Method of treatment or inhibition

Abstract

The present disclosure relates to the use of neuroactive steroids, including alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2β,3α,5β)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3α-hydroxy-3β- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5β-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β- OH), (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3α- dihydroprogesterone (3α-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), and betaxalone, for treating or at least partially inhibiting the development or progression of an infection caused by a neurotropic virus in a subject. This disclosure also relates to the use of neuroactive steroids for treating or at least partially inhibiting the development or progression of a condition associated with an infection caused by a neurotropic virus, such as encephalopathy or acute encephalitis.

Description

TITLE OF THE INVENTION"METHOD OF TREATMENT OR INHIBITION"

[0001] This application claims priority to Australian Provisional Patent Application No. 2024903261 entitled "Method of treatment or inhibition" filed 9 October 2024, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This invention relates generally to the use of neuroactive steroids, including alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5g-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), and betaxalone, for treating or at least partially inhibiting the development or progression of an infection caused by a neurotropic virus in a subject. This invention also relates to the use of neuroactive steroids for treating or at least partially inhibiting the development or progression of a condition associated with an infection caused by a neurotropic virus, such as encephalopathy or acute encephalitis.BACKGROUND OF THE INVENTION

[0003] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0004] Rabies virus infections have an annual death toll in the order of approximately 60,000 humans per annum worldwide, of which over one third are children. Rabies virus is spread by transmission through bats, dogs and othermammalian animals, and is transmitted from infected animals to humans through bites or scratches, or via contact between saliva or neural tissue from an infected animal and broken skin or a mucous membrane of a human. Recently, bat transmission of rabies virus has been increasing in the United States of America, with infected bats present in every state with the exception of Hawaii.

[0005] There is currently no known treatment for a rabies virus infection which is invariably fatal (near 100% mortality). Due to the presence of the virus in bats, rabies virus cannot be eliminated. The transmission of this virus is erratic and uncertain, especially when acquired through bats, and its incubation period can be long and variable.

[0006] In humans, a neurotropic virus, such as rabies virus, damages the nervous system in numerous ways. First, the virus commandeers directed neuronal transport in order to reach the central nervous system. The virus interacts with the p75 neurotrophin receptor (p75NTR) to gain entry into the neuron, typically at the axon, and is rapidly transported through the neuron and more widely through the nervous system of the host. During transport, this virus recruits and hijacks axonal and dendritic cargo trafficking components and affects motor complexes and adaptors that drive neuronal retrograde transport. This alters the cytoskeletal architecture and hinders the transport of normal cargo that is essential for maintaining optimal neuronal complexity, which results in a breakdown in central nervous system plasticity, neurogenesis, synaptogenesis, long term potentiation and impaired gene transcription in the cell nucleus. In doing so, the virus uses this hijacked system to travel and replicate at a speed faster than what normal neuronal transport processes would allow. Second, while it achieves this, the virus accelerates and amplifies the mechanisms that cause inflammation to a level that is harmful. This process of inflammation and resulting harm occur before adaptive immunity and antibodies develop, thereby leading to invasion and devastation of the central nervous system. Furthermore, secondary manifestations of this disruptive disorder of the central nervous system, such as dysautonomic storms and severe ischemic deficit, lead either to death or, in a very few cases, to severe disability incompatible with independent living. By way of examples, Figures 1 and 2 show simplified representations of the major neuronal processes involved following infection with a rabies virus (RABV).

[0007] This mechanism of action is adopted by a number of different neurotropic viruses.

[0008] New therapies for infections by neurotropic viruses are desired, particularly those that limit the effects of the neurotropic virus on the central nervous system. Therapies that simultaneously inhibit viral transport and the pro- inflammatory pathways caused by the viral activation of a Toll-like receptor (TLR) yet leave intact other adaptive immunity processes which promote healing and recovery are particularly desired.SUMMARY OF THE INVENTION

[0009] The present invention is predicated in part on the discovery that specific neuroactive steroids, including alfaxalone and alfadolone, inhibit the activation of the myeloid differentiation factor 88 (MyD88) pathway which induces pro-inflammatory cytokines by action at a Toll-like receptor in response to a neurotropic virus. Accordingly, it is conceived that such neuroactive steroids will be useful for reducing inflammation associated with a neurotropic virus infection, contemporaneously modulating neuronal transport of a neurotropic virus in a subject, and reducing the associated inflammation. The inventors have further found that particular neuroactive steroids, including alfaxalone and alfadolone, inhibit activation of the MyD88 pathway while simultaneously preserving the development of acquired adaptive immunity through the Tol l / i nterleu ki n-1 receptor domain-containing adapter-inducing interferon-p (TRIF) pathway. The inventors have also conceived that such neuroactive steroids will inhibit the induction of p75NTR by the induced MyD88 inflammatory pathway, and inhibit or reduce the interaction of the neurotropic virus with p75NTR by increasing the available amounts of mature neurotrophins, thereby inhibiting the transport of the neurotropic virus, and inhibiting or delaying the spread of the virus throughout the central nervous system of the subject and associated neuronal destruction. Based on these activities, particular neuroactive steroids, including alfaxalone and alfadolone, are considered to be useful for treating or at least partially inhibiting the development or progression of an infection by a neurotropic virus and a condition associated with an infection by a neurotropic virus.

[0010] Accordingly, in one aspect, there is provided a method of treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5|3-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0011] In particular embodiments, the infection is a central nervous system infection.

[0012] In some embodiments, the infection is associated with multisystem organ failure.

[0013] In some embodiments, the infection is associated with a condition selected from the group consisting of acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis and encephalomyelitis; especially acute encephalopathy or acute encephalitis.

[0014] In some embodiments, the infection is associated with the development of inflammation and / or a cytokine storm, especially wherein the inflammation and / or cytokine storm is associated with the activity of a Toll-like receptor. In particular embodiments, the Toll-like receptor is Toll-like receptor 4 or Toll-like receptor 7.

[0015] In particular embodiments, neuronal transport of the virus within the subject is associated with the activity of a member of the tumour necrosis factor receptor family, especially p75 neurotrophin receptor (p75NTR).

[0016] In particular embodiments, the neurotropic virus is a single stranded negative-sense RNA virus or single stranded positive-sense RNA virus.

[0017] In exemplary embodiments, the virus is selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus.

[0018] In some embodiments, the virus is rabies virus.

[0019] Also provided, in another aspect, is a method of treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering aneuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0020] In some embodiments, the infection is a central nervous system infection.

[0021] In some embodiments, the condition is associated with multisystem organ failure.

[0022] In some embodiments, the condition is selected from the group consisting of acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis and encephalomyelitis; especially acute encephalopathy or acute encephalitis.

[0023] In exemplary embodiments, the infection is associated with the development of inflammation and / or a cytokine storm, especially wherein the inflammation and / or cytokine storm is associated with the activity of a Toll-like receptor. In particular embodiments, the Toll-like receptor is Toll-like receptor 4 or Toll-like receptor 7.

[0024] In particular embodiments, neuronal transport of the virus within the subject is associated with the activity of a member of the tumour necrosis factor receptor family; especially p75NTR.

[0025] In preferred embodiments, the virus is a single stranded negativesense RNA virus or single stranded positive-sense RNA virus.

[0026] In exemplary embodiments, the virus is selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus.

[0027] In some embodiments, the virus is rabies virus.

[0028] In a further aspect, there is provided a method of inhibiting or reducing neuronal transport of a neurotropic virus in a subject, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0029] In another aspect, there is provided a method of inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0030] Also provided, in another aspect, is a method of inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virusin a Toll-like receptor expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, rena noIone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan- 20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3g- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the method preserves development of acquired adaptive immunity through the TRIF pathway. In particular embodiments, the Toll-like receptor is Toll-like receptor 4 or Toll-like receptor 7. In particular embodiments, the neurotropic virus is rabies virus.

[0031] In the aspects disclosed herein, the neuroactive steroid is, in some embodiments, substantially devoid of hormonal endocrine activity. In particular embodiments, the neuroactive steroid activates a pregnane X receptor (PXR).

[0032] In some embodiments, the neuroactive steroid has sedative and / or anaesthetic activity.

[0033] In some embodiments, the method comprises, consists or consists essentially of administering a combination of neuroactive steroids to the subject. In particular embodiments, the combination of neuroactive steroids is alfaxalone and alfadolone.

[0034] In some embodiments, the neuroactive steroid is alfaxalone, alfadolone or alfadolone acetate. In particular embodiments, the neuroactive steroid is alfaxalone.

[0035] In some embodiments, the neuroactive steroid is administered intravenously, orally, subcutaneously, intramuscularly or intranasally. In some embodiments, the neuroactive steroid is titrated up to a dose that causes a burst suppression in an electroencephalogram, or a dose that causes a bispectral index of 0. In exemplary embodiments, the neuroactive steroid is administered in an amount in the range of from about 0.05 mg to about 250 mg per kg body weight of thesubject. In particular embodiments, is administered in an amount that causes sedation of the subject. In some embodiments, the neuroactive steroid is administered in an amount that does not cause anaesthesia of the subject. In particular embodiments, the neuroactive steroid is administered in a modified-release formulation.

[0036] The methods disclosed herein may suitably further comprise administering one or more other therapeutic agents.

[0037] In some embodiments, the other therapeutic agent is selected from the group consisting of an analgesic, sedative, anaesthetic, antiviral, NMDA receptor antagonist, antidiuretic hormone, fluid therapy, inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetra hydrobiopterin deficiency, sedating neurop rotective agent, therapy for lactic acidosis or ketosis, and Toll-like receptor antagonist.

[0038] In some embodiments, the methods disclosed herein may suitably comprise administering a combination of Toll-like receptor antagonists.

[0039] In some embodiments, the analgesic is selected from the group consisting of fentanyl, pethidine, meperidine, anileridine, alfentanil, sufentanil, remifentanil, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, codeine, methadone, tramadol, buprenorphine, meperidine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, flurbiprofen, acetaminophen, aspirin, ibuprofen and naproxen.

[0040] In some embodiments, the sedative or anaesthetic is selected from the group consisting of desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, xenon, amobarbital, methohexital, thiamylal, thiopental, lorazepam, etomidate, ketamine, midazolam, haloperidol, diazepam, dexmedetomidine, melatonin and propofol.

[0041] In some embodiments, the antiviral is ribavirin. In some embodiments, the antiviral is a monoclonal antibody; especially a monoclonal antibody against rabies virus.

[0042] In some embodiments, the NMDA receptor antagonist is amantadine or ketamine.

[0043] In some embodiments, the calcium channel antagonist is nimodipine.

[0044] In some embodiments, the therapy for delayed ischemic deficit from nitric oxide excess is an inhibitor of inducible nitric oxide synthase, neuronal nitric oxide synthase or endothelial nitric oxide synthase.

[0045] In some embodiments, the therapy for tetrahydrobiopterin deficiency is sapropterin or biopterin.

[0046] In some embodiments, the sedating neuroprotective agent is melatonin.

[0047] In some embodiments, the Toll-like receptor antagonist is a Toll-like receptor 4 antagonist or Toll-like receptor 7 antagonist; especially a Toll-like receptor 4 antagonist.

[0048] In a further aspect, there is provided a use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the neurotropic virus is rabies virus.

[0049] In a further aspect, there is provided a use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3|3- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the neurotropic virus is rabies virus.

[0050] In another aspect, there is provided a use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing neuronal transport of a neurotropic virus in a subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0051] Also provided, in another aspect, is a use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan- 20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872),alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3g-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0052] In another aspect, there is provided a use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the medicament preserves development of acquired adaptive immunity through the TRIF pathway.

[0053] In particular embodiments, the medicament is to be used in combination with one or more further neuroactive steroids. In some embodiments, the medicament comprises a combination of neuroactive steroids, such as alfaxalone and alfadolone.

[0054] The uses described herein may suitably, in some embodiments, comprise the use of alfaxalone, alfadolone or alfadolone acetate as the neuroactive steroid.

[0055] In another aspect, there is provided a kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol,ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2g-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0056] Also provided, in another aspect, is a kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0057] The kit of the invention may, in some embodiments, further comprise one or more other therapeutic agents.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is a simplified representation of the major neuronal processes involved following infection with a neurotropic virus. By way of example, the neurotropic virus shown in Figure 1 is rabies virus (RABV). Two toll-like receptors are shown, TLR4, a receptor on the cell surface that interacts with RABV directly and TLR7, a receptor present within intracellular endosomes. Both TLR4 and TLR7interact with Toll / interleukin-1 receptor domain-containing adaptor protein (TIRAP) to activate a cascade of proteins, Interleukin-1 receptor-associated kinases (IRAK) 4 and 1, tumour necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), inhibitor of nuclear factor kappa-B kinase complex comprising subunits a, 8 (IKKa and P), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKf>), leading to the production of N FKB which switches on the production and secretion of inflammatory cytokines (IL-ip, IL-6, IL-8, IL-12) and TNFa. These inflammatory cytokines cause inflammation and cell damage. N FKB also causes the production of excess receptors p75NTR.

[0059] Figure 1 shows that RABV, in addition to direct action with cell surface TLR4, also combines with p75NTR on the cell surface of axons and dendrites, the p75NTR helping the RABV to enter the cell and be actively delivered to the neuron cell body by fast retrograde transport where it activates TLR7 receptors.

[0060] Figure 1 also shows that the system has two feed forward amplification steps:1. The secretion of inflammatory cytokines such as IL-ip, IL-6, IL-8, and TNFa, causes cell damage and release of cell damage debris PAMPS and DAMPS, which themselves feed forward to cause further direct stimulation of TLR4 leading to yet more MyD88-induced inflammatory cytokines;2. The MyD88 pathway also leads to increased production of p75NTR such that more of those receptors are available for: a. Combination with RABV to facilitate viral uptake into the cytoplasm; b. Interaction with RAB5 and 7 proteins to facilitate rapid retrograde transport of RABV; and c. Expression on the cell surface to interact with sortilin, RABV and pro-brain- derived neurotrophic factor (BDNF) which leads to direct activation of TRAF6 and subsequent increased secretion of inflammatory cytokines without activating MyD88.

[0061] Figure 2 is a line diagram derived from Figure 1 showing the routes of feed forward amplification (black arrows) and the points at which treatment with a neuroactive steroid interrupts the system, labelled with the numbering and letter sequence in the list below:1. Neuroactive steroids (for example, alfaxalone) increase the available amounts of mature neurotrophins (for example, BDNF) by action at pregnane X receptors (PXR);2. BDNF competes with neurotropic virus such as rabies virus (RABV) for binding sites on the p75NTR so decreasing RABV binding and p75NTR-assisted entry of RABV into the neuron;3. BDNF competes with p75NTR / RABV complexes for binding with RAB5 and RAB7 (Ras analog in brain (Rab) proteins) necessary for rapid retrograde intraneuronal transport of RABV to the neurons in the CNS, thereby decreasing RABV spread throughout the central nervous system of the subject;4. Neuroactive steroids inhibit the activation of MyD88 while preserving the TRIF pathway leading to adaptive immunity by Toll-like receptors, TLR4 and TLR7, achieving two things: a. Decreasing the production of inflammatory cytokines, and, b. Decreasing the secretion of more p75NTR;5. By decreasing cytokine production, less tissue damage occurs so decreasing the numbers of breakdown products pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPS), a. Lower concentrations of PAMPS and DAMPS lead to less TLR stimulation;6. By decreasing the secretion of p75NTR, less p75NTR is available for: a. Uptake of RABV, b. Retrograde transport of RABV, c. Direct activation of N FKB bypassing MyD88.

[0062] Figure 3 is a diagram showing how TLR4 activates the MyD88 pathway to produce inflammatory cytokines and the TRIF pathway to produce antiinflammatory chemokines and cytokines. This Figure also shows the presence of two feed forward amplification steps as discussed in relation to Figure 1 above.

[0063] Figure 4 is a series of graphs showing the effect of allopregnanolone, alfaxalone, alfadolone and dexamethasone on the secretion of different cytokines (IL- 13, IL-6 and TNF-a) in human peripheral blood mononuclear cells (PBMCs) against a background of TLR4 stimulation. Figure 4A shows the effect of alfaxalone and alfadolone compared to allopregnanolone and dexamethasone on the secretion of IL- ip. Figure 4B shows the effect of alfaxalone and alfadolone compared to allopregnanolone and dexamethasone on the secretion of IL-6. Figure 4C shows theeffect of alfaxalone and alfadolone compared to allopregnanolone and dexamethasone on the secretion of TNF-a.

[0064] Figure 5 is a diagram showing the intracellular signalling pathways activated by various Toll-like receptors. Figure 5 shows that Toll-like receptor 2 (TLR2) signals through the MyD88 pathway, but not TRIF, to activate the N FKB pathway. Figure 5 also shows that Toll-like receptor 3 (TLR3) signals through the TRIF pathway, but not MyD88, to activate both the N FKB and interferon-sensitive response elements (ISRE) pathways. The N FKB pathway induces inflammation while the ISRE pathway produces interferons and antibodies for adaptive immune response.

