such as gabapentin enacarbil.
Preferably, the gabapentinoid is gabapentin or pregabalin.
Typically, the gabapentinoid is a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
wherein
Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group;
R2 is a hydrogen or methyl group; or
Ri and R2 together form a C3-6 cycloalkyl group; and
R3 is a hydrogen, methyl, or carboxyl group.
A Ci -6 alkyl group may be a straight-chain or branched-chain alkyl group. Ci-6 alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
A C3-6 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
For the avoidance of doubt, the alkyl groups and cycloalkyl groups are unsubstituted.
Typically, Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group;R2 is a hydrogen or methyl group; and R3 is a hydrogen, methyl, or carboxyl group.
Preferably, Ri is a Ci-6 alkyl group, more preferably a -(CH2)o-2-iC4H9 group and most preferably an -1C4H9 group (i.e., an isobutyl group). Preferably, R2 is hydrogen.
Preferably, R3 is hydrogen.
A particularly preferred compound of formula (I) is one in which Ri is an -1C4H9 group and R2 and R3 are both hydrogen.
Compounds of formula (I) can contain one or several asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
A particularly preferred compound of formula (I) is pregabalin, i.e. (3S)-3- (aminomethyl)-5-methylhexanoic acid. Thus, a particularly preferred gabapentinoid is pregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof. Pregabalin has the following structure:
Another preferred compound of formula (I) is 4-methylpregabalin. Thus, another particularly preferred gabapentinoid is 4-methylpregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
Alternatively, typically Ri and R2 together form a C3-6 cycloalkyl group; and R3 is a hydrogen, methyl, or carboxyl group. Preferably, Ri and R2 together form a cyclopentyl or cyclohexyl group, more preferably a cyclohexyl group. Preferably, R3 is hydrogen.
Accordingly, another particularly preferred compound of formula (I) is one in which Ri and R2 together form a cyclohexyl group and R3 represents hydrogen. This compound is gabapentin. Thus, a particularly preferred gabapentinoid is gabapentin or a pharmaceutically acceptable salt thereof, or a prodrug thereof. An example of a prodrug of gabapentin is gabapentin enacarbil. Gabapentin has the following structure:
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, hydrosulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, mandelic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
As used herein, a prodrug of a compound of formula (I) is a structural analogue of a compound of formula (I) which is transformed in the body into a compound of formula (I) or a species which mimics the biological activity of the compound of formula (I). For example a prodrug of pregabalin is a structural analogue of pregabalin which is transformed in the body into pregabalin itself or a species which mimics the biological activity of pregabalin. Likewise, a prodrug of gabapentin is a structural analogue of gabapentin which is transformed in the body into gabapentin itself or a species which mimics the biological activity of gabapentin. By “in the body” is meant within the human or animal body following administration of the prodrug to the human or animal.
The compound of formula (I) is not typically formulated as a prodrug. Thus, preferably, the gabapentinoid used in the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example pregabalin or gabapentin or a pharmaceutically acceptable salt thereof. More preferably, the gabapentinoid used in the present invention is a compound of formula (I), for instance pregabalin or gabapentin.
Synthetic methods for preparing compounds of formula (I) and pharmaceutically salts thereof are well known in the art. For example, suitable methods are described in WO 98/003167, the contents of which are herein incorporated by reference in their entirety.
Treatment or prevention of acute organ damage induced by viral infection
Typically the patient to be treated is a mammal. Preferably the patient is a human.
The patient may have a confirmed or suspected viral infection, which may be a coronavirus infection or an influenza infection. The coronavirus may be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), or any related or similar virus.
The patient may not (yet) exhibit overt symptoms of viral infection, but will typically exhibit one or more symptoms of a disease associated with viral infection, particularly symptoms affecting the respiratory system. The patient may be exhibiting one or more symptoms of the coronavirus disease COVID-19. Symptoms may include fever, cough, shortness of breath or difficulty breathing, loss of smell and/or taste, tiredness, aches, runny nose, sore throat. Confirmation of a viral infection may be made by any suitable assay. For example, a real-time reverse-transcription polymerase chain reaction (rRT-PCR) assay may be used to detect viral RNA in a clinical sample from the patient.
Treatment is preferably administered to the patient prior to any respiratory symptom becoming severe. Patients who are particularly likely to develop severe symptoms are older people, people with suppressed immunity, and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer. Treatment is particularly suitable for such patients.
Treatment is preferably administered to prevent, arrest or reverse acute lung injury (ALI) in the patient. ALI may be characterised by alveolar-capillary membrane injury, inflammation, and/or increased permeability pulmonary edema.
Pharmaceutical compositions
The present invention involves the use of (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or gabapentin, or a pharmaceutically acceptable salt of either thereof, alone or in any combination. The NKi inhibitor and the gabapentinoid are herein referred to as “active ingredients”.
In one aspect, the present invention provides a pharmaceutical composition that comprises: (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; including for use in the treatment or prevention of acute organ damage, particularly when
induced by viral infection. Pharmaceutical compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.
The present invention extends to situations where the active ingredients discussed above are co-administered. More than one NKi inhibitor and/or more than one gabapentinoid may be co-administered. When the active ingredients are co-administered they can be present either in a single pharmaceutical composition or in separate pharmaceutical compositions, including in separate pharmaceutical compositions optimized for administration either by the same mode or a different mode. For example, the active ingredients may both be administered intravenously, orally, or by inhalation, either in a single pharmaceutical composition or, more preferably, in separate pharmaceutical compositions.