[0065] Figure 6 is a diagram showing the intracellular signalling pathways activated by TNFa. Figure 6 shows that TNFa can bypass the MyD88 and TRIF pathways but shares downstream pathways to activate N FKB.

[0066] Figure 7 is a diagram showing that IFNy activates a pathway to ISRE signalling that is independent of MyD88 and TRIF.

[0067] Figure 8 is a series of graphs showing the effect of alfadolone on the activation of N FKB in experiments on lung epithelial cells (line BEAS-2B) through different pathways, namely TLR2 activation of MyD88 (Figure 8A), TLR3 activation of TRIF (Figure 8B) and TNFa activation via a TLR-independent pathway (Figure 8C). Figures 8A and 8B show that alfadolone inhibited TLR2-mediated N FKB activation and TLR3-mediated N FKB activation, respectively. Figure 8C shows that alfadolone also inhibited TN Fa-induced N FKB activation.

[0068] Figure 9 is a series of graphs showing the effect of alfaxalone on the activation of N FKB in experiments on lung epithelial cells (line BEAS-2B), through different pathways, namely TLR2 activation of MyD88 (Figure 9A), TLR3 activation of TRIF (Figure 9B) and TNFa activation via a TLR-independent pathway (Figure 9C). Figures 9A-C show that alfaxalone did not modulate TLR2-mediated N FKB activation, TLR3-mediated N FKB activation, or TNFa-induced N FKB activation.

[0069] Figure 10 is a series of graphs showing the effect of alfadolone on the activation of ISRE in experiments on lung epithelial cells (line BEAS-2B). Figure 10 shows that ISRE was activated by different positive controls, namely Poly IC (Figure 10A), TNFa (Figure 10B) and IFNy (Figure IOC). Figure 10 shows that alfadolone did not inhibit ISRE activation caused by stimulation of the TRIF, JAK / STAT or TNFa pathways.

[0070] Figure 11 is a series of graphs showing the effect of alfaxalone on the activation of ISRE in experiments on lung epithelial cells (line BEAS-2B). Figure 11 shows that ISRE was activated by different positive controls, namely Poly IC (Figure 11A), TNFa (Figure 11B) and IFNy (Figure 11C). Figure 11 shows that alfaxalone did not inhibit ISRE activation caused by stimulation of the TRIF, JAK / STAT or TNFa pathways.

[0071] Figure 12 is a diagram summarising the inhibition effects of alfadolone on TLR2, TLR3 and TNFa-mediated N FKB signalling downstream of MyD88 and TRAF6. Figure 12 proposes that alfadolone's inhibition effect occurs downstream of TRIF / MyD88. It is contemplated that alfadolone targets a complex shared between TRIF, MyD88 and TNFa signalling because it is understood that TNFa does not use the MyD88 or TRIF pathways. It is hypothesized that the site of action for neuroactive steroids antagonizing N FKB effects via TLR2 stimulation is downstream of MyD88 / TIRAP and TRAF6 and occurs at TAKl or beyond (as indicated by the ellipse surrounding the "TAK1" element in Figure 12). This is different to N FKB effects via TLR4 stimulation of which activation starts upstream of TIRAP and TRAF6.

[0072] Figure 13 is a diagram showing the "TAK1 / TAB" complex (as indicated by the ellipse surrounding this complex) as a part of the TRIF pathway modulated by TLR3.

[0073] Figure 14 is a series of graphs showing the effect of alfadolone and alfaxalone on the secretion by BEAS-2B cells of the pro-inflammatory cytokine IL-6 in response to stimulation of TLR2 by Pam3CSK4 (Figure 14A), stimulation of TLR3 by Poly IC (Figure 14B), and stimulation of TLR4 by LPS (Figure 14C).

[0074] Figure 15A is a graph showing the effect of TLR stimulation on the secretion of CXCL10, which is a chemokine critical for innate immunity including the migration and localization of immune cells, and involved in acquired immunity and antibody production. Figure 15B is a graph showing the effect of alfadolone and alfaxalone on the secretion of CXCL10 in response to stimulation of TLR3 by Poly IC.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of thepresent invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0076] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0077] By "about" is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0078] The terms "administration concurrently" or "administering concurrently" or "co-administering" and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and / or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition. By "simultaneously" is meant that the agents are administered at substantially the same time, and desirably together in the same composition. By "contemporaneously" it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term "same site" includes the exact location, but can be within about 0.5 to about 15 centimetres, preferably from within about 0.5 to about 5 centimetres. The term "separately" as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order. The term "sequentially" as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.

[0079] The term "anaesthesia" is used herein to refer to a state of controlled, temporary loss of sensation or awareness. It may include some or all or analgesia, paralysis, amnesia and unconsciousness. General anaesthesia suppresses central nervous system activity and results in unconsciousness and complete lack ofsensation. Regional and local anaesthesia blocks transmission of nerve impulses from a specific part of the body. In such instances, the subject may remain fully conscious. In particular embodiments, the term "anaesthesia" refers to general anaesthesia. The term "anaesthetic" refers to a substance that induces anaesthesia.

[0080] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0081] The term "bispectral index" is used herein to refer to a technology used to monitor the depth of anaesthesia. The bispectral index is a measure of the level of consciousness of a subject by algorithmic analysis of the subject's EEG during anaesthesia. Bispectral index values range from 0 to 100, with a value of 0 representing the absence of cerebral cortical activity and a value of 100 representing the awake state. Values between 40 and 60 represent adequate general anaesthesia for a surgery and values less than 40 represent a deep hypnotic state. The bispectral index is calculated using a bispectral index monitor, which is commercially available from, for example, Medtronic pic (Minneapolis, USA).

[0082] The term "burst suppression" is used herein to refer to an electroencephalography (EEG) pattern that is observed in unconscious subjects involving alternating high amplitude bursts and low amplitude periods. Burst suppression patterns differ in the durations of the alternating periods. The "burst suppression ratio" measures the amount of time within an interval spent in the suppressed state and is calculated by (the total time of suppression / epoch length) x 100%.

[0083] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term "comprising" and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements arerequired or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0084] The term "cytokine release syndrome" or "CRS" refers to a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction. The term cytokine storm is often used interchangeably with CRS but, despite the fact that they have similar clinical phenotype, their characteristics are different. When occurring as a result of a therapy, CRS symptoms may be delayed until days or weeks after treatment. Immediate-onset CRS is a cytokine storm, although severe cases of CRS have also been called cytokine storms.

[0085] As used herein, the term "cytokine storm" refers to an excessively activated cytokine cascade or hypercytokinemia, i.e., an excessive or uncontrolled release of pro-inflammatory cytokines, which can be associated with a wide variety of infectious and noninfectious diseases or disorders. Cytokine storm syndromes are associated with a group of disorders (such as, but not limited to, influenza, asthma, hantavirus pulmonary syndrome, SIRS, macrophage activation syndrome, SARS, COVID-19, rabies virus infection and disseminated vascular coagulopathy), representing a variety of inflammatory causes. Typically, the primary symptoms of a cytokine storm are high fever, swelling and redness, extreme fatigue and nausea. In some cases, the immune reaction can result in bleeding, clotting, internal organ injury, or shock, and may be fatal.

[0086] By "derivative" is meant a molecule, such as a small molecule, that has been derived from the basic molecule by modification, for example by conjugation or complexing with other chemical moieties, the addition of a functional group or other medicinal chemistry techniques as would be understood in the art, for example, a molecule comprising an ester, amide, or an active metabolite of a compound. The term "derivative" also includes within its scope alterations that have been made to a parent molecule including additional groups, removal of groups or replacement of groups that provide for functionally equivalent molecules. The term "derivative" includes molecules wherein one or more hydrogen atoms have been replaced with another atom, such as a deuterium atom, or a labelled molecule, such as a tritiated molecule.

[0087] As used herein, the term "dosage unit form" refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.

[0088] By "effective amount", in the context of treating or at least partially inhibiting the development or progression of a condition is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and / or treating existing symptoms, of that condition. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. Non-limiting symptoms of infections, for example, include acute febrile illness, malaise, fatigue, headache, flushing, diarrhoea, nausea, vomiting, coughing including dry coughing, sore throat, runny nose, nasal congestion, and, in severe disease, symptoms of systemic inflammatory response syndrome including production of pro-inflammatory mediators, vascular leakage and organ failure.

[0089] As used herein, the term "inhibit", "inhibits", or "inhibiting" (and grammatical equivalents thereof), in the context of development of a disease, disorder or condition, refers to a delay in the onset of the disease, disorder or condition, reducing the manifestation of symptoms of the disease, disorder or condition, minimising development of the disease, disorder or condition, or the lessening of symptoms upon onset of the disease, disorder or condition. The terms are not meant to imply complete abolition of disease and encompasses any type of prophylactic treatment that reduces the incidence of the condition or delays the onset and / or slows progression of the condition. In the context of the progression of a disease, disorder or condition, these terms refer to a delay in or lack of the development or advancement of a disease, disorder or condition, reducing the manifestation of symptoms of the disease, disorder or condition or the lessening of symptoms of the disease, disorder or condition in a subject that already has the disease, disorder or condition. In the context of a viral infection, the phrase "inhibiting the progression of" may refer to the inhibition, reduction or delay of the invasion of the infectious agent into the central nervous system.

[0090] The term "inhibitor" as used herein refers to an agent that decreases or at least partially inhibits at least one function or biological activity of a target molecule.

[0091] The term "interaction", including its grammatical equivalents, when referring to an interaction between two molecules, refers to the physical contact of the molecules with one another. Generally, such an interaction results in an activity (which produces a biological effect, such as viral binding to a host cell and / or viral entry into a host cell) of one or both of said molecules. The physical contact typically requires binding or association of the molecules with one another and may involve the formation of an induced magnetic field or paramagnetic field, covalent bond formation, ionic interaction (such as, for example, as occurs in an ionic lattice), a hydrogen bond, or alternatively, a van der Waals interaction such as, for example, a dipole-dipole interaction, dipole-induced dipole interaction, induced dipole-induced dipole interaction, or a repulsive interaction, or any combination of the above forces of attraction. In particular embodiments, the interaction is a non-covalent interaction.

[0092] As used herein, the term "multisystem inflammatory syndrome in children" or"MIS-C" is a rare life-threatening illness where different body parts can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. Children with MIS-C may have a fever and various symptoms, including abdominal (gut) pain, vomiting, diarrhoea, neck pain, rash, bloodshot eyes, or feeling extra tired.

[0093] As used herein, the term "multisystem organ failure" refers to the dysfunction in two or more organ systems caused by inflammation, such as from an infection or injury.

[0094] The term "neuroactive steroid" is used herein to refer to a natural or synthetic steroid that alters neuronal excitability by binding to a membrane-bound receptor, such as a receptor for an inhibitory or excitatory neurotransmitter (e.g. gamma-amino-butyric acid). In particular embodiments, the neuroactive steroid exerts inhibitory actions on neurotransmission.

[0095] The term "neurotropic virus" as used herein refers to a virus that is capable of affecting the nervous system of a subject, such as a human host. In some embodiments, the virus is capable of causing a central nervous system disease with both neuroinvasive and neurovirulent properties. In particular embodiments, entry of the virus into a neuronal cell and / or neuronal transport of the virus is associatedwith an activity of a member of the tumour necrosis factor receptor family, such as p75NTR.

[0096] By "pharmaceutically acceptable carrier" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, fillers, detergents, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives and the like.

[0097] Similarly, a "pharmaceutically acceptable" salt, solvate or prodrug of a compound as provided herein is a salt, solvate or prodrug that is not biologically or otherwise undesirable.

[0098] As used herein, the terms "salts" and "prodrugs" include any pharmaceutically acceptable salt, ester, hydrate or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a neuroactive steroid, or an active metabolite or residue thereof. The term "pharmaceutically acceptable salts" refers without limitation to derivatives of the disclosed neuroactive steroids wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g. by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate and valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salt can be synthesised from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in, for example, Remington: The Science and Practice of Pharmacy, Adeboye Adejare and Joseph Remington (Ed), Academic Press, London, 23rdEdition, 2021; Stahl and Wermuth (2002) Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; and Berge et al. (1977) Journal of Pharmaceutical Science, 66: 1-19, each of which is incorporated herein by reference in its entirety.

[0099] The terms "reduce", "inhibit", "decrease", "prevent", and grammatical equivalents when used in reference to the level of a substance and / or phenomenon in a first sample relative to a second sample, mean that the quantity of substance and / or phenomenon in the first sample is lower than in the second sample by any amount that is statistically significant using any art-accepted statistical method of analysis. When these terms are used to refer to the action of a compound or therapeutic agent, the first sample may be a sample in the presence of the compound or therapeutic agent and the second sample may be a comparative sample without the compound or therapeutic agent. In one embodiment, the reduction may be determined subjectively, for example when a patient refers to their subjective perception of disease symptoms, such as pain, headache, fatigue, nausea, motor symptoms, coughing, sore throat, nasal congestion, runny nose, etc. In another embodiment, the reduction may be determined objectively, for example when the amount of virus (e.g. viral load) in a sample from a subject is lower than in an earlier sample from the subject. In another embodiment, the quantity of substance and / or phenomenon in the first sample is at least 10% lower than the quantity of the same substance and / or phenomenon in a second sample. In another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 25% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 50% lower than the quantity of the same substance and / or phenomenon in a second sample. In a further embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 75% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / orphenomenon in the first sample is at least 90% lower than the quantity of the same substance and / or phenomenon in a second sample.

[0100] The terms "sedation," "sedating" and the like are used herein to refer to a depression of consciousness resulting in a state of calm or sleep produced by a substance. Minimal sedation is typically given to relieve anxiety and has little effect on patient awareness. However, a moderately sedated subject has a depressed consciousness but is capable of responding to external stimuli. A deeply sedated subject only responds purposefully to repeated or painful stimuli. In particular embodiments, the terms "sedation," "sedating" and the like refer to moderate or deep sedation. A "sedative" refers to a substance that is a central nervous system depressant and induces sedation.

[0101] The term "subject" as used herein refers to a vertebrate subject, particularly a mammalian subject, for whom therapy or prophylaxis is desired. Suitable subjects include, but are not limited to, primates; birds; livestock animals such as sheep, cows, horses, deer, donkeys and pigs; laboratory test animals such as rabbits, mice, rats, guinea pigs and hamsters; companion animals such as cats and dogs; and captive wild animals such as foxes, deer and dingoes. In particular embodiments, the subject is a primate, suitably a human. However, it will be understood that the aforementioned terms do not imply that symptoms are present.

[0102] As used herein, the term "systemic inflammatory response syndrome" or "SIRS" refers to a clinical response arising from a non-specific insult with two or more of the following measurable clinical characteristics; a body temperature greater than 38°C or less than 36°C, a heart rate greater than 90 beats per minute, a respiratory rate greater than 20 per minute, a white blood cell count (total leukocytes) greater than 12,000 per mm3or less than 4,000 per mm3, or a band neutrophil percentage greater than 10%. From an immunological perspective, it may be seen as representing a systemic response to an infectious (e.g. pathogen) or non-infectious insult (e.g. major surgery) or systemic inflammation. Confirmation of infection can be determined using any suitable procedure known in the art, illustrative examples of which include blood culture, nucleic acid detection (e.g. PCR, mass spectroscopy, immunological detection (e.g. ELISA), isolation of bacteria from infected cells, cell lysis and imaging techniques such as electron microscopy.

[0103] The term "therapeutic agent" includes a compound that induces a desired pharmacological and / or physiological effect. The term also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those compounds specifically mentioned herein including but not limited to salts, esters,amides, prodrugs, active metabolites, analogues and the like, unless otherwise specified. When the above term is used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogues, etc. The term "therapeutic agent" is not to be construed narrowly but extends to small molecules, polymers, proteinaceous molecules such as peptides, polypeptides and proteins as well as compositions comprising them and genetic molecules such as RNA, DNA and mimetics and chemical analogues thereof as well as cellular agents.

[0104] The term "titrated" as used herein refers to the administration of incremental doses of a molecule, such as a neuroactive steroid, to a subject until a desired effect is reached, such as sedation and / or anaesthesia.

[0105] As used herein, the terms "treatment", "treating", and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease, disorder or condition and / or adverse effect attributable to the disease, disorder or condition. These terms also cover any treatment of a condition, disorder or disease in a subject, particularly in a human, and include: (a) inhibiting the disease, disorder or condition, i.e. arresting its development; or (b) relieving the disease, disorder or condition, i.e. causing regression of the disease, disorder or condition.