For the avoidance of doubt, in the product comprising (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; as a combined preparation for simultaneous, concurrent, separate or sequential use, the product may comprise either a single pharmaceutical composition that comprises both (a) and (b) (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a) and a second (i.e., separate) pharmaceutical composition that comprises (b). Where (b) comprises more than two or more gabapentinoids, the product may comprise either a single pharmaceutical composition that comprises both (a) and each of the gabapentinoids (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a), a second (i.e., separate) pharmaceutical composition that comprises the first gabapentinoid, e.g. pregablin, and a third (i.e., separate) pharmaceutical composition that comprises the second gabapentinoid, e.g. gabapentin, and so on for any further gabapentinoid.
Co-administration of the active ingredients according to the present invention includes simultaneous, separate and sequential administration.
In general, administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.).
The preferred route of administration will depend upon the specific active ingredient to be delivered, and a skilled person can easily choose an appropriate route. For
example, aprepitant is preferably delivered orally, whereas fosaprepitant is preferably administered intravenously. Pregabalin and gabapentin are both typically delivered orally.
For oral administration, the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
For administration by injection, the pharmaceutical compositions typically take the form of an aqueous injectable solution. Examples of suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
For administration by inhalation, the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler. Alternatively, the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant. Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydro fluoroalkanes.
Pharmaceutical compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art.
Pharmaceutical compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as
amelioration of side effects. However, it is generally preferred that the compositions of the invention do not contain any further active ingredients (i.e. the pharmaceutical compositions contain only (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof.
Dosages and dosage regimes
Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations.
Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.
NKi inhibitors, such as aprepitant and fosaprepitant, and pharmaceutically acceptable salts thereof, are currently approved for use in treating nausea and vomiting in patients, including those suffering from cancer who may also be suffering from nausea and vomiting as a result of chemotherapy and/or surgery . It is thus preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating nausea and vomiting, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. It is thus preferred in the present invention that the gabapentinoid is not prescribed and/or administered to the patient for the purpose of treating any of these indications, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
The present invention is explained in more detail in the following by referring to the Examples, which are not to be construed as limitative.
EXAMPLES
Example 1 - NKi inhibitors
This example demonstrates that aprepitant and other NKI receptor antagonists exhibit great efficacy in the treatment and prevention of SARS-type Acute Lung Injury (ALI).
It is known that SARS is characterized by haemorrhagic fluid in pleural cavity, localized haemorrhage under pleura, pleural adhesions and focal sub-pleural haemorrhage, thrombus present at pulmonary artery, lung bilateral consolidation (focal or extensive), red-coloured haemorrhagic infarct present at cut surface of lung and focal haemorrhage in mucosa, blood-stained purulent or pale red fluid in lumen, congestion and focal haemorrhage in mucosa at the level of trachea. The present inventors have observed that these characteristics are mirrored in ALI induced in rabbits by inhalation of sodium hypochlorite solution. This inhalation model is therefore used as a surrogate for ALI induced by viral infection.
Materials and Methods
30 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation).
Subsequently, from days 3 to 7, a group of 3 rabbits (Group 1) was administered an oral dose of aprepitant at 10 mg/kg body weight per day, another group of 3 rabbits (Group 2) was administered an oral dose of 40 mg/kg body weight per day, a third group (Group 3) was administered an oral dose of 80 mg/kg body weight per day and a fourth group (Group 4) was administered an oral dose of lOOmg/kg body weight per day.
In parallel, aprepitant was administered as an aerosol by inhalation, also from days 3 to 7, to a group of 3 rabbits (Group 5) at a dose of 0.05 mg/kg body weight per day, to another group of three rabbits (Group 6) at a dose of 0.1 mg/kg body weight per day, to another group of three rabbits (Group 7) at a dose of 0.2 mg/kg body weight per day and to another group of three rabbits (Group 8) at a dose of 0.4 mg/kg body weight per day. A placebo consisting only of aerosol with no drug added administered from days 3 to 7 to a group of 3 rabbits (Placebo Group; Group 9). In parallel, 3 rabbits were kept under identical conditions but were not administered any treatment nor the aforementioned sodium hypochlorite solution (Control Group; Group 10).
Aerosol was administered by means of a paediatric inhalation mask connected to a nebulising system with an air compressor with the following characteristics: particle size of 0.5 to 10 micrometres, average particle size 4 micrometres, compressor pressure range 30 to 36 psi (210 to 250 KPa/2.1 to 2.5 bar), operating pressure range 8 to 16 psi (50 to 100 kPa/0.5 to 1.0 bar), flow rate 6 to 8 litres/min.
On day 7 of the experiment all animals were euthanized and necropsied. Five lung tissue samples were taken from each animal, each corresponding to tissue from the five lung lobes (right superior, right middle, right inferior, left superior and left inferior) and pleura. Autopsy findings were noted. Histology and immunohistochemical studies were performed on all samples.
In said immunohistochemistry studies, a sample of each sample was dehydrated by treatment with increasing concentrations of ethanol and finally xylene. Subsequently said dried samples were embedded in paraffin, thus creating a block. Said paraffin blocks were cut on a microtome to a thickness of 5 pm, and the resulting sections (slices) were placed on slides suitable for conducting immunohistochemistry techniques. Subsequently, the sections were deparaffinised by immersion in xylene and then rehydrated through immersion in a series of solutions containing decreasing concentrations of ethanol and, finally, water. Subsequently, these samples were subjected to 10 times atmospheric pressure (10.1 bar) in citrate buffer at pH 6.0, in order to obtain greater exposure to antigens.