[0106] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Abbreviations

[0107] The following abbreviations are used throughout the application: p75NTR =p75 neurotrophin receptorMyD88 = myeloid differentiation factor 88NMDA =N-methyl-D-aspartatePXR = pregnane X receptorCRS =cytokine release syndromeMIS-C = multisystem inflammatory syndrome in childrenSIRS =systemic inflammatory response syndromeARDS =acute respiratory distress syndromeSARS =severe acute respiratory syndromeN FKB = nuclear factor kappa-light-chain-enhancer of activated B cellsRab =Ras-associated binding proteinRABV = rabies virusTRIF =Toll / interleukin-l receptor domain-containing adapterinducing interferon-pTLR =Toll-like receptorTNF-a =tumour necrosis factor-alphaTNFR1 =tumour necrosis factor receptor 1DAMPS =damage-associated molecular patternsPAMPS = pathogen-associated molecular patternsIL = interleukinIL-6 = interleukin-6IL-ip = interleukin-1 betaTIRAP =Toll / interleukin-l receptor domain-containing adaptor proteinTRAF6 =tumour necrosis factor receptor (TNFR)-associated factor 6TRAF3 =tumour necrosis factor receptor (TNFR)-associated factor 3IRAK = interleukin-1 receptor-associated kinases IRAKIKP =kappa-B kinase subunit betaBDNF = brain-derived neurotrophic factorIKKa & P = inhibitor of nuclear factor kappa-B kinase complex comprising subunits a,pCCL2 =CC motif chemokine ligand 2CCL5 =CC motif chemokine ligand 5CXCL10 =CXC motif chemokine ligand 10IFN = interferon type I IFN =type I interferon type III IFN =type III interferon pro-BDNF = pro-brain-derived neurotrophic factor m-BDNF = mature brain-derived neurotrophic factorISRE = interferon-sensitive response elementPoly IC = polyinosinic: polycytidylic acidPam3CSK4 = Pam3CysSerLys4JAK = Janus KinaseJAKi inhibitor of Janus KinaseSTAT = signal transducers and activators of transcriptionIFNAR2 = interferon alfa and beta receptor subunit 2TRAM =TRIF-related adaptor moleculeTAK1 = transforming growth factor-p-activated kinaseACHP =2-Amino-6-chloro-4-(l-phenylethylamino)-pyridineLPS = lipopolysaccharidePBMC = peripheral blood mononuclear cells3. Neuroactive Steroids

[0108] The inventor has determined that particular neuroactive steroids, including alfaxalone and alfadolone, will be useful for treating or at least partiallyinhibiting the development or progression of an infection by a neurotropic virus, and a condition associated with an infection by a neurotropic virus.

[0109] Accordingly, the methods and uses disclosed herein comprise administering or contacting a cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, rena noIone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan- 20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3g- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0110] In some embodiments, the methods and uses disclosed herein comprise administering or contacting a cell with a combination of neuroactive steroids. In particular embodiments, the combination of neuroactive steroids is alfaxalone and alfadolone. In some embodiments, the methods and uses involve administering or contacting a cell with alfaxalone and alfadolone, or a pharmaceutically acceptable salt or solvate of either of the foregoing.

[0111] In some embodiments, the neuroactive steroid is substantially devoid of hormonal endocrine activity, especially wherein the neuroactive steroid is devoid of hormonal endocrine activity.

[0112] In particular embodiments, the neuroactive steroid activates a pregnane X receptor (PXR), i.e. is a PXR agonist.

[0113] In some embodiments, the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, renanolone, 2f>-(2,2- dimethyl-4-morpholinyl)-3a-hyd roxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, and alfadoloneacetate. In particular embodiments, the neuroactive steroid is alfaxalone. In alternative embodiments, the neuroactive steroid is alfadolone or alfadolone acetate. In some embodiments, the neuroactive steroid is alfadolone. In some embodiments, the neuroactive steroid is alfaxalone and alfadolone or alfadolone acetate.

[0114] The neuroactive steroids may be in neutral form or may be in the form of salts (especially pharmaceutically acceptable salts), solvates (including hydrates), solvates (including hydrates) of salts and polymorphs. In preferred embodiments, such forms are pharmaceutically acceptable forms. The neuroactive steroids may be prepared in crystalline or non-crystalline form, and may be optionally hydrated or solvated. The invention includes stoichiometric hydrates as well as compounds containing variable amounts of water. Solvates include stoichiometric solvates and non-stoichiometric solvates.

[0115] In some embodiments, the neuroactive steroid is in the form of a sulfate salt. In some embodiments, the neuroactive steroid is pregnanolone sulfate or progesterone sulfate.

[0116] It is to be understood that the present invention encompasses all isomers of the neuroactive steroids and their pharmaceutically acceptable derivatives (e.g. salts), including all geometric, tautomeric and optical forms (e.g. enantiomers), and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in the neuroactive steroids, the present invention includes within its scope all possible diastereomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. In some embodiments, the neuroactive steroid is ent- progesterone or ent-pregnanolone.

[0117] While non-sedative and non-anaesthetic neuroactive steroids are contemplated by the methods and uses herein, in some embodiments, the neuroactive steroid is one having sedative and / or anaesthetic activity. In particular embodiments, the neuroactive steroid has sedative and anaesthetic activity. Neuroactive steroids such as alfadolone or alfaxalone may be used alone in situations where inflammatory modulation is required but sedation is undesirable. For example, in some embodiments, alfadolone is used alone where inflammatory modulation is required but sedation is undesirable. In some embodiments, a combination of neuroactive steroids is used, such as alfaxalone and alfadolone, for example in critical care where sedation and central nervous system suppression is desired for neuroprotection in established disease.

[0118] The neuroactive steroids can be prepared using chemical synthesis using techniques known in the art and / or can be obtained from commercial sources. For example, methods for preparing alfaxalone, alfadolone and alfadolone acetate are described in WO 2020 / 006596 Al, the entire contents of which are incorporated by reference herein. Neuroactive steroids, including alfaxalone, alfadolone, alfadolone acetate, ganaxolone, renanolone and 2p-(2,2-dimethyl-4-morpholinyl)- 3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate are also commercially available from, for example, Sigma-Aldrich, Inc. (St Louis, USA), Alfa Chemistry (Romkonkoma, USA), BOC Sciences (Shirley, USA), J&H CHEM Co., Ltd. (Hangzhou, China), Santa Cruz Biotechnology Inc. (Dallas, USA) and MedKoo Biosciences (Durham, USA).4. Compositions

[0119] In accordance with the present invention, neuroactive steroids selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof are useful in compositions and methods for treating or at least partially inhibiting the development or progression of an infection by a neurotropic virus, and a condition associated with an infection by a neurotropic virus. While it is possible that the neuroactive steroids may be administered in an undiluted form, it is preferable to present such compounds in the form of a composition. Thus, the methods and uses of the invention may involve administering to a subject or contacting a cell with a composition comprising a neuroactive steroid and a pharmaceutically acceptable carrier or diluent, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3|3- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In preferred embodiments, the composition is a pharmaceutical composition.

[0120] The neuroactive steroid may be formulated into the pharmaceutical composition as a neutral or salt form.

[0121] As will be appreciated by those skilled in the art, the choice of pharmaceutically acceptable carrier or diluent will be dependent on the route of administration and on the nature of the condition and subject to be treated. The particular carrier or delivery system and route of administration may be readily determined by a person skilled in the art. The carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the neuroactive steroid is not depleted during preparation of the formulation and the neuroactive steroid is able to reach the site of action intact. The compositions may be administered through a variety of routes including, but not limited to, oral, rectal, topical, intranasal, inhalation, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration. In particular embodiments, the pharmaceutical composition is administered via oral, intranasal, subcutaneous, intramuscular or intravenous administration; especially intravenous administration.

[0122] The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and may be preserved against reduction, oxidation and microbial contamination.

[0123] A person skilled in the art will readily be able to determine appropriate formulations for the neuroactive steroids using conventional approaches. Techniques for formulation and administration may be found in, for example,Remington: The Science and Practice of Pharmacy, Adeboye Adejare and Joseph Remington (Ed), Academic Press, London, 23rdEdition, 2021.

[0124] Identification of preferred pH ranges and suitable excipients, such as antioxidants, is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press). Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane (Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers. Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulfite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.

[0125] For injection or infusion, the neuroactive steroid may be formulated in an aqueous solution, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, dextrose solution or physiological saline buffer, such as phosphate buffered saline (PBS). The composition may further comprise a cyclodextrin as discussed in WO 2011 / 088503 Al, the contents of which are incorporated by reference herein. In particular embodiments, the cyclodextrin is a P-cyclodextrin or a modified form thereof, especially a sulfoalkyl ether p-cyclodextrin or a methylated, hydroxyalkylated, branched, alkylated, acylated or anionic derivative thereof; more especially (7) sulfobutyl ether p-cyclodextrin. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0126] The compositions may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline, dextrose solution or sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance. Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and non-ethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as non-ionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives and hydrophilicbeeswax derivatives. The liquid containing the composition may also contain suitable excipients, such as stabilisers or agents that increase the solubility of the neuroactive steroids. In some embodiments, the compositions are formulated in a form suitable for dissolution or dilution into a liquid for administration such as at a point of care (e.g. a powder or a gel).

[0127] Alternatively, the neuroactive steroid can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration, which is also contemplated for the practice of the invention. In some embodiments, the neuroactive steroid is formulated for oral administration in a dosage form such as a tablet, pill, capsule, liquid, gel, syrup, slurry, suspension, lozenge and the like for oral ingestion by a subject. In particular embodiments, the neuroactive steroid is formulated for oral administration in a solid dosage form, such as a tablet, pill, lozenge or capsule. In such embodiments, the pharmaceutically acceptable carrier may comprise a number of excipients including, but not limited to, a diluent, disintegrant, binder, lubricant, glidant, cyclodextrin and the like.

[0128] Suitable diluents (also referred to as "fillers") include, but are not limited to, lactose (including lactose monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, isomalt, microcrystalline cellulose, powdered cellulose, starch, pre-gelatinised starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose, silicates (e.g. silicon dioxide), polyvinyl alcohol, talc, and combinations thereof.

[0129] Suitable disintegrants include, but are not limited to, sodium carboxymethyl cellulose, pre-gelatinised starch, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, sodium starch glycolate, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, sodium alginate and combinations thereof.

[0130] Suitable binders include, but are not limited to, microcrystalline cellulose, gelatine, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose and combinations thereof.

[0131] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol and combinations thereof.

[0132] Suitable glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and combinations thereof.

[0133] The composition may also include a buffer and / or antioxidant as discussed supra. Further components of any one of the dosage forms discussed herein may include, but are not limited to, surfactants, flavouring agents, sweeteners, preservatives, and the like.

[0134] Pharmaceutical formulations for parenteral administration include aqueous solutions of the neuroactive steroid in water-soluble form. Additionally, suspensions of the neuroactive steroid may be prepared as nanoparticles or as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilisers or agents that increase the solubility of the neuroactive steroids to allow for the preparation of highly concentrated solutions. The formulation may also comprise a cyclodextrin as discussed supra.

[0135] Sterile solutions may be prepared by combining the compound in the required amount in the appropriate solvent with other excipients as described above as required, followed by sterilisation, such as filtration. Generally, dispersions are prepared by incorporating the various sterilised active compounds into a sterile vehicle which contains the basic dispersion medium and the required excipients as described above. Sterile dry powders may be prepared by vacuum- or freeze-drying a sterile solution comprising the active compounds and other required excipients as described above. In some embodiments, the sterile dry powders are reconstituted for administration as liquids.

[0136] Pharmaceutical preparations for oral use can be obtained by combining the neuroactive steroids with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more neuroactive steroids as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilising processes.

[0137] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterise different combinations of particle doses.

[0138] Pharmaceuticals which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilisers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilisers may be added.

[0139] The neuroactive steroids may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations. In some embodiments, the modified-release formulation is a delayed-release, extended-release or targeted-release formulation; especially an extended-release formulation.

[0140] The neuroactive steroids may be administered in a local rather than systemic manner, such as by injection directly into a tissue, which is preferably subcutaneous or omental tissue, often in a depot or sustained release formulation. In other embodiments, the neuroactive steroid is systemically administered.

[0141] Furthermore, the neuroactive steroid may be administered in a targeted drug delivery system, such as in a particle which is suitable targeted to and taken up selectively by a cell or tissue. In some embodiments, the compound is contained or otherwise associated with a vehicle selected from liposomes, micelles, dendrimers, biodegradable particles, artificial DNA nanostructure, lipid-based nanoparticles and carbon or old nanoparticles. In illustrative examples of this type, the vehicle is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), PLA-PEG copolymers and combinations thereof.

[0142] In cases of local administration or selective uptake, the effective local concentration of the agent may not be related to plasma concentration.

[0143] In some embodiments, the compositions are suitable for inhalation or intranasal delivery and are in the form of, for example, solutions, aerosols, dry powders, suspensions or emulsions. For example, the composition may be administered to the respiratory tract as a nasal or pulmonary inhalation aerosol or solution for a nebuliser, or as a microfine powder (e.g. with particles in the order of 1 to 10 pm in diameter or less) for insufflation, alone or in combination with an inert carrier, such as lactose or glucose, or with other pharmaceutically acceptable excipients, such as a cyclodextrin (e.g. beta-cyclodextrin), starch, sodium carboxymethylcellulose and the like.

[0144] Aerosol formulations include those in which the neuroactive steroid is provided in a pressurised pack with a suitable propellant such as a pressurised metered dose inhaler (pMDI). Whilst the propellant may be a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, the propellant is more preferably a non-chlorofluorocarbon propellant such as carbon dioxide, hydrofluoroalkanes (such as HFA-134a) or another suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of the neuroactive steroid may be controlled by provision of a metered valve. For delivery to the lung, a particle size of approximately 1 to 5 pm is useful, as particles smaller than 1 pm are generally exhaled without delivery to the lung and particles larger than 10 pm are mostly trapped by oropharyngeal deposition and do not reach the lung. Devices propelled by HFA-134a deliver smaller droplets which penetrate more readily into the bronchial airways. For drug delivery via the nasal passage, a suitable particle size is, for example, 20-80 pm, as smaller particles (less than 10 pm) get carried into the tracheobronchial region, whilst bigger particles (greater than 100 pm) get rapidly cleared from the nasal passageway.

[0145] The neuroactive steroid may also be provided in a pharmaceutical formulation which forms a gel in the nasal cavity. The neuroactive steroid may, alternatively, be formulated in a powder composition which may be presented in unit dose form for example in capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0146] It is advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. The determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0147] While the neuroactive steroid may be the sole active agent administered to the subject, the administration of other active agents concurrently with said neuroactive steroid is within the scope of the invention. For example, in some embodiments, the neuroactive steroid may be administered concurrently with one or more antivirals, anti-inflammatory agents, agents which inhibit the cytokine storm, analgesic, sedative, anaesthetic, NMDA receptor antagonist, antidiuretic hormone, fluid therapy, inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetrahydrobiopterin deficiency, sedating neuroprotective agent, therapy for lactic acidosis or ketosis, and / or Toll-like receptor antagonist. The neuroactive steroid may be therapeutically used after the other active agent or may be therapeutically used together with the other active agent. The neuroactive steroid may be administered separately, simultaneously or sequentially with the other active agent.

[0148] Accordingly, the methods and uses described herein may further comprise administering one or more other therapeutic agents. In particular embodiments, the one or more other therapeutic agents are selected from the group consisting of an antiviral, anti-inflammatory agent, agent which inhibits the cytokine storm, analgesic, sedative, anaesthetic, NMDA receptor antagonist, antidiuretic hormone (i.e. vasopressin), fluid therapy (e.g. saline, Ringer's lactate solution or plasmalyte), inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetrahydrobiopterin deficiency, sedating neuroprotective agent, therapy for lactic acidosis or ketosis (e.g. sodium bicarbonate, intravenous fluid, electrolytes, sodium nitroprusside, glucose, insulin, fructose or sorbitol), and Toll-like receptor antagonist.

[0149] Representative antivirals include abacavir sulfate, acyclovir sodium, adefovir, amantadine hydrochloride, amprenavir, atazanavir, baloxavir marboxil, bictegravir, boceprevir, bulevirtide, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine mesylate, didanosine, docosanol, dolutegravir, doravinine, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, ensitrelvir, entecavir, etravirine, famciclovir, fomivirsen sodium, fosamprenavir, foscarnet sodium, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, inosine pranobex, indinavir sulfate, lamivudine, lamivudine / zidovudine, letermovir, lopinavir, loviride, maraviroc, methisazone, molnupiravir, moroxydine, nelfinavir mesylate, nirmatrelvir, nirmatrelvir and ritonavir, nevirapine, nitazoxanide, norvir, oseltamivir phosphate, penciclovir, peramivir, pleconaril, polophyllotoxin, raltegravir, remdesivir, ribavirin, rilpivarine, rimantadine hydrochloride, ritonavir, saquinavir, saquinavir mesylate, simeprevir, sofosbuvir, stavudine, taribavirin, telaprevir, telbivudine, tenofovirdisoproxil, tenofovir alafenamide, tipranavir, trifluridine, trizivir, tromantadine, truvada, umifenovir, valacyclovir, valacyclovir hydrochloride, valganciclovir, zalcitabine, zanamivir, zidovudine and mixtures thereof; especially ribavirin.

[0150] In some embodiments, the antiviral is an anti-herpetic agent, antiinfluenza agent or interferon.

[0151] In some embodiments, the antiviral is a monoclonal antibody, especially a monoclonal antibody against rabies virus. Suitable antibodies include, but are not limited to, Rabishield (SII RMab), Twinrab (M777-16-3 and 62-71-3), rhRIG, SYN023 or CL184 (CR57 and CR4098).

[0152] In some embodiments, the ancillary active agent is an antiinflammatory agent, representative examples of which include steroidal antiinflammatory agents such as but not limited to compounds containing a 17-carbon 4-ring system, including sterols, various hormones (as anabolic steroids), and glycosides. Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and mixtures thereof.

[0153] Alternatively, the anti-inflammatory agent may be a nonsteroidal anti-inflammatory agent, non-limiting examples of which include agents that are aspirin-like in their action, including, but not limited to, ibuprofen, naproxen (e.g. naproxen sodium), and acetaminophen. Additional examples of non-steroidal antiinflammatory agents include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate,safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic (including meclofentamate sodium), flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.

[0154] In other embodiments, the anti-inflammatory agent includes, without limitation, transforming growth factor-beta 3 (TGF-P3), an anti-tumour necrosis factor-alpha (anti-TNF-a) agent, an inhibitor or antagonist of IL-6 or IL-6 receptor, IL-1 receptor, IL-ip, TNF, GM-CSF, IFN-y, JAK-STAT signalling, CCR2, complement component C5, IRAK4 and M-CSF receptor, or a combination thereof.

[0155] The neuroactive steroid may also be administered concurrently with agents which inhibit the cytokine storm. For example, suitable agents include compounds that target fundamental immune pathways, such as the chemokine network and the cholinergic anti-inflammatory pathway. For example, JAK inhibitors, such as JAK 1 and JAK 2 inhibitors, can inhibit the cytokine storm, and in some cases, are also antiviral. Representative JAK inhibitors include those disclosed in U.S. Pat. No. 10,022,378, such as Jakafi, Tofacitinib, and Baricitinib, as well as LY3009104 / INCB28050, Pacritinib / SB1518, VX-509, GLPG0634, INC424, R-348, CYT387, TG 10138, AEG 3482, and pharmaceutically acceptable salts and prodrugs thereof. Still further examples include CEP-701 (Lestaurtinib), AZD1480, INC424, R- 348, CYT387, TG 10138, AEG 3482, 7-iodo-N-(4-morpholinophenyl)thieno[3,2- d]pyrimidin-2-amine, 7-(4-aminophenyl)-N-(4-morpholinophenyl)thieno[3,2- d]pyrimidin-2-amine, N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) acrylamide, 7-(3-aminophenyl)-N-(4-morpholinophenyl)thieno[3,2- d]pyrimidin-2-amine, N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) acrylamide, N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, methyl 2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxylate, N-(4- morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(4-amino-3- methoxyphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N,N- dimethyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)benzenesulfonamide, l-ethyl-3-(2-methoxy-4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin- -7-yl)phenyl)urea, N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 2-methoxy-4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenol, 2- cyano-N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)acetamide, N-(cyanomethyl)-2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidine-7-carboxamide, N-(3-(2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)phenyl)methanesulfonamide, l-ethyl-3-(4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)-2- (trifluoromethoxy)phenyl)urea, N-(3-nitrophenyl)-7-phenylthieno[3,2-d]pyrimidin- 2-amine, 7-iodo-N-(3-nitrophenyl)thieno[3,2-d]pyrimidin-2-amine, Nl-(7-(2- ethylphenyl)thieno[3,2-d]pyrimidin-2-yl)benzene-l,3-diamine, N-tert-butyl-3-(2- (4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, Nl- (7-iodothieno[3,2-d]pyrimidin-2-yl)benzene-l,3-diamine, 7-(4-amino-3-(trifluoromethoxy)phenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3- (2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N- (cyanomethyl)-N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyri mid in-7- yl)phenyl) methanesulfonamide, N-(cyanomethyl)-N-(4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(3-(5-methyl-2-(4-morpholinophenylamino)-5H-pyrrolo[3,2-d]pyri mid in-7- yl)phenyl) methanesulfonamide, 4-(5-methyl-2-(4-morpholinophenylamino)-5H- pyrrolo[3,2-d]pyrimidin-7-yl) benzenesulfonamide, N-(4-(5-methyl-2-(4- morpholinophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-7- yl)phenyl) methanesulfonamide, 7-iodo-N-(4-morpholinophenyl)-5H-pyrrolo[3,2- d Jpyri mid in-2-a mine, 7-(2-isopropylphenyl)-N-(4-morpholinophenyl)thieno[3,2- d Jpyri mid in-2-a mine, 7-bromo-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2- amine, N7-(2-isopropylphenyl)-N2-(4-morpholinophenyl)thieno[3,2-d]pyrimidine- 2,7-diamine, N7-(4-isopropylphenyl)-N2-(4-morpholinophenyl)thieno[3,2- d Jpyri mid ine-2,7-dia mine, 7-(5-amino-2-methylphenyl)-N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(cyanomethyl)-4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, 7-iodo-N-(3- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-amino-3-nitrophenyl)-N- (4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-methoxypyridin-3-yl)- N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, (3-(7-iodothieno[3,2- d Jpyri mid in-2-ylamino)phenyl) methanol, N-tert-butyl-3-(2-(3- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-tert- butyl-3-(2-(3-(hydroxymethyl)phenylamino)thieno[3,2-d]pyrimidin-7- yl)benzenesulfonamide, N-(4-morpholinophenyl)-7-(4-nitrophenylthio)-5H- pyrrolo[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl) benzenesulfonamide, 7-(4- amino-3-nitrophenyl)-N-(3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N- (3,4-dimethoxyphenyl)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(3,4-dimethoxyphenylamino)thieno[3,2-d]pyrimidin-7- yl)benzenesulfonamide, 7-(2-aminopyrimidin-5-yl)-N-(3,4- dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7- (2,6-dimethoxypyridin-3-yl)thieno[3,2-d]-pyrimidin-2-amine, N-(3,4- dimethoxyphenyl)-7-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-d]pyrimidin-2-amine, 7-iodo-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-tert- butyl-3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7- yl)benzenesulfonamide, 2-cyano-N-(4-methyl-3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, ethyl 3-(2- (4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzoate, 7-bromo-N-(4- (2-(pyrrolidin-l-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3-(2-(4-(2- (pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(cyanomethyl)-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)benzamide, N-tert-butyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin- 7-yl)benzamide, N-tert-butyl-3-(2-(4-(l-ethylpiperidin-4- yloxy) phenylami no)thieno-[3, 2-d Jpyri mid in-7-yl) benzenesulfonamide, tert-butyl-4- (2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-lH-pyrazole-l- carboxylate, 7-bromo-N-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)thieno[3,2- d Jpyri mid in-2-a mine, N-tert-butyl-3-(2-(4-((4-ethylpiperazin-l- yl)methyl)phenylamino)- -th ieno[3, 2-d Jpyri mid in-7-yl) benzenesulfonamide, N-(4- ((4-ethyl pi perazin- 1-yl) methyl) phenyl)-7-(l H-pyrazol-4-yl)thieno[3,2-d]pyrimidin- 2-amine, N-(cyanomethyl)-3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2- d Jpyri mid in-7-yl) benzamide, N-tert-butyl-3-(2-(4-(2-( pyrrol id in-1- yl)ethoxy)phenylamino)thieno[3,2-d]-pyrimidin-7-yl) benzenesulfonamide, tertbutyl pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7- yl)benzylcarbamate, 3-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2- d Jpyri mid in-7-yl) benzenesulfonamide, 7-(3-chloro-4-fluorophenyl)-N-(4-(2- (pyrrolidin-l-yl)ethoxy)phenyl)thieno-[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2-(4- ( 1-ethylpi peridi n-4-yloxy)phenylami no)thieno[3, 2-d Jpyri midi n-7-yl)-l H-pyrazole-1- carboxylate, 7(benzo[d][l,3]dioxol-5-yl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, tert-butyl 5-(2-(4- (morpholi nomethyl) phenylami no)thieno[3, 2-d] pyrim id in-7-yl)- 1 H-indole-1- carboxylate, 7-(2-aminopyrimidin-5-yl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2- d]pyrimidin-2-amine, tert-butyl 4-(2-(-4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-5,6-di-hydropyridine-l(2H)-carboxylate, tert-butyl morpholinomethyl)phenylamino)thieno[3,2- d Jpyri mid in-7-yl) benzylcarbamate, N-(3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N- (4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)acetamide, N-(3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2- d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-(4-(4-methylpiperazin-l- yl)phenyl)-N-(4-(morpholinomethyl)phenyl)thieno-[3,2-d]pyrimidin-2-amine, N-(2- methoxy-4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyri mid in-7- yl)phenyl)acetamide, 7-bromo-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin- 2-amine, (3-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) methanol, (4-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) methanol, (3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) methanol, (4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl) methanol, N-(pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin- 7-yl)benzyl)methanesulfonamide, tert-butyl morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, N- (4-(morphol inomethyl) phenyl)-7-(3-(pi perazin- 1-yl) phenyl)thieno[3, 2-d Jpyri midi n- 2-amine, 7-(6-(2-morpholinoethylamino)pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-(2- (pyrrolidin-l-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-(aminomethyl)phenyl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2- amine, N-(4-(l-ethylpiperidin-4-yloxy)phenyl)-7-(lH-pyrazol-4-yl)thieno[3,2- d]pyrimidin-2-amine, N-(2, 4-dimethoxyphenyl)-7-phenylthieno[3, 2-d] pyrimidineamine, 7-bromo-N-(3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4- d imethoxyphenyl)-7-phenylthieno[3, 2-d ]pyrimidin-2-a mine, and pharmaceutically acceptable salts and prodrugs thereof.

[0156] Alternatively, or in addition, HMGB1 antibodies and / or COX-2 inhibitors can be used, which downregulate the cytokine storm. Examples of such compounds include Actemra (Roche) and Celebrex (celecoxib), a COX-2 inhibitor. IL- 8 (CXCL8) inhibitors can also be used.

[0157] Suitable analgesics include, but are not limited to, an opioid analgesic such as oxycodone, morphine, pethidine, codeine, hydrocodone, dihydrocodeine, dihydromorphine, fentanyl, buprenorphine, butorphanol, hydromorphone, levallorphan, levorphanol, methadone, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxymorphone, tapentadol, tramadol, propoxyphene, ketobemidone, alfentanil, sufentanil, remifentanil or pentazocine; an NSAID as discussed supra; paracetamol; flupirtine; nefopam; retigabine; duloxetine;promethazine; carisoprodol; anileridine; an anticonvulsant-type analgesic including pregabalin, gabapentin, gabapentin enacarbil, carbamazepine, topiramate or lamotrigine; a tricyclic antidepressant such as clomipramine, amitriptyline, desipramine, imipramine, doxepin or nortriptyline; an antidepressant such as trazodone, duloxetine or milnacipran; an enkephalinase inhibitor such as phosphoramidon, racecadotril, bestatin, / V-([(R,S)-2-benzyl-3[(S)(2-amino-4- methylthio)butyldithio]-l-oxopropyl)-L-phenylalanine benzyl ester (RB101), RB3007, / V-((S)-2-benzyl-3[(S)-2-amino-4-methylthio)butyldithio-]-l-oxopropyl)-L- alanine benzyl ester (RB120), opiorphin, thiorphin, kelatorphan, D-phenylalanine, tynorphin or spinorphin; opioid peptides such as an endorphin, an enkephalin, a dynorphin, adrenorphin, amidorphin, an endomorphin, a hemorphin, a rubiscolin, a casomorphin, a deltorphin or a dermorphin; a barbiturate such as amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital or thiopental; an NMDA receptor antagonist such as dextromethorphan, ketamine, neramexane or memantine; an alpha-adrenergic such as clonidine, guanfacine or dexmedetomidine; a tachykinin antagonist such as aprepitant or maropitant; a muscarinic acetylcholine receptor antagonist such as oxybutynin, propiverine, trospium, flavoxate, darifenacin, solifenacin, temaverine or ipratropium; a nicotinic acetylcholine receptor agonist such as varenicline, tebanicline or nicotine; a transient receptor potential vanilloid type 1 (TRPV1) receptor agonist such as resiniferatoxin or capsaicin; a TRPV1 receptor antagonist such as capsazepine or mavatrep; a transient receptor potential ankyrin 1 (TRPA1) receptor agonist such as cinnemaldehyde; a TRPA1 receptor antagonist such as GRC 17536, CB-625, mecamylamine, 4-nitro- / V-(2,2,2-trichloro-l-((4- chlorophenyl)sulfanyl)ethyl) benzamide (AMG2504), 4-methoxy- / V-(2,2,2-trichloro- l-((4-chlorophenyl)sulfanyl)ethyl)benzamide (AMG5445), 4-bromo- / V-(2,2,2- trichloro-l-((4-chlorophenyl)sulfanyl)ethyl)benzamide (AMG7160), / V-(2,2,2- trichloro-l-((4-chlorophenyl)sulfanyl)ethyl)benzamide (AMG9090), 4-methyl- / V- [2,2,2-trichloro-l-(4-nitro-phenylsulfanyl)-ethyl]-benzamide (CM Pl), 4-methyl- / V- [2,2,2-trichloro-l-(4-chlorophenylsulfanyl)ethyl]benzamide (CMP2), N-[2,2,2- trichloro-l-(4-chlorophenylsulfanyl)ethyl]acetamide (CMP3), 1,2,3,6-tetrahydro- l,3-dimethyl- / V-[4-(l-methylethyl)phenyl]-2,6-dioxo-7H-purine-7-acetamide (HC- 030031), 2-(l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydro-7H-purin-7-yl)- / V-[4-(l- methyl propyl) phenyl ]acetamide (Chembridge-5861528), 4-(4-chlorophenyl)-3- methylbut-3-en-2-oxime (AP-18), or (lE,3E')-l-(4-fluorophenyl)-2-methyl-l- penten-3-one oxime (A-967079); a transient receptor potential vanilloid subtype 3 (TRPV3) receptor antagonist such as GRC 15300 (SAR292833); a corticosteroid such as dexamethasone; a serotonin receptor agonist such as eletriptan, sumatriptan,naratriptan, solmitriptan or rizatriptan; a phosphodiesterase type 5 (PDE5) inhibitor such as sildenafil, tadalafil or vardenafil; a muscle relaxant such as diazepam, lorazepam, methocarbamol, cyclobenzaprine, metaxalone, tizanidine or baclofen; a serotonin reuptake inhibitor such as sertraline, desmethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, escitalopram, fenfluoramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine or trazodone; a noradrenaline reuptake inhibitor such as maprotiline, reboxetine, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, hydroxybuproprion, nomifensine or viloxazine; a serotonin and noradrenaline reuptake inhibitor such as venlafaxine, desvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran or imipramine; a 5- lipoxygenase inhibitor such as esculetin or zileuton; a calcium channel blocker such as ziconotide or ethosuximide; a sodium channel modulator such as bupivacaine, lidocaine, mexiletine or phenytoin; and salts and combinations thereof.

[0158] In some embodiments, the analgesic is selected from the group consisting of fentanyl, pethidine, meperidine, anileridine, alfentanil, sufentanil, remifentanil, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, codeine, methadone, tramadol, buprenorphine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, flurbiprofen, acetaminophen, aspirin, ibuprofen and naproxen.

[0159] Suitable anaesthetic or sedative agents may include, but are not limited to, procaine, amethocaine, lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, tetracaine, etidocaine, desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, barbiturates (e.g. amobarbital, thiamylal, methohexital, thiopental), benzodiazepines (e.g. diazepam, lorazepam, midazolam), etomidate, ketamine, propofol, dexmedetomidine, melatonin, xenon, haloperidol, and salts and combinations thereof.

[0160] Suitable NMDA receptor antagonists include, but are not limited to, dextromethorphan, ketamine, neramexane, amantadine or memantine; especially amantadine or ketamine.

[0161] Representative calcium channel antagonists include ziconotide, ethosuximide, nimodipine, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, pranidipine, fendiline, gallopamil, verapamil and diltiazem; especially nimodipine.

[0162] In some embodiments, the therapy for delayed ischemic deficit from nitric oxide excess is an inhibitor of inducible nitric oxide synthase, neuronal nitric oxide synthase or endothelial nitric oxide synthase.

[0163] Suitable therapies for tetrahydrobiopterin deficiency include, but are not limited to, sapropterin and biopterin.