The samples were then allowed to cool to room temperature over 10 minutes. Endogenous peroxidase activity was blocked by treatment with 3% hydrogen peroxide over 30 min at room temperature. After washing the samples with 0.05 M Tris buffer, they were incubated with 10 % non-immune pig serum over 30 minutes at room temperature. In order to verify the expression of NK1 receptors, the cell samples were incubated in the presence of anti-NKl antibodies (S8305, Sigma-Aldrich) diluted 1:1000 at 4 °C overnight. After this time they were washed in 0.05M Tris buffer at room temperature. Subsequently, Envision System-HRP (Dako) reagents were added for 30 min at room temperature. Once this time had expired, the samples were again washed with 0.05 M Tris buffer, and immunoreactivity was visualized by light microscopy with a chromogenic solution with 3,3'-diaminobenzidine (DAB+; Dako, USA). In order to differentiate the cell nuclei, these were lightly stained with haematoxylin. Samples that were not incubated with the primary antibody, but wherein this was replaced by a non-immune serum were used as negative controls. In order to evaluate markers in these immunohistochemical assays, specific primary antibodies were used against them at a concentration 1 : 1000, as detailed in Table 1. Furthermore, for each of the sampled sections were placed on slides and stained with haematoxylin-eosin before subsequently being deparaffinised by immersion in xylene and then rehydrated through immersion in a series of solutions containing decreasing concentrations of ethanol and, finally, immersing them in water, eosin (20 seconds) and hematoxylin (40 seconds). All experiments were performed in sextuplicate. In order to evaluate the degree of immunostaining in each of the six sections, a cell-count was performed in 20 high-power fields (400x) using an Olympus brand microscope (CX31 model). The total number of cells and the number of cells displaying immunostaining were counted in each one of the fields in order to subsequently determine the percentage of cells displaying said immunostaining. In the sections (slides) stained with hematoxylin/eosin the area occupied by fibrosis was assessed.
Results Results 1.1
Treatment with NK1R antagonists prevents and avoids SARS-type lung damage induced at the level of macroscopic autopsy findings.
This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with NK1 receptor antagonists compared to the control group (untreated), and shows that Aprepitant, induces an improvement thereof when is administered orally or by inhalation. In this regard, the use of non-peptide NK1 receptor antagonists prevents the development and progression of SARS-type ALI.
Table 2. Macroscopic autopsy findings in cases treated with the drug Aprepitant orally versus control cases.
The results shown in Table 2 show a reduction of all the macroscopic findings in autopsy in the samples derived from the groups treated orally with aprepitant compared to the control group (untreated) and that oral treatment with NK1 receptor antagonists reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
Table 3. Macroscopic autopsy findings in cases treated with the inhaled Aprepitant drug versus placebo cases.
The results shown in Table 3 show a reduction of all the macroscopic pathologic findings in autopsy in the samples derived from the groups treated by inhalation with aprepitant compared to the placebo group (treated only with inhalation but without added drug) and that treatment by inhalation with NK1 receptor antagonists reduces the presence of these macroscopic findings in autopsy.
Results 1.2
Treatment with NK1R antagonists prevents and avoids SARS-type lung damage induced at the level of microscopic findings.
This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with NK1 receptor antagonists compared to the control group (untreated), and shows that Aprepitant induces an improvement thereof when is administered orally or by inhalation. In this regard, the use of non-peptide NK1 receptor antagonists prevents the development and progression of progression of SARS-type ALI.
Table 4 Microscopic autopsy findings in cases treated with the drug Aprepitant orally versus control cases.
The results shown in Table 4 show a reduction of all the microscopic findings in autopsy in the samples derived from the groups treated orally with Aprepitant compared to the control group (untreated) and that oral treatment with NK1 receptor antagonists reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
Table 5. Microscopic autopsy findings in cases treated with the inhaled Aprepitant drug versus placebo cases.
The results shown in Table 5 show a reduction of all the macroscopic pathologic findings in autopsy in the samples derived from the groups treated by inhalation with Aprepitant compared to the placebo group (treated only with inhalation but without added drug) and that treatment by inhalation with NK1 receptor antagonists reduces the presence of these macroscopic findings in autopsy.
Results 1.3
Treatment with NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with NK1 receptor antagonists. The results obtained show that the NK1 receptor agonist, Aprepitant, induces a reduction thereof when administered as treatment. Thus, the use of non-peptide NK1 receptor antagonists may prevent the binding of SARS-inducing viruses to lung cells.
Table 6. Immunohistochemical expression in cases treated with the drug Aprepitant orally versus control cases in lung.
Table 7. Immunohistochemical expression in cases treated with the inhaled Aprepitant drug versus placebo cases in lung.
The results shown in Table 6 show a reduction of the molecular targets to which SARS- inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group. The results shown in Table 7 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group. Thus, the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as SARS- type ALI.