[0164] Exemplary sedating neuroprotective agents include melatonin, dexmedetomidine and propofol.

[0165] In some embodiments, the methods and uses involve the administration of one or more Toll-like receptor antagonists, such as a Toll-like receptor 2 antagonist, Toll-like receptor 4 antagonist or Toll-like receptor 7 antagonist; especially a Toll-like receptor 4 antagonist or Toll-like receptor 7 antagonist; more especially a Toll-like receptor 4 antagonist. Representative Tolllike receptor antagonists include eritoran, (R)-ethyl 6-(N-(2-chloro-4- fluorophenyl)sulfamoyl)cyclohex-l-enecarboxylate (TAK-242, resatorvid), candesartan, valsartan, fluvastatin, atorvastatin, (4R,7R,8aR)-l'-[2-[4-[[2-(2,4- dichlorophenoxy)acetyl]amino]phenyl]acetyl]-6-oxospiro[3,4,8,8a-tetrahydro-2 / 7- pyrrolo[2,l-b][l,3]thiazine-7,2l-pyrrolidine]-4-carboxamide (ST2825), chloroquine, hydroxychloroquine, 6,7-dimethoxy-2-(4-(4-methylpiperazin-l-yl)phenyl)-N-(2- morpholinoethyl)quinazolin-4-amine (CPG-52364), p-aminoarteether maleate (SM934), OPN-305, T2.5, NI-0101, 1A6, IRS-954, DV-1179, IMO-3100, IMO-8400, IMO-9200, IHN-ODN 2088, IHN-ODN-24888, miR-146a, miR-21, lipid-conjugated non-anticoagulant heparin nanoparticle (NAHNP), high-density lipoprotein (HDL)-like nanoparticle, bare gold nanoparticle, glycolipid-coated gold nanoparticle and peptidegold nanoparticle hybrid, P12.

[0166] Suitable inotropes include, but are not limited to, digoxin, berberine, calcium sensitisers (e.g. levosimendan), catecholamines (e.g. dopamine, dobutamine, dopexamine, adrenaline, isoproterenol, noradrenaline), angiotensin II, eicosanoids (e.g. prostaglandins), phosphodiesterase inhibitors (e.g. enoximone, milrinone, amrinone, theophylline), glucagon and insulin.

[0167] Representative antiarrhythmics include, but are not limited to, sodium channel antagonists (e.g. ajmaline, disopyramide, procainamide, quinidine, sparteine, lidocaine, mexiletine, phenytoin, tocainide, encainide, flecainide, morcizine and propafenone), beta-blockers (e.g. atenolol, bisoprolol, carvediol, esmolol, metoprolol, nebivolol, propranolol and timolol), potassium channel antagonists (e.g. amiodarone, dofetilide, dronedarone, E-4031, ibutilide, sotalol and vernakalant),calcium channel antagonists (e.g. diltiazem and verapamilo), adenosine, digoxin and magnesium sulfate.

[0168] Suitable vasodilators include, but are not limited to, angiotensin II receptor blockers (e.g. losartan, irbesartan, olmesartan, eprosartan, candesartan, valsartan, fimasartan, telmisartan and azilsartan), ACE inhibitors (e.g. captopril, analapril, lisinopril, benazepril, fosinopril, quinapril, ramipril, perindopril, moexipril, trandolapril, alacepril, zofenopril, imidapril and cilazapril), a calcium channel antagonist as described supra, methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride, hydralazine and minoxidil.

[0169] As previously described, the neuroactive steroid may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. Suitable unit dosages and maximum daily dosages of the neuroactive steroid may be determined in accordance with the unit doses and maximum daily doses used conventionally. In some embodiments, a unit dosage form may comprise the neuroactive steroid in an amount in the range of from about 0.25 pg to about 2000 mg. The neuroactive steroid may be present in an amount of from about 0.25 pg to about 2000 mg / mL of carrier. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.5. Methods of Use

[0170] Particular neuroactive steroids, including alfaxalone and alfadolone, have been found to inhibit the activation of MyD88 by a Toll-like receptor in response to a neurotropic virus. Based on this activity, such neuroactive steroids are considered to be useful for treating or at least partially inhibiting the development or progression of an infection by a neurotropic virus, and a condition associated with an infection by a neurotropic virus.

[0171] In one aspect, there is provided a method of treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5|3-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. Also provided is a use of a neuroactive steroid for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus; a neuroactive steroid for use in treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus; and a use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0172] Suitable embodiments of the neuroactive steroid or salt or solvate thereof are as discussed supra.

[0173] While the treatment of any viral infection is contemplated, in particular embodiments, the infection is a central nervous system infection. In some embodiments, the infection is a chronic (i.e. an infection of at least six months) or acute infection, especially an acute infection (i.e. an infection of less than six months).

[0174] The infection may be associated with several conditions or symptoms depending on the virus and location of infection in the subject. In particular embodiments, the infection is associated with a condition of the central nervous system, including the brain and / or spinal cord. Suitable conditions include, but are not limited to, multisystem organ failure, acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis, encephalomyelitis, an acute inflammatory condition, cytokine release syndrome (CRS), multisystem inflammatory syndrome in children (MIS-C), systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and severe acute respiratory syndrome (SARS). In particular embodiments, the infection is associated with acute encephalopathy or acute encephalitis.

[0175] In some embodiments, the infection is associated with presence of CRS or a cytokine storm. Illustrative examples of this type include wherein the CRS or cytokine storm comprises an elevation of at least 50% compared to basal state of one or more cytokines selected from IFN-y, IFN-p, TNF-a, IL-ip, IL-6, IL-17A and CC motif chemokine ligand 2 (CCL2). Non-limiting symptoms associated with a cytokine storm include one or more symptoms selected from high fever, swelling and redness, extreme fatigue, nausea, bleeding, clotting, internal organ injury, and shock, or any combination thereof.

[0176] The infection may also be associated with the development of inflammation, especially inflammation of a component of the central nervous system, such as the brain or spinal cord. In some embodiments, the infection is associated with the development of excessive inflammation and / or a cytokine storm. Excessive inflammation may, for example, include a prolonged state of overactivity of an inflammatory response leading to ongoing excessive release of inflammatory cytokines and cytotoxic cells. This may result in ultrastructural damage and dysfunction to neurons, astrocytes, glia and / or the central nervous system.

[0177] In some embodiments, the infection is associated with inflammation and / or a cytokine storm. In some embodiments, the inflammation or cytokine storm is associated with an activity of a Toll-like receptor (e.g. Toll-like receptor 2, Toll-like receptor 4 or Toll-like receptor 7; especially Toll-like receptor 4 or Toll-like receptor 7; more especially Toll-like receptor 4), such as activation of MyD88.

[0178] The neurotropic virus may be any virus that is capable of infecting nerve tissue, especially the central nervous system. In preferred embodiments, infection of the nerve tissue and / or neuronal transport of the virus is associated with activity of a member of the tumour necrosis factor receptor family, such as p75NTR.The neurotropic virus may be a double stranded DNA virus, single stranded DNA virus, double stranded RNA virus, single stranded positive-sense RNA virus, single stranded negative-sense RNA virus, single stranded RNA reverse transcriptase virus or double stranded DNA reverse transcriptase virus.

[0179] In particular embodiments, the virus is a single stranded negativesense RNA virus or single stranded positive-sense RNA virus virus.

[0180] In some embodiments, the virus is a single stranded negative-sense RNA virus. In some embodiments, the virus is a rhabdovirus, filovirus, paramyxovirus, arenavirue, bunyavirus or bornavirus.

[0181] For example, in some embodiments, the virus is a rhabdovirus, such as one selected from the group consisting of a lyssavirus, vesiculovirus and ephemerovirus. In some embodiments, the virus is a lyssavirus selected from the group consisting of Aravan virus, Australian bat lyssavirus, Bokeloh bat lyssavirus, Duvenhage virus, European bat 1 lyssavirus, European bat 2 lyssavirus, Gannoruwa bat lyssavirus, Irkut virus, Khujand virus, Madagascar bat lyssavirus, rabies virus, Lagos bat virus, Mokola virus, Shimoni bat virus, West Caucasian bat virus, Ikoma lyssavirus and Lleida bat lyssavirus; especially rabies virus. In some embodiments, the virus is a vesiculovirus selected from the group consisting of Vesicular stomatitis virus, Carajas virus, Chandipura virus, Cocal virus, Eptesicus virus, Isfahan virus, Jurona virus, Malpais Spring virus, Maraba virus, Morreton virus, New Jersey virus, Perinet virus, Piry virus, Radi virus, Jinghong bat virus, Yug Bogdanovac virus and vesicular stomatitis Alagoas virus. Alternatively, the virus may be an ephemerovirus selected from the group consisting of bovine ephemeral fever virus, Berrimah virus, Kimberley virus, Hayes Yard virus, Puchong virus, Adelaide River virus, Obodhiang virus, porcine ephemerovirus 1, porcine ephemerovirus 2, Yata virus, New Kent County virus, kotonkan virus and Koolpinyah virus.

[0182] In some embodiments, the virus is a filovirus selected from the group consisting of a Cuevavirus, Dianlovirus, Ebolavirus, Marburgvirus, Striavirus, and Thamnovirus; especially a Marburg virus, Zaire ebolavirus, Sudan ebolavirus, Reston ebolavirus, TaT Forest ebolavirus or Bundibugyo ebolavirus.

[0183] In other embodiments, the virus is a paramyxovirus. For example, the virus may be selected from the group consisting of a henipavirus, orthopneumovirus and orthomyxovirus. In some embodiments, the virus is a henipavirus selected from the group consisting of Nipah virus, Cedar virus, Kumasi virus, Hendra virus, Mojiang virus and Langya virus; especially Nipah virus. In alternative embodiments, the virus is an orthopneumovirus selected from the groupconsisting of human respiratory syncytial virus A2, human respiratory syncytial virus Bl, and Morbillivirus; especially measles virus and paramyxovirus such as mumps virus. In other embodiments, the virus is an orthomyxovirus; especially an influenza virus; more especially influenza A virus, influenza B virus, influenza C virus and influenza D virus.

[0184] In some embodiments, the virus is an arena virus, such as one which causes lymphocytic choriomeningitis or Lassa fever. In some embodiments, the virus is a bunyavirus, especially California encephalitis virus. In some embodiments, the virus is a bornavirus, such as Borna disease virus 1 (BoDV-1) or variegated squirrel bornavirus 1 (VSBV-1).

[0185] The virus may, alternatively, be a single stranded positive-sense RNA virus. In some embodiments, the virus is a coronavirus, picornavirus, togavirus or flavivirus. In particular embodiments, the virus is a coronavirus selected from the group consisting of human coronavirus 229E, human coronavirus NL63, human coronavirus OC43, human coronavirus HKU1, Middle East respiratory syndrome- related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In other embodiments, the virus is a picornavirus selected from the group consisting of enterovirus, rhinovirus, hepatitis A virus, cardiovirus, aphthovirus, poliovirus 1, poliovirus 2, poliovirus 3, parechovirus, erbovirus, kobuvirus, teschovirus and coxsackie. The virus may, alternatively, be a togavirus selected from the group consisting of rubella, Venezuelan equine encephalitis, eastern equine encephalitis virus, western equine encephalitis virus, ross river virus and chikungunya virus. In some embodiments, the virus is a flavivirus selected from the group consisting of West Nile virus, Hepatitis C virus, dengue virus, tick-borne encephalitis virus, Japanese encephalitis virus, yellow fever virus, Zika virus, Palm Creek virus and Parramatta River virus.

[0186] In some embodiments, the virus is a double stranded RNA virus. In some embodiments, the virus is a reovirus, for example, rotavirus.

[0187] In some embodiments, the virus is a double stranded DNA virus, such as one selected from the group consisting of an adenovirus, herpes virus and poxvirus. In particular embodiments, the virus is an adenovirus, especially a human adenovirus selected from the group consisting of human adenovirus A, human adenovirus B, human adenovirus C, human adenovirus D, human adenovirus E, human adenovirus F and human adenovirus G. Alternatively, the virus may be a herpes virus selected from the group consisting of herpes simplex virus 1, herpessimplex virus 2, human herpes virus 6, ateline alphaherpesvirus 1, bovine alphaherpesvirus 2, cercopithecine alphaherpesvirus 2, leporid alphaherpesvirus 4, macacine alphaherpesvirus 1, macacine alphaherpesvirus 2, macacine alphaherpesvirus 3, macropodid alphaherpesvirus 1, macropodid alphaherpesvirus 2, panine alphaherpesvirus 3, papiine alphaherpesvirus 2, pteropodid alphaherpesvirus 1, saimiriine alphaherpesvirus 1, varicella-zoster virus and beta herpes viruses such as cytomegalovirus and Epstein-Barr virus. The virus may, alternatively, be a poxvirus selected from the group consisting of smallpox virus, cowpox virus, myxoma virus, monkeypox virus, and vaccinia virus.

[0188] In other embodiments, the virus is a single stranded RNA reverse transcriptase virus, for example, one that is selected from the group consisting of human T-lymphotropic Viruses Type 1, human T-lymphotropic Viruses Type 2, human immunodeficiency virus (HIV), feline leukemia viruses, feline sarcoma viruses, chicken leukemia viruses, chicken sarcoma viruses, mouse leukemia viruses, mouse sarcoma viruses, equine infectious anemia virus, bovine leukemia virus, caprine arthritis-encephalitis virus, human tropic spastic paraparesis virus, rous sarcoma virus, avian sarcoma leukosis virus and avian myeloblastosis virus.

[0189] Alternatively, the virus may be a double stranded DNA reverse transcriptase virus, such as Hepatitis B virus.

[0190] In alternative embodiments, the virus is a single stranded DNA virus. Suitable viruses include, but are not limited to, parvovirus, densovirus, circovirus, nanovirus and geminivirus.

[0191] In particular embodiments, the virus may be selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus. In some embodiments, the virus is rabies virus.

[0192] Neuroactive steroids selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2g-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5g-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341),(3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (3g-0H), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone and pharmaceutically acceptable salts and solvates thereof are also proposed to be useful for treating or at least partially inhibiting the development or progression of conditions associated with an infection by a neurotropic virus, especially a central nervous system condition. Accordingly, in a further aspect, there is provided a method of treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In a still further embodiment, there is provided a use of a neuroactive steroid for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus; a neuroactive steroid for use in treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus; and a use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan- 20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3g- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0193] Suitable embodiments of the neuroactive steroid or salt or solvate thereof are as discussed supra.

[0194] In particular embodiments, the infection is a central nervous system infection, especially an infection of the brain or spinal cord.

[0195] Suitable infections are as discussed supra. In particular embodiments, the virus a single stranded negative-sense RNA virus or single stranded positive-sense RNA virus; especially one selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus; more especially rabies virus.

[0196] The condition may be any condition which is associated with an infection by a neurotropic virus. In particular embodiments, the condition is a central nervous system condition, especially a condition of the brain or spinal cord. The condition may be an acute (i.e. less than six months in duration) or chronic condition (i.e. at least six months in duration), especially an acute condition.

[0197] Suitable conditions include, but are not limited to, multisystem organ failure, acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis, encephalomyelitis, an acute inflammatory condition, cytokine storm, CRS, MIS-C, SIRS, ARDS and SARS; especially acute encephalopathy or acute encephalitis.

[0198] In some embodiments, the condition is an inflammatory condition, especially a condition involving inflammation of a component of the central nervous system, such as the brain or spinal cord.

[0199] In some embodiments, the condition is an inflammatory condition and / or a cytokine storm. In some embodiments, the inflammatory condition or cytokine storm is associated with an activity of a Toll-like receptor (e.g. Toll-like receptor 2, Toll-like receptor 4 or Toll-like receptor 7; especially Toll-like receptor 4or Toll-like receptor 7; more especially Toll-like receptor 4), such as activation of MyD88.

[0200] In a related aspect, there is provided a method of inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. Also provided is a use of a neuroactive steroid for inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, a neuroactive steroid for use in inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, and a use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2- morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a- hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p- pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58, 17f>)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

[0201] Suitable embodiments of the neuroactive steroid or salt or solvate thereof are as discussed supra. Suitable embodiments of the neurotropic viruses are as discussed elsewhere herein.

[0202] Representative p75NTR expressing cells include, but are not limited to, a vertebrate cell, particularly a mammalian or avian cell, especially a mammalian cell, that expresses at least one p75NTR. The cell may be a vertebrate cell, such as a primate cell; an avian cell; a livestock animal cell such as a sheep cell, cow cell, horse cell, deer cell, donkey cell and pig cell; a laboratory test animal cell such as a rabbit cell, mouse cell, rat cell, guinea pig cell and hamster cell; a companion animal cell such as a cat cell and dog cell; and a captive wild animal cell such as a fox cell, deer cell and dingo cell. In particular embodiments, the p75NTR expressing cell is a human cell. In specific embodiments, the p75NTR expressing cell is a neuron of the peripheral or central nervous system, monocyte, macrophage, microglia, mast cell, eosinophil, B cell or natural killer cell; especially a neuron.