Results 1.4
Treatment with NK1R antagonists inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with NK1 receptor antagonists. The results obtained show that the NK1 receptor agonist, Aprepitant, induces a reduction thereof when administered as treatment. Thus, the use of non-peptide NK1 receptor antagonists may prevent the binding of SARS-inducing viruses to renal cells. Table 8. Immunohistochemical expression in cases treated with the drug Aprepitant orally versus control cases in kidney.
Table 9. Immunohistochemical expression in cases treated with the inhaled Aprepitant drug versus placebo cases in kidney.
The results shown in Table 8 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group. The results shown in Table 9 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with
control group. Thus, the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease. Results 1.5
Treatment with NK1R antagonists inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with NK1 receptor antagonists. The results obtained show that the NK1 receptor agonist, Aprepitant, induces a reduction thereof when administered as treatment. Thus, the use of non-peptide NK1 receptor antagonists may prevent the binding of MERS-inducing viruses to lung cells.
Table 10. Immunohistochemical expression in cases treated with the drug Aprepitant orally versus control cases in lung.
Table 11. Immunohistochemical expression in cases treated with the inhaled Aprepitant drug versus placebo cases in lung.
The results shown in Table 10 show a reduction of the molecular targets to which MERS- inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group. The results shown in Table 11 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group. Thus, the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS- type ALI.
Results 1.6
Treatment with NK1R antagonists inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with NK1 receptor antagonists. The results obtained show that the NK1 receptor agonist, Aprepitant, induces a reduction thereof when administered as treatment. Thus, the use of non-peptide NK1 receptor antagonists may prevent the binding of SARS-inducing viruses to renal cells.
Table 12. Immunohistochemical expression in cases treated with the orally Aprepitant drug versus placebo cases in kidney.
Table 13. Immunohistochemical expression in cases treated with the inhaled Aprepitant drug versus placebo cases in kidney.
The results shown in Table 12 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving oral treatment when compared with control group. The results shown in Table 13 show a reduction of the molecular targets to which MERS-inducing Cov-Type viruses bind also in the samples derived from the groups receiving inhalation treatment when compared with control group. Thus, the use of non-peptide NK1 receptor antagonists both orally and by inhalation may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
Conclusion
NKi inhibitor is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells.
Example 2 - Gabapentinoid (i): Pregabalin
This example demonstrates that pregabalin exhibits great efficacy in the treatment and prevention of SARS-type Acute Lung Injury (ALI) used alone or in combination with NKi inhibitor.
Materials and Methods Conducted in parallel with Example 1.
24 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation). Subsequently, from days 3 to 7, a group of 3 rabbits (Group 11) was administered an oral dose of Pregabalin of 1 mg/kg body weight per day, another group of 3 rabbits (Group 12) was administered an oral dose of 3 mg/kg body weight per day, a third group (Group 13) was administered an oral dose of Pregabalin of 5 mg/kg body weight per day and a fourth group (Group 14) was administered an oral dose of Pregabalin of 7mg/kg body weight per day. In the other hand, from days 3 to 7, a group of 3 rabbits (Group 15) was administered an oral dose of 1 mg/kg body weight per day of Pregabalin combined with lOmg/Kg body weight of Aprepitant, another group of 3 rabbits (Group 16) was administered an oral dose of 3 mg/kg body weight per day of Pregabalin combined with lOmg/Kg body weight of Aprepitant, a third group (Group 17) was administered an oral dose of 5 mg/kg body weight of Pregabalin per day combined with lOmg/Kg body weight of Aprepitant and a fourth group (Group 18) was administered an oral dose of Pregabalin of 7mg/kg body weight combined with lOmg/Kg body weight of Aprepitant per day.
On day 7 of the experiment all animals were euthanized and necropsied. Five lung tissue samples were taken from each animal, each corresponding to tissue from the five lung lobes (right superior, right middle, right inferior, left superior and left inferior) and pleura. Autopsy findings were noted. Histology and immunohistochemical studies were performed on all samples as in Example 1.
Results
Results 2.1
Treatment with Pregabalin prevents and avoids SARS-type lung damage induced at the level of macroscopic autopsy findings.
This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with Pregabalin compared to the control group
(untreated), and shows that Pregabalin induces an improvement thereof. In this regard, the use of Pregabalin prevents the development and progression of SARS-type ALI. In particular, the results shown in Table 14 show a reduction of all the macroscopic findings in autopsy in the samples derived from the groups treated with Pregabalin compared to the control group (untreated) and that Pregabalin reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
Table 14. Macroscopic autopsy findings in cases treated with the drug Pregabalin versus control.
Results 2.2
Treatment with Pregabalin prevents and avoids SARS-type lung damage induced at the level of microscopic findings.
This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with Pregabalin compared to the control group (untreated), and shows that Pregabalin induces an improvement thereof when is administered. In this regard, the use of Pregabalin prevents the development and progression of SARS-type ALL In particular, the results shown in Table 15 show a reduction of all the microscopic findings in autopsy in the samples derived from the groups treated with Pregabalin compared to the control group (untreated) and that Pregabalin reduces the presence of all unfavourable pathological microscopic findings in autopsy. Table 15. Microscopic autopsy findings in cases treated with Pregabalin versus control cases.
Results 2.3
Treatment with Pregabalin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses. Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of SARS-inducing viruses to lung cells. Table 16. Immunohistochemical expression in cases treated with Pregabalin versus control cases in lung.
The results shown in Table 16 show a reduction of the molecular targets to which SARS- inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Pregabalin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as SARS-type ALI.