[0203] In some embodiments, the interaction is a non-covalent interaction (e.g. binding). In particular embodiments, the neuroactive steroid inhibits or reduces the interaction of a surface protein (e.g. a glycoprotein) from a neurotropic virus with p75NTR, such as rabies virus glycoprotein.

[0204] In some embodiments, interaction of a neurotropic virus with p75NTR initiates or triggers the cell death cascade, facilitates cellular entry of the neurotropic virus and / or is associated with neuronal transport of the neurotropic virus.

[0205] In some embodiments, the methods and uses inhibit or reduce the interaction of a neurotropic virus with p75NTR and sort! II n .

[0206] Without wishing to be bound by theory, transport of a neurotropic virus through the nervous system is facilitated by the interaction of the neurotropic virus with p75NTR. In particular, the neurotropic virus is proposed to compete with proneurotrophins for binding to p75NTR, which then facilitates neuronal cellular entry, viral transcription, and transport within the nervous system and / or to the central nervous system. The internalisation of p75NTR is proposed to lead to rapid intraneuronal transport of the neurotropic virus in endosomes to the cell body and nucleus, leading to subsequent viral nuclear transcription and furious spread in the CNS with attendant effects of reduced CNS plasticity and massive CNS dysfunction and failure of critical systems. The interaction with p75NTR is also proposed to recruit the cell death cascade and cause severe neuronal destruction and necroptosis. Cell death is achieved by binding of proneurotrophins, such as pro brain-derivedneurotrophic factor, with p75NTR and sortilin, with a neurotropic virus, such as rabies virus mimicking the activity of a proneurotrophin in this complex. However, sortilin is also known to also associate with tropomyosin receptor kinase A, B and C, and promotes efficient anterograde transport of these receptors to their site of action, together with mature neurotrophins. As such, sortilin acts as a positive modulator of neurotrophin induced neuronal survival. It is proposed that a neuroactive steroid will induce sortilin towards prosurvival mechanisms and away from prodeath mechanisms in the central nervous system. It is conceived that the neuroactive steroid will increase mature neurotrophin levels, such as mature brain-derived neurotrophic factor, in the central nervous system, thereby increasing the association of sortilin with tropomyosin receptor kinase A, B and C and mature neurotrophins. It is conceived that this will lead to a downstream increase in the prosurvival mechanisms and decrease the role of sortilin in facilitating the cellular death cascade, decrease the interaction of sortilin with p75NTR and fail to deliver the sortilin / p75NTR complex required by the neurotropic virus for uptake, transport and pathogenicity of the neurotropic virus. This is proposed to decrease the interaction of the neurotropic virus with p75NTR, thereby slowing or inhibiting the neuronal transport of the neurotropic virus and the associated neuronal destruction. It is proposed that this strategy would also allow the adaptive immune system time to have an effect on the neurotropic virus and be useful for treating or inhibiting the development or progression of the infection, disease or condition caused by or associated with the neurotropic virus.

[0207] It is also proposed that the increased mature neurotrophin levels will also decrease the interaction between a neurotropic virus and a Ras-associated binding protein (Rab), which hinders delivery of trophic factors and the neuroplasticity that they support, by competing for binding to the Rab, such as Rab5 and Rab7. This effect is proposed to increase neuroplasticity and neuronal growth and reduce neuronal transport of the neurotropic virus, as Rab is involved in neuronal intracellular vesicular transport. The dynein motor pump engages microtubules in axons and dendrites to deliver trophic factors that drive gene transcription and synaptic plasticity to the cell soma. This plasticity is enhanced by increased mature neurotrophin transport through the dynein motor. As such, it is also conceived that the increased mature neurotrophin levels will reduce or inhibit transcription of viral proteins, such as the rabies virus polymerase, associated with Dynein light chain 1.

[0208] It has also been demonstrated that neuroactive steroids inhibit or reduce an effect of activation of a Toll-like receptor, such as activation of MyD88, inflammation (e.g. central nervous system inflammation) and the like. Accordingly,the invention further provides, in another aspect, a method of inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, rena noIone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan- 20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p- methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the method simultaneously preserves development of acquired adaptive immunity through the TRIF pathway. In yet another aspect, there is provided a use of a neuroactive steroid for inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, a neuroactive steroid for use in inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, and a use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17P)-3-hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, andpharmaceutically acceptable salts and solvates thereof. In some embodiments, the use of the neuroactive steroid preserves development of acquired adaptive immunity through the TRIF pathway. In some embodiments, the neuroactive steroid is for use in preserving development of acquired adaptive immunity through the TRIF pathway. In some embodiments, the medicament preserves development of acquired adaptive immunity through the TRIF pathway.

[0209] The methods and uses disclosed herein may, in some embodiments, comprise a combination of neuroactive steroids. In particular embodiments, the combination of neuroactive steroids is alfaxalone and alfadolone.

[0210] In particular embodiments, the Toll-like receptor is Toll-like receptor 2, Toll-like receptor 4 or Toll-like receptor 7; especially Toll-like receptor 4 or Tolllike receptor 7; more especially Toll-like receptor 4.

[0211] Suitable embodiments of the neuroactive steroid or salt or solvate thereof are as discussed supra. Suitable embodiments of the neurotropic viruses are as discussed elsewhere herein.

[0212] Representative Toll-like receptor expressing cells include a vertebrate cell, particularly a mammalian or avian cell, especially a mammalian cell, that expresses at least one Toll-like receptor (e.g. Toll-like receptor 2, Toll-like receptor 4 or Toll-like receptor 7; especially Toll-like receptor 4 or Toll-like receptor 7; more especially Toll-like receptor 4). The cell may be a vertebrate cell, such as a primate cell; an avian cell; a livestock animal cell such as a sheep cell, cow cell, horse cell, deer cell, donkey cell and pig cell; a laboratory test animal cell such as a rabbit cell, mouse cell, rat cell, guinea pig cell and hamster cell; a companion animal cell such as a cat cell and dog cell; and a captive wild animal cell such as a fox cell, deer cell and dingo cell. In particular embodiments, the Toll-like receptor expressing cell is a human cell. In specific embodiments, the Toll-like receptor expressing cell is a neuron of the peripheral or central nervous system, monocyte, macrophage, microglia, granulocyte, dendritic cell, astrocyte or oligodendrocyte.

[0213] Suitably, the cell also expresses MyD88 (i.e. the cell is a Toll-like receptor and MyD88 expressing cell). In particular embodiments, the cell has been contacted with the neurotropic virus.

[0214] In some embodiments, the activation of MyD88 by a Toll-like receptor in response to the neurotropic virus initiates or triggers the development of inflammation and / or a cytokine storm. In particular embodiments, the activation of MyD88 by a Toll-like receptor in response to the neurotropic virus induces NFKBnuclear translocation and expression of pro-inflammatory cytokine genes, such as IL- 6.

[0215] Toll-like receptors are known to activate immune cell responses following recognition of a structurally conserved molecule derived either from a microbe, such as a virus, bacterium or parasite, or from the damage / necrosis caused by a microbe. One pathway is associated with MyD88 activity (e.g. via the formation of a Toll-like receptor 4 / myeloid differentiation factor 2 complex and resulting signalling leading to activation of MyD88), and results in the stimulation of feed forward aggressive inflammation and increased cytokine production. This pathway causes cellular dysfunction and cell death (necroptosis). The second pathway involves TRIF and is neuroprotective and conserves cell function and integrity and leads to dendritic cell and microglial activation and consequent immune protection. Excessive stimulation of the MyD88 pathway before development of antibodies through TRIF stimulation leads to overwhelmingly damaging inflammation. Without wishing to be bound by theory, neuroactive steroids are proposed to inhibit the pathway involving MyD88 but to not simultaneously inhibit or affect the second (i.e. the TRIF) pathway, thereby reducing inflammation and associated conditions, and allow time for adaptive immunity to develop.

[0216] Without wishing to be bound by theory, it is conceived that the MyD88-dependent pathway primarily effects innate immunity by triggering the expression of pro-inflammatory signal transduction pathways. Cytokines (IL-ip, IL- 6 and TNFa) play a key role in stimulating p38 MAPK and N FKB pathways. It is conceived that p38 MAPK and N FKB pathways, when stimulated, induce increased expression of p75NTR on the cell surface, predominantly in neurons and astrocytes. While p75NTR has many functions, its expression in neurons is a marker for neurodegeneration. Further, the TLR-induced increase in p75NTR on the surface of neurons acts as a receptor for neurotropic viruses, such as rabies virus, and proneurotrophins, and then causes a feed forward amplification of the MyD88 inflammatory pathway by a direct action on TRAF6 by the internalised virus / p75NTR complex, for example, RABV / p75NTR. Inhibition of MyD88 is, therefore, postulated to also simultaneously reduce expression of p75NTR on dendritic cells and on the cell surface of neurons and its associated effects. It is also postulated that particular neuroactive steroids, including alfaxalone and alfadolone, are capable of simultaneously inhibiting the MyD88 inflammatory pathway, inhibiting an increase in expression of p75NTR on the surface of dendritic cells and neurons, inhibiting neurotropic virus interaction with p75NTR on the neuronal surface, and inhibiting theinternalisation and fast intraneuronal transport of p75NTR / virus complexes, while preserving TRIF mediated adaptive immunity.

[0217] In any one of the aspects described herein the neuroactive steroid is, preferably, alfaxalone, alfadolone or alfadolone acetate; especially alfaxalone or alfadolone. In some embodiments, the neuroactive steroid is alfaxalone. In some embodiments, the neuroactive steroid is alfadolone.

[0218] In some embodiments, the neuroactive steroid is alfaxalone and alfadolone.

[0219] Any one of the methods and uses described above may involve administration of an effective amount of the neuroactive steroid or a salt or solvate thereof as described in Section 4 supra. The neuroactive steroid may be administered via any suitable route of administration, such as oral, rectal, topical, intranasal, inhalation, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration. In particular embodiments, the neuroactive steroid is administered via oral, intramuscular, intranasal or intravenous administration; especially intravenous administration. The neuroactive steroid may, preferably, be administered in the form of a composition. Suitable compositions are discussed in Section 4 supra.

[0220] The dosage and frequency will depend on the subject, the condition, disease or disorder to be treated and the route of administration. A skilled person will readily be able to determine suitable dosages and frequency of such dosages.

[0221] In some embodiments, the neuroactive steroid is administered in an amount in the range of from about 0.05 mg to about 250 mg per kg body weight of the subject (and all one tenth integer mg therebetween); especially about 0.1 mg to about 200 mg, about 0.25 mg to about 100 mg, about 0.35 to about 50 mg, about 0.5 mg to about 25 mg, or about 1 mg to about 10 mg per kg body weight of the subject.

[0222] While the neuroactive steroid may be administered in a fixed dose or a dose depending on the body weight of the subject and / or severity of the condition, in some embodiments, the neuroactive steroid is titrated up to a dose that exerts a desired effect, such as burst suppression or a specific bispectral index. In some embodiments, the neuroactive steroid is titrated up to a dose that causes a burst suppression, especially a burst suppression ratio of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% or about 100%.

[0223] In some embodiments, the neuroactive steroid is titrated up to a dose that causes a bispectral index of less than about 25, 20, 15, 10, 5 or about 0. In preferred embodiments, the neuroactive steroid is titrated up to a dose that causes a bispectral index of about 0 (i.e. the absence of cerebral cortical activity).

[0224] In some embodiments, the neuroactive steroid is administered in an amount that exerts a desired effect, such as burst suppression (e.g. a burst suppression ratio of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% or about 100%) or a specific bispectral index (e.g. a bispectral index of less than about 25, 20, 15, 10, 5 or about 0).

[0225] The neuroactive steroid may be administered at a frequency of, for example, once daily, or twice or three times daily. The treatment may be continued for multiple days, weeks, months or years; especially multiple days or weeks.

[0226] In some embodiments, the neuroactive steroid is administered in an amount for an initial time period, such as about two to about four weeks (and all integer days therebetween), followed by a lower amount until the condition has been treated or progression or development of the condition has been inhibited, such as about one week to about four weeks (and all integer days therebetween). In some embodiments, the neuroactive steroid is administered in an amount that causes sedation and anaesthesia of the subject for an initial time period, such as about two to about four weeks (and all integer days therebetween), followed by an amount that causes sedation of the subject but does not cause anaesthesia of the subject until the condition has been treated or progression or development of the condition has been inhibited, such as about one week to about four weeks (and all integer days therebetween). In some embodiments, the neuroactive steroid is administered in a high amount until antibodies to the neurotropic virus or a viral protein are detected in the central nervous system, followed by a lower amount until the condition has been treated or progression or development of the condition has been inhibited.

[0227] In particular embodiments, the neuroactive steroid is administered in an amount that causes sedation of the subject. In some embodiments, the neuroactive steroid is administered in an amount that does not cause anaesthesia of the subject. In alternative embodiments, the neuroactive steroid is administered in an amount that causes sedation and anaesthesia of the subject

[0228] Any one of the methods or uses described above may suitably involve the administration of one or more other therapeutic agents as described in Section 4 supra, such as an antiviral, anti-inflammatory agent, agent which inhibits the cytokine storm, analgesic, sedative, anaesthetic, NMDA receptor antagonist,antidiuretic hormone, fluid therapy, inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetra hydrobiopterin deficiency, sedating neuroprotective agent, therapy for lactic acidosis or ketosis, and / or Toll-like receptor antagonist. In embodiments where the methods involve the administration of one or more other therapeutic agents or the pharmaceutical composition comprises one or more other therapeutic agents, the dosages and frequency of administration are determined by reference to the usual dose and manner of administration of the said agents.

[0229] In some embodiments, a further therapeutic agent (e.g. an antiviral) is not administered to the subject.

[0230] In another aspect, there is provided a kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, and the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3- hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zura noIone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)- 19-nor-5g-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-0H), (3a,5a)-3-hydroxy- 13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a- DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. Suitable neuroactive steroids, infections and neurotropic viruses are as described supra.

[0231] Also provided, in another aspect, is a kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, and the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2f>- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-ylmethanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3P-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof. Suitable neuroactive steroids, conditions, infections and neurotropic viruses are as described supra.

[0232] The kit of the invention may, in some embodiments, further comprise one or more other therapeutic agents. Suitable therapeutic agents are as discussed in Section 4 supra.

[0233] The kits disclosed herein may comprise a combination of neuroactive steroids. In particular embodiments, the combination of neuroactive steroids is alfaxalone and alfadolone.

[0234] A skilled person will be well aware of suitable assays used to evaluate the inhibition or reduction of the interaction of a neurotropic virus with p75NTR. For example, the method may include contacting the receptor with a neuroactive steroid and assessing the inhibition of the interaction with the neurotropic virus. Alternatively, the method may include screening for the inhibition or reduction of the activity, presence or expression of a downstream cellular target or product, or a downstream effect, such as nuclear translocation, cellular entry of the neurotropic virus, neuronal transport of the neurotropic virus or activation of cytokines or factors involved in the necroptotic cell-death pathway. Detecting such inhibition or reduction may be achieved utilising techniques including, but not limited to, ELISA, a binding assay (e.g. a radioligand binding assay or fluorescence binding assay), surface plasmon resonance, immunofluorescence, Western blots, immunoprecipitation, immunostaining, scintillation proximity assays, competitive inhibition assays or a colorimetric assay.

[0235] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples.EXAMPLES

[0236] All materials used are commercially available and were obtained from commercial sources unless otherwise specified.EXAMPLE 1 - TLR4 STIMULATION AND INHIBITION FUNCTIONAL ASSAYS USING HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLSMaterials and Methods

[0237] Allopregnanolone, alfaxalone, and alfadolone were obtained from Steraloids Inc. Newport, RI, USA (catalogue no. P3500-000, 5a-pregnan-3a-ol-ll, 20-DIONE; catalogue no. P2200-000 5a-pregnan-3a, 21- diol-11, 20-dione; and catalogue no. P3800-000 5a-pregnan-3a-ol-20-one).

[0238] TLR stimulation and inhibition functional assays using human peripheral blood mononuclear cells (PBMCs) secretion of cytokines interleukin ip (IL- 1P), interleukin 6 (IL-6), and tumour necrosis factor a (TNFa) as readouts of TLR activation, using multiplex technology, were obtained from Eurofins Discovery (Eurofins Discovery Panlabs TLR4 Inflammation inhibition assays). These assays were specific for human TLR4 and were used to assess the effect of allopregnanolone, alfaxalone, and alfadolone (100 pM, 10 pM, 1 pM, 100 nM, 10 nM and 1 nM) on the production of the inflammatory cytokines IL-ip, IL-6, and TNFa caused by the stimulation of human TLR4 by lipopolysaccharide (LPS), which is a natural stimulant of inflammation via TLR4 binding.