Results 2.4 Treatment with Pregabalin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of SARS-inducing viruses to renal cells.
Table 17. Immunohistochemical expression in cases treated with Pregabalin versus control cases in renal cells
The results shown in Table 17 show a reduction of the molecular targets to which
SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Pregabalin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
Results 2.5 Treatment with Pregabalin inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of MERS-inducing viruses to lung cells.
Table 18. Immunohistochemical expression in cases treated with Pregabalin versus control cases in the lung cells.
The results shown in Table 18 show a reduction of the molecular targets to which MERS- inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Pregabalin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS-type ALI.
Results 2.6
Treatment with Pregabalin inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Pregabalin. The results obtained show that Pregabalin induces a reduction thereof when administered as treatment. Thus, the use of Pregabalin may prevent the binding of SARS-inducing viruses to renal cells.
Table 19. Immunohistochemical expression in cases treated with Pregabalin versus control cases in the renal cells of the kidney.
The results shown in Table 19 show a reduction of the molecular targets to which MERS- inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Pregabalin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease. The same may be expected of other gabapentinoids (see Example 3).
Conclusion
Pregabalin is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells.
Example 3 - Gabapentinoid fii): Gabapentin
This example demonstrates that gabapentin exhibits great efficacy in the treatment and prevention of SARS-type Acute Lung Injury (ALI) used alone or in combination with NKi inhibitor.
Materials and Methods Conducted in parallel with Example 1. 24 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a
day for 7 days (days 1 to 7 of experimentation). Subsequently, from days 3 to 7, a group of 3 rabbits (Group 19) was administered an oral dose of Gabapentin of 3 mg/kg body weight per day, another group of 3 rabbits (Group 20) was administered an oral dose of 6 mg/kg body weight of Gabapentin per day, a third group (Group 21) was administered an oral dose of Gabapentin of 9 mg/kg body weight per day and a fourth group (Group 22) was administered an oral dose of Gabapentin of 12 mg/kg body weight per day. In the other hand, from days 3 to 7, a group of 3 rabbits (Group 23) was administered an oral dose of 1 mg/kg body weight per day of Gabapentin combined with lOmg/Kg body weight of Aprepitant, another group of 3 rabbits (Group 24) was administered an oral dose of 3 mg/kg body weight per day of Gabapentin combined with lOmg/Kg body weight of Aprepitant, a third group (Group 25) was administered an oral dose of 5 mg/kg body weight of Gabapentin per day combined with lOmg/Kg body weight of Aprepitant and a fourth group (Group 26) was administered an oral dose of Gabapentin of 7mg/kg body weight combined with lOmg/Kg body weight of Aprepitant per day.
On day 7 of the experiment all animals were euthanized and necropsied. Five lung tissue samples were taken from each animal, each corresponding to tissue from the five lung lobes (right superior, right middle, right inferior, left superior and left inferior) and pleura. Autopsy findings were noted. Histology and immunohistochemical studies were performed on all samples as in Example 1.
Results
Results 3.1
Treatment with Gabapentin prevents and avoids SARS-type lung damage induced at the level of macroscopic autopsy findings.
This example shows the macroscopic finding in autopsy that were analysed in the samples derived from the groups treated with Gabapentin compared to the control group (untreated), and shows that Gabapentin induces an improvement thereof. In this regard, the use of Gabapentin prevents the development and progression of SARS-type ALI. In particular, the results shown in Table 20 show a reduction of all the macroscopic findings in autopsy in the samples derived from the groups treated with Gabapentin compared to the control group (untreated) and that Gabapentin reduces the presence of all unfavourable pathological macroscopic findings in autopsy.
Table 20. Macroscopic autopsy findings in cases treated with the drug Gabapentin versus control.
Results 3.2
Treatment with Gabapentin prevents and avoids SARS-type lung damage induced at the level of microscopic findings.
This example shows the microscopic finding in autopsy that were analysed in the samples derived from the groups treated with Gabapentin compared to the control group (untreated), and shows that Gabapentin induces an improvement thereof when is administered. In this regard, the use of Gabapentin prevents the development and progression of SARS-type ALI. In particular, the results shown in Table 21 show a reduction of all the microscopic findings in autopsy in the samples derived from the groups treated with Gabapentin compared to the control group (untreated) and that Gabapentin reduces the presence of all unfavourable pathological microscopic findings in autopsy. Table 21. Microscopic autopsy findings in cases treated with Gabapentin versus control cases.
Results 3.3
Treatment with Gabapentin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Gabapentin. The results obtained show that Gabapentin induces a reduction thereof when administered as treatment. Thus, the use of Gabapentin may prevent the binding of SARS-inducing viruses to lung cells.
Table 22. Immunohistochemical expression in cases treated with Gabapentin versus control cases in lung.
SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Gabapentin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as SARS-type ALI.
Results 3.4 Treatment with Gabapentin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses.
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Gabapentin. The results obtained show that Gabapentin induces a reduction thereof when administered as treatment. Thus, the use of Gabapentin may prevent the binding of SARS-inducing viruses to renal cells.
Table 23. Immunohistochemical expression in cases treated with Gabapentin versus control cases in renal cells
_
The results shown in Table 23 show a reduction of the molecular targets to which SARS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Gabapentin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
Results 3.5
Treatment with Gabapentin inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Gabapentin. The results obtained show that Gabapentin induces a reduction thereof when administered as treatment. Thus, the use of Gabapentin may prevent the binding of MERS-inducing viruses to lung cells. Table 24. Immunohistochemical expression in cases treated with Gabapentin versus control cases in the lung cells.
MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Gabapentin may prevent the development and progression of viral infection in the tissues of the respiratory tract, and of resulting respiratory tract injuries and diseases such as MERS-type ALI.
Results 3.6
Treatment with Gabapentin inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
Expression levels of molecular targets bound by CoV-type viruses were analysed in the samples derived from the control group and the groups treated with Gabapentin. The results obtained show that Gabapentin induces a reduction thereof when administered as treatment. Thus, the use of Gabapentin may prevent the binding of SARS-inducing viruses to renal cells.
Table 25. Immunohistochemical expression in cases treated with Gabapentin versus control cases in the renal cells.
MERS-inducing Cov-Type viruses bind in the samples derived from the groups receiving treatment when compared with control group. Thus, the use of Gabapentin may prevent the development and progression of viral infection in renal cells, and of resulting renal cell injuries and disease.
Conclusion Gabapentin is shown to be an effective treatment for the types of lung damage experienced in SARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells. The same may be expected of other gabapentinoids (see Example 2).
Example 4 - assessment of the groups treated with a combination of Aprepitant and Pregabalin (from Example 2)
Results 4.1 Macroscopic autopsy findings in cases treated with the combination of Aprepitant and
The use of Aprepitant and Pregabalin prevents the development and progression of SARS- type ALI. Improvement in all macroscopic characteristics is greater than with either drug used separately (compare to Results 1.1 and 2.1).
Results 4.2
Microscopic autopsy findings in cases treated with the combination of Aprepitant and
The use of Aprepitant and Pregabalin prevents the development and progression of SARS- type ALI. Improvement in all microscopic characteristics is greater than with either drug used separately (compare to Results 1.2 and 2.2).
Results 4.3
Treatment with Aprepitant and Pregabalin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses
The use of Aprepitant and Pregabalin reduces the expression of the molecule targets of
SARS-inducing coronavirus and coronavirus-like viruses. Reduction is greater than with either drug used separately (compare to Results 1.3 and 2.3). Results 4.4
Treatment with Aprepitant and Pregabalin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses
The use of Aprepitant and Pregabalin reduces the expression of the molecule targets of SARS-inducing coronavirus and coronavirus-like viruses. Reduction is greater than with either drug used separately (compare to Results 1.4 and 2.4). Results 4.5
Treatment with Aprepitant and Pregabalin inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
MERS-inducing coronavirus. Reduction is greater than with either drug used separately (compare to Results 1.5 and 2.5).
Results 4.6
Treatment with Aprepitant and Pregabalin inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
MERS-inducing coronavirus. Reduction is greater than with either drug used separately
(compare to Results 1.6 and 2.6).
Conclusion The combination of Aprepitant and Pregabalin is shown to be more effective than either drug alone as a treatment for the types of lung damage experienced in S ARS and MERS patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells. The same may be expected of other combinations of NKi inhibitor and gabapentinoids (see Example 5).
Example 5 - assessment of the groups treated with a combination of Aprepitant and
Gabapentin (from Example 3) Results 5.1
The use of Aprepitant and Gabapentin prevents the development and progression of SARS- type ALI. Improvement in all macroscopic characteristics is greater than with either drug used separately (compare to Results 1.1 and 3.1). Results 5.2
Microscopic autopsy findings in cases treated with the combination of Aprepitant and
The use of Aprepitant and Gabapentin prevents the development and progression of SARS- type ALL Improvement in all microscopic characteristics is greater than with either drug used separately (compare to Results 1.2 and 3.2).
Results 5.3
Treatment with Aprepitant and Gabapentin inhibits lung cell expression of targets necessary for the binding of SARS-inducing coronavirus and cor onavirus -like viruses
The use of Aprepitant and Gabapentin reduces the expression of the molecule targets of
SARS-inducing coronavirus and coronavirus-like viruses. Reduction is greater than with either drug used separately (compare to Results 1.3 and 3.3).
Results 5.4
Treatment with Aprepitant and Gabapentin inhibits renal cell expression of targets necessary for the binding of SARS-inducing coronavirus and coronavirus-like viruses
The use of Aprepitant and Gabapentin reduces the expression of the molecule targets of
SARS-inducing coronavirus and coronavirus-like viruses. Reduction is greater than with either drug used separately (compare to Results 1.4 and 3.4).
Results 5.5
Treatment with Aprepitant and Gabapentin inhibits lung cell expression of targets necessary for the binding of MERS-inducing coronavirus
The use of Aprepitant and Gabapentin reduces the expression of the molecule targets of
MERS-inducing coronavirus. Reduction is greater than with either drug used separately (compare to Results 1.5 and 3.5).
Results 5.6
Treatment with Aprepitant and Gabapentin inhibits renal cell expression of targets necessary for the binding of MERS-inducing coronavirus
The use of Aprepitant and Gabapentin reduces the expression of the molecule targets of
MERS-inducing coronavirus. Reduction is greater than with either drug used separately (compare to Results 1.6 and 3.6).
Conclusion
The combination of Aprepitant and Gabapentin is shown to be more effective than either drug alone as a treatment for the types of lung damage experienced in S ARS and MERS
patients. There is evidence also of a preventative effect, including prevention of lung injury, as well as prevention of the development and progression of both SERS and MERS-inducing viral infection in both lung and kidney cells. The same may be expected of other combinations of NKi inhibitor and gabapentinoids (see Example 4).
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Huang, Jin Bao, Hong Yan Li, Jia Fu Liu, Chang Qing Lan, Qing Hua Lin, Shu Xing Chen, Hong Ying Zhang, et al. 2015. “Histopathological Findings in a Critically Ill Patient with Avian Influenza A (H7N9).” Journal of Thoracic Disease 7 (12): E672-77. https://doi.Org/10.3978/i.issn.2072-1439.2015.11.59. - Jeffers, Scott A., Sonia M. Tusell, Laura Gillim-Ross, Erin M. Hemmila, Jenna E. Achenbach, Gregory
J. Babcock, William D. Thomas, et al. 2004. “CD209L (L-SIGN) Is a Receptor for Severe Acute Respiratory Syndrome Coronavirus.” Proceedings of the National Academy of Sciences of the United States of America 101 (44): 15748-53. https://doi.org/10.1073/pnas.0403812101.
Kuba, Keiji, Yumiko Imai, Shuan Rao, Hong Gao, Feng Guo, Bin Guan, Yi Huan, et al. 2005. “A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus -Induced Lung Injury.” Nature Medicine 11 (8): 875-79. https://doi.org/10.1038/nml267.
Liu, L., Q. Wei, X. Alvarez, H. Wang, Y. Du, H. Zhu, H. Jiang, et al. 2011. “Epithelial Cells Lining Salivary Gland Ducts Are Early Target Cells of Severe Acute Respiratory Syndrome Coronavirus Infection in the Upper Respiratory Tracts of Rhesus Macaques.” Journal of Virology 85 (8): 4025-30. https://doi.org/10.1128/jvi.02292-10.
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Example 6 - clinical assessment of NK1 inhibitor in COVID-19 patients
Aprepitant (with standard of care)
A phase III, single center, two-arm, open-label, randomized, controlled study has been designed to evaluate the efficacy and safety of aprepitant plus standard care compared with standard care alone in patients hospitalised with COVID-19. Patients will be randomized in a 1:1 ratio. Patients in all groups will receive the standard care (medications, therapies and interventions per standard hospital treatment protocols) during the study.
The patients in control group will receive only the standard care whereas the patients in experimental groups will receive aprepitant plus standard care. In the experimental groups, aprepitant treatment will be given for 14 days. In experimental groups, patients will receive the standard approved dose of aprepitant as a regimen of 125 mg capsule on first day and 80 mg capsule once daily on second to fourteenth days. This dose regimen is based on the recommended dose of aprepitant approved for treatment of chemotherapy induced vomiting and nausea.
The study will consist of a screening visit of up to 3 days and will continue with the baseline visit at day 0. Screening and baseline visit can occur at the same day, if the participant has met all study inclusion and exclusion criteria. Primary evaluation period will be 21 days, and a final assessment will be performed at day 21 or the day of patient discharged. The table below summarises the study timetable.
The study has the following primary objectives:
• To evaluate the effect of aprepitant + standard care compared with standard care alone on duration of hospitalization in patients with COVID-19;
• To evaluate the effect of aprepitant + standard care compared with standard care alone on clinical improvement in patients with COVID-19;
The study has the following secondary objectives:
• To evaluate the effect of aprepitant + standard care compared with standard care alone on survival of patients with COVID-19;
• To evaluate the efficacy of aprepitant + standard care compared with standard care alone on other relevant outcomes (see section endpoints) in patients with COVID-19 • To evaluate the safety and tolerability of aprepitant in patients with COVID-19 • To assess the effect of aprepitant on inflammation and pro thrombotic activity in patients with COVID-19
• To evaluate the effect of aprepitant + standard care compared with standard care alone on progression to renal failure requiring dialysis in patients with COVID-19 • To evaluate the effect of aprepitant + standard care compared with standard care alone on health-related quality of life in patients with COVID-19 • To evaluate the plasma concentration of aprepitant The study has the following primary endpoints:
• Duration of hospitalization at day 21 or discharge (Days of hospital admission measured as the difference between the date of admission and the date of discharge)
• Time to clinical improvement (Based on modified 6-point ordinal scale) at day 21 or Discharge
The study has the following secondary endpoints:
• Survival (Based on all-cause mortality) at day 21 or discharge
• Need and duration of intensive care unit stay at day 21 or discharge
• Number of days free of mechanical ventilation at day 21 or discharge
• Change from baseline Sp02/Fi02 at day 21 or discharge
• Change in the SARS-CoV-2 viral load by RT-PCR test of nasopharyngeal samples on day 0, day 4 and end of study.
• Incidence of adverse events and serious adverse events
• Number of patients who cannot tolerate aprepitant treatment.
• Change in laboratory biomarkers associated with inflammation and coagulopathy during the study
• Incidence of progression to renal failure requiring dialysis at day 21 or discharge
• EQ-5D-5L scores at baseline and end of the study
• Plasma concentration of aprepitant ( Day 0, Day 4, Day 14)
The study is expected to show benefits of NK1R antagonists (and aprepitant in particular) by two possible mechanisms. NK1R antagonists inhibit Substance P signalling via NK1R and thus reduce both initiation and development of inflammatory processes, particularly in the lung, thereby having an anti-inflammatory effect and preventing / reducing acute organ damage and/or cytokine storm. In addition, NK1R antagonists may
inhibit the expression of ACE2 and CD290L (particularly in the lung) thereby reducing the ability of SARS-inducing coronaviruses and coronavirus-like viruses to bind to and enter cells.