[0239] Allopregnanolone, alfaxalone, and alfadolone (the "Test Agents") were solubilized in dimethyl sulfoxide (DMSO; the Vehicle) and then diluted in water to make appropriate stocks for use in the assay. The stocks were then diluted in culture medium [Roswell Park Memorial Institute (RPMI) 1640 medium with 10% v / v heat-inactivated fetal bovine serum (FBS), 1% v / v penicillin / streptomycin, and 2 mM L-glutamine] to 20X the desired assay concentrations. Cryopreserved human PBMCs were drip-thawed, plated, and allowed to settle for 1 hour at 37°C, 5% CO2. The Test Agents and controls were added to the settled PBMCs and incubated at 37°C, 5% CO2 for 1 hour. The Vehicle (10% aqueous solution of DMSO) was used as a no inhibition positive control and dexamethasone (100 nM) was used as a reference inhibitor control. The PBMCs were then stimulated by the addition of LPS (from Salmonella minnesota R595, 100 ng / mL) and incubated at 37°C, 5% CO2 for 24 hours. LPS alone was used as a positive control and Vehicle only treatment was used as a negative control. After the main incubation, cell culture supernatants were harvested and assayed for the cytokines IL-ip, IL-6, and TNFa, using standard Luminex protocols.

[0240] This involved adding each supernatant sample to a mixture of colour-coded beads, pre-coated with analyte-specific capture antibodies (IL-ip, IL-6 and TNFa). The antibodies bind to the analytes of interest. Biotinylated detectionantibodies specific for the analytes of interest (IL-ip, IL-6 and TN Fa) were added to form an antibody-antigen sandwich. Phycoerythrin (PE)-conjugated streptavidin was then added to bind to the biotinylated detection antibodies. The beads were then read on a dual-laser flow-based detection instrument (Luminex 100™ analyser). One laser classified the bead and determined the analyte being detected and the second laser determined the magnitude of the PE-derived signal, which is in direct proportion to the amount of analyte bound (IL-ip, IL-6 and TNFa).

[0241] Levels of cytokine induction were interpolated from standard curves using 5-parameter non-linear regression analyses. The interpolated data were then standardised and analysed such that:1. Mean measured response to vehicle = A;2. Mean measured response to LPS = B;3. True response to LPS = B - A = C;4. Measured response in a sample = D;5. True response in a sample named s = D - A = E;6. If, for example, an individual sample s contained 1000 nM alfaxalone and the responses measured were for TNFa then true response E was calculated as % inhibition of TNFa response by lOOOnM alfaxalone = C-FX 100%;7. Since the samples were performed in triplicate, 3 such values for % inhibition of the TNFa response to LPS were calculated for each of the 6 concentrations of alfaxalone; giving 18 values in total;8. Those 18 values were plotted as an alfaxalone dose response curve for inhibition of TNFa response to LPS induced activation of TLR4 and subjected to a 4-parameter non-linear regression analysis, where y = (A+((B- A) / (l + ((C / x)^D)))).

[0242] Steps 1-8 above were repeated for each of the three Test Agents (allopregnanolone, alfaxalone, and alfadolone) and for each of the cytokine analytes, IL-ip, IL-6 and TNFa.Results

[0243] The effect of each neuroactive steroid on the secretion of IL- 1 [3, IL- 6, and TNF-a is presented in Figure 4.

[0244] Allopregnanolone did not significantly inhibit the secretion of IL-6, TNF-a and IL-ip at the concentrations tested.

[0245] Alfaxalone and alfadolone both inhibited the secretion of the inflammatory cytokines IL-ip, IL-6 and TNF-a in a dose related manner indicating that these compounds inhibit the MyD88 pathway shown in Figure 3.

[0246] Further, alfadolone and alfaxalone caused inhibition of LPS- stimulated secretion of IL- 1(3 and IL-6 equivalent to that caused by dexamethasone and greater than the dexamethasone effect on TNF-a secretion, at the concentrations tested in this model. This observation is of note because dexamethasone is known for significant serious side effects due to its endocrine and metabolic properties, none of which being features of alfadolone and alfaxalone.

[0247] This example shows that the non-hormonal neuroactive steroids, alfadolone and alfaxalone, inhibit the secretion of inflammatory cytokines stimulated by the TLR4-mediated MyD88 pathway.EXAMPLE 2 - INFLUENCE OF THE NEUROACTIVE STEROIDS ALFAXALONE AND ALFADOLONE ON NFKB RESPONSE ELEMENTS MEDIATED THROUGH THE MYD88 PATHWAY AND ON ISRE-MEDIATED THROUGH THE TRIF PATHWAYMaterials and MethodsReporter cell line set uo

[0248] A TLR2 agonist Pam3CysSerLys4 (Pam3CSK4) was chosen to study N FKB response elements through stimulation of MyD88-dependent signalling in the absence of stimulation of the TRIF pathway. TLR2 is restricted to the MyD88 pathway. The activated pathways were monitored by a measurement of downstream stimulation of N FKB response elements (see Figure 5), utilising a green fluorescent protein (GFP) reporter gene.

[0249] Pam3CSK4 is a synthetic lipopeptide that triggers inflammation by activating TLR2 and its co-receptor TLR1, which then leads to the activation of the N FKB pathway and the release of pro-inflammatory cytokines, mimicking a bacterial infection signal.

[0250] TRIF-dependent signalling in the absence of MyD88 stimulation was evaluated through activation of cells with TLR3 agonist polyinosin ic: polycytidyl ic acid (Poly IC). Poly IC is a synthetic molecule that mimics viral double-stranded RNA and acts as a potent immune stimulant, triggering an inflammatory response by activating TLR3. In inflammation, poly IC induces the production of pro-inflammatory cytokineslike IL-6 and TNFa. The activated pathways were monitored by a measurement of downstream stimulation of ISRE (see Figure 5) utilising a GFP reporter gene. ISRE is a DNA sequence motif that activates the transcription of a group of genes known as interferon-stimulated genes (ISG). By regulating IFNa and IFNg signalling, ISGs control inflammation. Interferon responses are vital for antiviral defence, with ISREs crucial for regulating IFN signalling.

[0251] TNFa-mediated signalling was used as a positive control for the N FKB reporter, as this cytokine stimulation utilises a pathway independent of MyD88 and TRIF, but with shared downstream pathways leading to stimulation of the N FKB response element (see Figure 6).

[0252] Interferon gamma (IFNy) mediated signalling was used as a positive control for the ISRE reporter, as this cytokine stimulation utilises a TRIF-independent pathway via JAK / STAT signalling, leading to stimulation of the ISRE response element (see Figure 7).Generation of reporter cell lines

[0253] Lung epithelial cells, line BEAS-2B, were obtained from American Type Culture Collection (ATCC), Manassas, Virginia, USA (Catalogue Number: CRL- 9609).

[0254] BEAS-2B cells are a type of human bronchial epithelial cell that is widely used as an in vitro model for studying inflammation. In the context of inflammation, BEAS-2B cells can be exposed to irritants, cytokines, or other stimuli, triggering their response by releasing inflammatory mediators like cytokines (IL-6, IL-8, TNFa). Upon stimulation, BEAS-2B cells release inflammatory markers that researchers measure to understand the extent of the inflammatory response. These markers include: (I) cytokines such as IL-6, IL-8, IL-ip and TNF-a, which are frequently measured; and (II) adhesion molecules such as VCAM-1 and ICAM-1, which are important in recruiting immune cells to inflamed tissues. BEAS-2B cells are used to evaluate the efficacy of potential therapeutic agents in mitigating inflammation.

[0255] The BEAS-2B cells were grown in Roswell Park Memorial Institute (RPMI) medium supplemented with 10% foetal bovine serum (FBS) and passaged twice weekly. To generate reporter cell lines, the cells were transduced with lentiviruses encoding the relevant reporter constructs. These reporter constructs contain a gene encoding GFP under the control of multimerized N FKB or ISRE responsive elements located upstream of a minimal promoter. Validation of reporter activity was confirmed using positive control stimulation TNFa (50 ng / mL), IFNa (50

[0256] Cells were maintained in culture and used for experiments between passage 3 and 12 days post transduction.Compounds

[0257] 2-Amino-6-chloro-4-(l-phenylethylamino)-pyridine (i.e. ACHP), which is a selective IKKa / IKKB inhibitor, was obtained from Tocris Bioscience, Bristol, UK (Catalogue Number: 4547) and used as a positive control to inhibit N FKB reporter activity. Tofacitinib, which is a JAK inhibitor, was obtained from Stratech Scientific, Ely, UK (Catalogue Number: CP-690550) and used as a positive control to inhibit ISRE reporter activity. Alfaxalone and alfadolone were obtained from Shaanxi Dideu Medichem Co. Ltd, China. ACHP, tofacitinib, alfaxalone and alfadolone were initially solubilised in DMSO to generate stocks then diluted with 1% FBS in RPMI for use in the assay with a final DMSO concentration in the assay of 0.015%. Tested concentrations of ACHP, tofacitinib, alfaxalone and alfadolone were as follows:. ACHP (IKK inhibitor) - 1, 0.1 and 0.01 pM• Tofacitinib (JAK inhibitor) - 1, 0.1 and 0.01 pM. Alfaxalone - 10, 3, 1, 0.3, 0.1, 0.03, 0.01 pM. Alfadolone - 10, 3, 1, 0.3, 0.1, 0.03, 0.01 pM.Reporter assays

[0258] On the day prior to experiment start, cells were plated from continuous culture into flat bottom tissue culture - treated plates. Cells were returned to the incubator and left to adhere overnight.

[0259] On the day of the experiment, media was removed from the cells and replaced with low serum media (1% FBS in RPMI). Cells were returned to the incubator for 1 h.

[0260] Cells were then dosed with the appropriate compound at the indicated concentrations or vehicle (DMSO) control. The final concentration of DMSO on the cells was 0.015%. Cells were returned to the incubator for 1 h prior to the addition of an inflammatory stimulant, namely Pam3CSK4, Poly IC, or TNFa.

[0261] Controls and cytokines were added to the cells in appropriate wells after the 1 h incubation of cells with inhibitors, alfaxalone, or alfadolone. Plates were then placed on an Incucyte plate imager obtained from Sartorius, Gottingen, Germany, in an incubator and monitored for GFP expression over the subsequent 48 h.

[0262] GFP fluorescence and cell confluence were detected and analysed using Incucyte software. Data was reported as mean fluorescence intensity (MFI) per well and plotted using GraphPad Prism. Each reported data is mean±standard error of the mean (SEM) of three independent experiments.ResultsEffect of alfadolone and alfaxalone on the activation of N FKB

[0263] The effects of alfadolone on the activation of N FKB through different pathways, namely TLR2 activation of MyD88, TLR3 activation of TRIF and TNFa activation of a TLR-independent pathway are shown in Figures 8A, 8B and 8C, respectively.

[0264] Figures 8A and 8B show that alfadolone inhibited TLR2- mediated N FKB activation and TLR3-mediated N FKB activation, respectively. Figure 8C shows that alfadalone also inhibited TNFa-induced N FKB activation.

[0265] The effects of alfaxalone on the activation of N FKB through different pathways, namely TLR2 activation of the MyD88 pathway, TLR3 activation of the TRIF pathway and TNFa activation of a TLR-independent pathway are shown in Figures 9A, 9B and 9C, respectively.

[0266] Figures 9A-C show that alfaxalone did not modulate TLR2- mediated N FKB activation, TLR3-mediated N FKB activation, or TNFa-induced N FKB activation.Effect of alfadolone and alfaxalone on the activation of ISRE

[0267] The effects of alfadolone on the activation of ISRE via TLR3 activation of the TRIF pathway, which was stimulated by Poly IC, TNFa or IFNy, are shown in Figures 10A, 10B and IOC, respectively.

[0268] The effects of alfaxalone on the activation of ISRE via TLR3 activation of the TRIF pathway, which was stimulated by Poly IC, TNFa or IFNy, are shown in Figures 11A, 11B and 11C, respectively.

[0269] Neither alfadolone nor alfaxalone inhibited ISRE activation (via the TRIF or JAK / STAT pathway). These results suggest that neither alfadolone nor alfaxalone inhibited the TRIF pathway and, thus, preserved subsequent activation of interferon immune responses including antibody production.EXAMPLE 3 - INFLUENCE OF THE NEUROACTIVE STEROIDS ALFAXALONE AND ALFADOLONE ON THE SECRETION OF PRO-INFLAMMATORY CYTOKINE IL-6 AND CHEMOKINE CXCL10Materials and Methods

[0270] Lung epithelial cells, line BEAS-2B, were obtained from ATCC, Manassas, Virginia, USA (Catalogue Number: CRL-9609). The BEAS-2B cells were grown in 10% FBS in RPMI and passaged twice weekly. Cells were maintained in culture and used for experiments between passage 3 and 12 days post transduction.

[0271] Alfaxalone and alfadolone were obtained from Shaanxi Dideu Medichem Co. Ltd, China. Alfaxalone and alfadolone were initially solubilised in DMSO to generate stocks then diluted for use in the assay with a final DMSO concentration in the assay of 0.015%.

[0272] Tested concentrations of alfaxalone and alfadolone were as follows:• alfaxalone - 10, 3, 1, 0.3, 0.1, 0.03, 0.01 pM• alfadolone - 10, 3, 1, 0.3, 0.1, 0.03, 0.01 pM.

[0273] On the day prior to experiment start, cells were plated from continuous culture into flat bottom tissue culture-treated plates. Cells were returned to the incubator and left to adhere overnight. On the day of the experiment, media was removed from the cells and replaced with low serum media (1% FBS in RPMI). Cells were returned to the incubator for 1 h and were then dosed with the appropriate compound at the indicated concentrations or vehicle (DMSO) control. The final concentration of DMSO on the cells was 0.015%. Cells were returned to the incubator for 1 h prior to the addition of a TLR stimulant, namely Pam3CSK4, Poly IC, or LPS (100 ng / mL).

[0274] Supernatants were collected from each well at 48 hours post dosing and stimulation. Supernatants for the three independent experiments were stored and analysed for IL-6, a pro-inflammatory cytokine produced by the MyD88 pathway, and CXCL10, a chemokine stimulated by the expression of interferon-induced genes, which plays a critical role in antiviral immune responses, regulating immune cell differentiation and activation. These were measured using multiplexed bead-based ELISA assays obtained from Thermo Fisher Scientific Inc., Massachusetts, United States, according to the manufacturer's instructions. TLR2, TLR3 and TLR4 were stimulated with Pam3CSK4, Poly IC, and LPS, respectively. Alfadolone and alfaxaloneconcentration response curves were dosed in combination with each stimulus and in unstimulated cells (i.e. DMSO vehicle controls).Results

[0275] Figure 14 shows the effect of alfadolone and alfaxalone on the secretion of the pro-inflammatory cytokine IL-6 in response to stimulation of TLR2 by Pam3CSK4 (Figure 14A), stimulation of TLR3 by Poly IC (Figure 14B), and stimulation of TLR4 by LPS (Figure 14C). As seen in Figure 14, the secretion of IL-6 caused by all three stimuli at TLR2, TLR3 and TLR3 were inhibited by alfadolone. Figure 14B shows that alfaxalone had a small inhibitory effect in the Poly IC stimulation of TLR3 in this model.

[0276] Figure 15 shows the effect of alfadolone and alfaxalone on the secretion of CXCL10, which is a chemokine critical for innate immunity including the migration and localization of immune cells and involved in acquired immunity and antibody production. Figure 15A shows that Poly IC, which stimulates TLR3 and activates the TRIF pathway, caused CXCL10 secretion. Figure 15B shows that neither alfadolone nor alfaxalone inhibited CXCL10 production resulting from activation of the TRIF pathway.Discussion

[0277] Example 1, in Figure 4, shows that neuroactive steroids, exemplified by alfadolone and alfaxalone, inhibit the secretion of inflammatory cytokines stimulated by the TLR4- mediated MyD88 pathway.

[0278] Example 2, in Figures 10 and 11, shows that alfaxalone and alfadolone do not inhibit the activation of ISRE. These results indicate that neuroactive steroids such as alfaxalone and alfadolone preserve activity initiated by the TRIF pathway that leads to acquired immunity through production of interferon and antibodies.

[0279] Example 2, in Figure 8, shows that alfadolone inhibited multiple pathways that lead to secretion of inflammatory mediators promoted by N FKB activation. These pathways included (i) TLR2- mediated N FKB activation, which was activated by Pam3CSK4 through the MyD88 pathway but not the TRIF pathway, (ii) TLR3-mediated N FKB activation, which was activated by Poly IC through the TRIF pathway but not the MyD88 pathway, and (iii) TNFa-induced NFKB activation, which is independent and downstream of both the MyD88 and TRIF pathways. Noting that TNFa does not use the MyD88 or TRIF pathways, the observed inhibitory effect of alfadolone on TNFa-induced N FKB activation suggests inhibition downstream of theTRIF / MyD88 pathway. It is contemplated that alfadolone targets a complex shared between the TRIF, MyD88 and TNFa signalling pathways. The proposed mechanism of action of alfadolone on TLR2, TLR3 and TNFa-mediated N FKB activation is shown in Figures 12 and 13.