1ALT, AST, BUN, CRP, Creatinine, LDH, Sodium, potassium, chloride, direct /indirect/ total bilirubin, ferritin; 2 D-Dimer, INR, partial thromboplastin time, prothrombin time, fibrinogen; 3 HbsAg, Anti-HCV and HIV 1-2 Ag+Ab ; 4 Sp02 to be measured by pulse oximetry, Fi02 to be measured by supplemental oxygen; imaging performed as part of the participant’s routine clinical care.
Claims
1. A pharmaceutical composition which comprises:
(a) a NK1 inhibitor; and/or (b) a gabapentinoid; for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection.
2. The pharmaceutical composition for use according to claim 1, wherein the NK1 inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, tradipitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition for use according to claim 2, wherein the NK1 inhibitor is aprepitant or fosaprepitant, or pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition for use according to claim 3, wherein the NK1 inhibitor is aprepitant.
5. The pharmaceutical composition for use according to claim 3, wherein the NK1 inhibitor is fosaprepitant dimeglumine.
6. The pharmaceutical composition for use according to anyone of the preceding claims, wherein the gabapentinoid is gabapentin, pregabalin, mirogabalin, gabapentin enacarbil, or a pharmaceutically acceptable salt thereof.
7. The pharmaceutical composition for use according to claim 6, wherein the gabapentinoid is gabapentin or pregabalin, or pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition for use according to any one of the preceding claims, wherein the organ is lung or kidney.
9. The pharmaceutical composition for use according to any one of the preceding claims, wherein the virus is a coronavirus or influenza virus, optionally SARS-CoV-2, SARS-CoV or MERS-CoV.
10. The pharmaceutical composition for use according to any one of the preceding claims, wherein the method of treatment also comprises the standard of care for the viral infection, which may optionally comprise administration of dexamethasone.
11. A NK1 inhibitor as defined in any one of claim 1 to 5, for use a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection as defined in claim 1, 8, 9 or 10, optionally wherein the method comprises co administration with a gapanetinoid as defined in any one of claims 1 and 6 or 7.
12. A gabapentinoid as defined in any one of claims 1 and 6 or 7, for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection as defined in claim 1, 8, 9 or 10, optionally wherein the method comprises co administration with a NK1 inhibitor as defined in any one of claims 1 to 5.
13. A method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection, which method comprises administering to said patient (a) a NK1 inhibitor as defined in any one of claims 1 to 5, and/or (b) a gabapentinoid as defined in any one of claims 1 and 6 or 7, optionally wherein (a) and (b) are co administered.
14. A product comprising (a) a NK1 inhibitor as defined in any one of claims 1 to 5, and/or (b) a gabapentinoid as defined in any one of claims 1 and 6 or 7, optionally wherein (a) and (b) are provided as a combined preparation for simultaneous, concurrent, separate or sequential use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection as defined in claim 1, 8, 9 or 10.
15. Use of a NK1 inhibitor as defined in any one of claims 1 to 5 in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection as defined in claim 1, 8, 9 or 10,
optionally wherein the method comprises co-administration with a gabapentinoid as defined in any one of claims 1 and 6 or 7.
16. Use of a gabapentinoid as defined in any one of claims 1 and 6 or 7 in the manufacture of a medicament for use in a method for the prevention or treatment of acute organ damage and/or cytokine storm induced by viral infection as defined in claim 1, 8, 9 or 10, optionally wherein the method comprises co-administration with a NK1 inhibitor as defined in any one of claims 1 to 5.
17. A pharmaceutical composition which comprises:
(a) a NK1 inhibitor as defined in any one of claims 1 to 5; and
(b) gabapentinoid as defined in any one of claims 1 and 6 or 7.
18. A kit which comprises : (a) a pharmaceutical composition comprising a NK1 inhibitor as defined in any one of claims 1 to 5; and
(b) a pharmaceutical composition comprising a gabapentinoid as defined in any one of claims 1 and 6 or 7.
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WO2022243430A1 (en) * | 2021-05-20 | 2022-11-24 | Plus Vitech, S.L. | Treatment of acne |
WO2022253748A1 (en) * | 2021-06-03 | 2022-12-08 | Plus Vitech, S.L. | Combinations for the treatment of hpv |
US11883411B2 (en) | 2022-02-25 | 2024-01-30 | Lanzhou Veterinary Research Institute, Chinese Academy Of Agricultural Sciences | Use of compound aprepitant in preparation of drug for preventing or treating African swine fever (ASF) |
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WO2022253748A1 (en) * | 2021-06-03 | 2022-12-08 | Plus Vitech, S.L. | Combinations for the treatment of hpv |
CN114425053A (en) * | 2022-02-25 | 2022-05-03 | 中国农业科学院兰州兽医研究所 | Application of aprepitant compound in preparation of drugs for preventing or treating African swine fever |
US11883411B2 (en) | 2022-02-25 | 2024-01-30 | Lanzhou Veterinary Research Institute, Chinese Academy Of Agricultural Sciences | Use of compound aprepitant in preparation of drug for preventing or treating African swine fever (ASF) |
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