[0280] Example 2, in Figure 9, shows that alfaxalone did not inhibit the activation of N FKB, either via TLR2 activation by Pam3CSK4 or TLR3 activation by Poly IC.

[0281] Example 3, in Figure 14, showed that alfadolone inhibited the secretion of the pro-inflammatory cytokine IL-6 caused by stimulation at TLR2, TLR3 and TLR4.

[0282] Example 3, in Figure 15B, showed that alfadolone and alfaxalone did not inhibit the secretion of CXCL10 resulting from stimulation of TLR3 by Poly IC. This absence of an inhibitory effect by alfadolone and alfaxalone on CXCL10 secretion is consistent with the N FKB and ISRE reporter assay data using reporter cells of Example 2 where alfadolone and alfaxalone were found to not modulate the ISRE pathway. These results indicate that the neuroactive steroids inhibit N FKB and pro- inflammatory cytokines and do not affect ISRE signalling downstream of TRIF / MyD88.

[0283] It is generally recognised that the intracellular signalling pathways involving TRIF and MyD88, along with their downstream effects through cytokines and chemokines, are shared mechanisms triggered by the various TLRs. It is noted that Examples 1-3 investigated the effects of neuroactive steroids at different Tolllike receptors, namely TLR4 in Example 1, TLR2 and TLR3 in Example 2 and TLR2, TLR3 and TLR4 in Example 3. In particular, Example 2 used TLR2 and TLR3 to activate N FKB downstream of the MyD88 and TRIF pathways whereas Example 1 used activators of TLR4 to stimulate the same MyD88 and TRIF intracellular mechanisms. Since alfaxalone was active in Example 1 in inhibiting TNFa and other NFKB-mediated inflammatory cytokines against a background of TLR4 stimulation, these results taken together indicate that alfaxalone has an action on the TLR4 pathway between the TLR4 receptor on the cell surface and TIRAP / MyD88 as shown in Figure 1.

[0284] It is worth noting that neurotropic viruses such as rabies virus target TLR4 through PAMPS and DAMPs at the cell surface and, thus, it is expected that alfaxalone will inhibit inflammatory (MyD88 / NFKB) responses while leaving TRIF (ISRE) mediated chemokine defences intact.

[0285] The results from Examples 1-3 demonstrated that neuroactive steroids as exemplified by alfaxalone and alfadolone have actions at different points in the pathways leading to inflammation initiated by TLR activation. These resultssuggest that particular neuroactive steroids alone or a combination of neuroactive steroids, such as a combination of alfaxalone and alfadolone, may be useful in the methods, uses and kits disclosed herein. Further, whether alone or in a combination, it is demonstrated that neuroactive steroids, such as alfaxalone and alfadolone, inhibit pro-inflammatory cytokine production whilst preserving the production of adaptive immunity through the TRIF system by production of trophic factors, chemokines and antibodies.

[0286] Examples 1-3 showed that neuroactive steroids such as alfaxalone and alfadolone differentially modulate innate and acquired immune responses, tending to dampen down inflammation whilst preserving adaptive immunity. This therapeutic modality may be harnessed for prevention and treatment of neurotropic viral infections.

[0287] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0288] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0289] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.EMBODIMENTS

[0290] Exemplary embodiments include, but are not limited to:1. A method of treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19- nor-5g-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3- hydroxyandrostane-17-carbonitrile (3 -OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.2. The method according to embodiment 1, wherein the infection is a central nervous system infection.3. The method according to embodiment 1 or embodiment 2, wherein the infection is associated with multisystem organ failure.4. The method according to any one of embodiments 1-3, wherein the infection is associated with a condition selected from the group consisting of acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis and encephalomyelitis.5. The method according to embodiment 4, wherein the condition is acute encephalopathy.6. The method according to embodiment 4, wherein the condition is acute encephalitis.7. The method according to any one of embodiments 1-6, wherein the infection is associated with the development of inflammation and / or a cytokine storm.8. The method according to embodiment 7, wherein the inflammation and / or cytokine storm is associated with the activity of a Toll-like receptor.9. The method according to embodiment 8, wherein the Toll-like receptor is Tolllike receptor 4 or Toll-like receptor 7.10. The method according to any one of embodiments 1-9, wherein neuronal transport of the virus within the subject is associated with the activity of a member of the tumor necrosis factor receptor family.11. The method according to embodiment 10, wherein the member of the tumor necrosis factor receptor family is p75 neurotrophin receptor (p75NTR).12. The method according to any one of embodiments 1-11, wherein the virus is a single stranded negative-sense RNA virus or single stranded positive-sense RNA virus.13. The method according to any one of embodiments 1-12, wherein the virus is selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus.14. The method according to embodiment 13, wherein the virus is rabies virus.15. A method of treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infectionis caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (3(3- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.16. The method according to embodiment 15, wherein the infection is a central nervous system infection.17. The method according to embodiment 15 or embodiment 16, wherein the condition is associated with multisystem organ failure.18. The method according to any one of embodiments 15-17, wherein the condition is selected from the group consisting of acute encephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis and encephalomyelitis.19. The method according to embodiment 18, wherein the condition is acute encephalopathy.20. The method according to embodiment 18, wherein the condition is acute encephalitis.21. The method according to any one of embodiments 15-20, wherein the infection is associated with the development of inflammation and / or a cytokine storm.22. The method according to embodiment 21, wherein the inflammation and / or cytokine storm is associated with the activity of a Toll-like receptor.23. The method according to embodiment 22, wherein the Toll-like receptor is Toll-like receptor 4 or Toll-like receptor 7.24. The method according to any one of embodiments 15-23, wherein neuronal transport of the virus within the subject is associated with the activity of a member of the tumor necrosis factor receptor family.25. The method according to embodiment 24, wherein the member of the tumor necrosis factor receptor family is p75NTR.26. The method according to any one of embodiments 15-25, wherein the virus is a single stranded negative-sense RNA virus or single stranded positive-sense RNA virus.27. The method according to any one of embodiments 15-26, wherein the virus is selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus.28. The method according to embodiment 27, wherein the virus is rabies virus.29. A method of inhibiting or reducing neuronal transport of a neurotropic virus in a subject, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19- nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.30. A method of inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.31. A method of inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,5P)-21-chloro-3-hydroxy- 2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a- hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p- pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.32. The method according to embodiment 31, wherein the method preserves development of acquired adaptive immunity through the Toll / interleukin-1 receptor domain-containing adapter-inducing interferon-p (TRIF) pathway.33. The method according to embodiment 31 or embodiment 32, wherein the Toll-like receptor is Toll-like receptor 4 or Toll-like receptor 7.34. The method according to any one of embodiments 29-33, wherein the virus is rabies virus.35. The method according to any one of embodiments 1-34, wherein the method comprises, consists or consists essentially of administering a combination of neuroactive steroids to the subject.36. The method according to embodiment 35, wherein the combination of neuroactive steroids is alfaxalone and alfadolone.37. The method according to any one of embodiments 1-35, wherein the neuroactive steroid is alfaxalone, alfadolone or alfadolone acetate.38. The method according to embodiment 37, wherein the neuroactive steroid is alfaxalone.39. The method according to embodiment 37, wherein the neuroactive steroid is alfadolone or alfadolone acetate.40. The method according to any one of embodiments 1-29 and 34-39, wherein the neuroactive steroid is administered intravenously, orally, subcutaneously, intramuscularly or intranasally.41. The method according to any one of embodiments 1-29 and 34-40, wherein the neuroactive steroid is administered in a modified-release formulation.42. The method according to any one of embodiments 1-29 and 34-40, wherein the neuroactive steroid is titrated up to a dose that causes a burst suppression in an electroencephalogram.43. The method according to any one of embodiments 1-29 and 34-40, wherein the neuroactive steroid is titrated up to a dose that causes a bispectral index of 0.44. The method according to any one of embodiments 1-29 and 34-41, wherein the neuroactive steroid is administered in an amount in the range of from about 0.05 mg to about 250 mg per kg body weight of the subject.45. The method according to any one of embodiments 1-29 and 34-41, wherein the neuroactive steroid is administered in an amount that causes sedation of the subject.46. The method according to embodiment 45, wherein the neuroactive steroid is administered in an amount that does not cause anaesthesia of the subject.47. The method according to any one of embodiments 1-29 and 34-46, wherein the method further comprises administering one or more other therapeutic agents.48. The method according to embodiment 47, wherein the therapeutic agent is selected from the group consisting of an analgesic, sedative, anaesthetic, antiviral, N- methyl-D-aspartate (NMDA) receptor antagonist, antidiuretic hormone, fluid therapy, inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetrahydrobiopterin deficiency, sedating neuroprotective agent, therapy for lactic acidosis or ketosis, and Toll-like receptor antagonist.49. The method according to embodiment 48, wherein the analgesic is selected from the group consisting of fentanyl, pethidine, meperidine, anileridine, alfentanil, sufentanil, remifentanil, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, codeine, methadone, tramadol, buprenorphine, meperidine, meclofenamate sodium, diflunisal, tolmetin, ketoprofen, flurbiprofen, acetaminophen, aspirin, ibuprofen and naproxen.50. The method according to embodiment 48, wherein the sedative or anaesthetic is selected from the group consisting of desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, xenon, amobarbital, methohexital, thiamylal, thiopental, lorazepam, etomidate, ketamine, midazolam, haloperidol, diazepam, dexmedetomidine, melatonin and propofol.51. The method according to embodiment 48, wherein the antiviral is ribavirin.52. The method according to embodiment 48, wherein the antiviral is a monoclonal antibody.53. The method according to embodiment 52, wherein the monoclonal antibody is a monoclonal antibody against rabies virus.54. The method according to embodiment 48, wherein the NMDA receptor antagonist is amantadine or ketamine.55. The method according to embodiment 48, wherein the calcium channel antagonist is nimodipine.56. The method according to embodiment 48, wherein the therapy for delayed ischemic deficit from nitric oxide excess is an inhibitor of inducible nitric oxide synthase, neuronal nitric oxide synthase or endothelial nitric oxide synthase.57. The method according to embodiment 48, wherein the therapy for tetrahydrobiopterin deficiency is sapropterin or biopterin.58. The method according to embodiment 48, wherein the sedating neuroprotective agent is melatonin.59. The method according to embodiment 48, wherein the Toll-like receptor antagonist is a Toll-like receptor 4 antagonist or Toll-like receptor 7 antagonist.60. The method according to embodiment 48 or embodiment 59, wherein the Toll-like receptor antagonist is a Toll-like receptor 4 antagonist.61. Use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,5P)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28- (2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21- (pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.62. The use according to embodiment 61, wherein the virus is rabies virus.63. Use of a neuroactive steroid in the manufacture of a medicament for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone,alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin- 4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20- dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4- en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy- 3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3-hydroxyandrostane-17-carbonitrile (3(3- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.64. The use according to embodiment 63, wherein the virus is rabies virus.65. Use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing neuronal transport of a neurotropic virus in a subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- di hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.66. Use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin- 4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20- dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4- en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy- 38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872),alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (3(3- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), Sadi hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.67. Use of a neuroactive steroid in the manufacture of a medicament for inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19- nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3- hydroxyandrostane-17-carbonitrile (3 -OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.68. The use according to embodiment 67, wherein the medicament preserves development of acquired adaptive immunity through the TRIF pathway.69. The use according to any one of embodiments 61-68, wherein the medicament comprises a combination of neuroactive steroids.70. The use according to embodiment 69, wherein the combination of neuroactive steroids is alfaxalone and alfadolone.71. The use according to any one of embodiments 61-69, wherein the neuroactive steroid is alfaxalone, alfadolone or alfadolone acetate.72. A kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58,178)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.73. A kit comprising a neuroactive steroid when used for treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.74. The kit according to embodiment 72 or embodiment 73, wherein the kit further comprises one or more other therapeutic agents.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of treating or at least partially inhibiting the development or progression of an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19- nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3P,5P,17f>)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

2. A method of treating or at least partially inhibiting the development or progression of a condition associated with an infection in a subject, wherein the infection is caused by a neurotropic virus, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58, 17f>)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- d I hydroprogesterone (3a-DHP), ent-progesterone, dihydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

3. The method according to claim 2, wherein the condition is associated with multisystem organ failure and / or selected from the group consisting of acuteencephalopathy, acute encephalitis, myelitis, meningitis, meningoencephalitis and encephalomyelitis.

4. The method according to claim 3, wherein the condition is acute encephalopathy or acute encephalitis.

5. The method according to any one of claims 1-4, wherein the infection is a central nervous system infection.

6. The method according to any one of claims 1-5, wherein the infection is associated with the development of inflammation and / or a cytokine storm.

7. The method according to claim 6, wherein the inflammation and / or cytokine storm is associated with the activity of a Toll-like receptor.

8. The method according to claim 7, wherein the Toll-like receptor is Toll-like receptor 4.

9. The method according to any one of claims 1-8, wherein neuronal transport of the virus within the subject is associated with the activity of a member of the tumor necrosis factor receptor family.

10. The method according to claim 9, wherein the member of the tumor necrosis factor receptor family is p75NTR.

11. A method of inhibiting or reducing neuronal transport of a neurotropic virus in a subject, the method comprising, consisting or consisting essentially of administering a neuroactive steroid to the subject, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (2p,3a,58)-21-chloro- 3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 2p-(2,2-dimethyl-4- morpholinyl)-3a-hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org- 21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19- nor-58-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17f>)-3- hydroxyandrostane-17-carbonitrile (3 -OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

12. The method according to any one of claims 1-11, wherein the virus is a single stranded negative-sense RNA virus or single stranded positive-sense RNA virus.

13. The method according to any one of claims 1-12, wherein the virus is selected from the group consisting of Marburg virus, Nipah virus, Zika virus, Hendra virus, West Nile virus, Japanese encephalitis virus, an Ebolavirus and rabies virus.

14. The method according to claim 13, wherein the virus is rabies virus.

15. A method of inhibiting or reducing the interaction of a neurotropic virus with p75NTR in a p75NTR expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent-pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy-2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a-hydroxy-ll,20-dioxo-5a- pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-3p-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-5p-pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (3(3,58, 17P)-3-hydroxyandrostane-17-carbonitrile (38- OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), 3a- di hydroprogesterone (3a-DHP), ent-progesterone, di hydrodeoxycorticosterone (DHDOC), tetrahydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

16. A method of inhibiting or reducing activation of MyD88 by a Toll-like receptor in response to a neurotropic virus in a Toll-like receptor expressing cell, the method comprising, consisting or consisting essentially of contacting the cell with a neuroactive steroid, wherein the neuroactive steroid is selected from the group consisting of alfaxalone, alfadolone, alfadolone acetate, pregnanediol, pregnanolone, ent- pregnanolone, pregnanedione, allopregnanediol, allopregnanedione, acebrochol, ganaxolone, hydroxydione, minaxolone, renanolone, (28,3a,58)-21-chloro-3-hydroxy- 2-morpholin-4-ylpregnan-20-one (Org-20599), 28-(2,2-dimethyl-4-morpholinyl)-3a- hydroxy-ll,20-dioxo-5a-pregnan-21-yl methanesulfonate (Org-21465), 20-(hydroxyimino)pregn-4-en-3-one (EIDD-036), posovolone (Co 134444), zuranolone (SAGE-217), 3a-hydroxy-38-methyl-21-(pyrazolo[3',4'-c]pyridin-2'-yl)-19-nor-58- pregnan-20-one (SGE-872), alfaxalone / alfadolone (CT1341), (38,58,178)-3- hydroxyandrostane-17-carbonitrile (38-OH), (3a,5a)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), 3a-dihydroprogesterone (3a-DHP), ent- progesterone, di hydrodeoxycorticosterone (DHDOC), tetra hydrodeoxycorticosterone (THDOC), betaxalone, and pharmaceutically acceptable salts and solvates thereof.

17. The method according to claim 16, wherein the method preserves development of acquired adaptive immunity through the Toll / interleukin-1 receptor domain-containing adapter-inducing interferon-8 (TRIF) pathway.

18. The method according to claim 16 or claim 17, wherein the Toll-like receptor is Toll-like receptor 4.

19. The method according to any one of claims 15-18, wherein the virus is rabies virus.

20. The method according to any one of claims 1-14, wherein the method comprises, consists or consists essentially of administering a combination of neuroactive steroids to the subject.

21. The method according to claim 20, wherein the combination of neuroactive steroids is alfaxalone and alfadolone.

22. The method according to any one of claims 1-19, wherein the neuroactive steroid is alfaxalone, alfadolone or alfadolone acetate.

23. The method according to claim 22, wherein the neuroactive steroid is alfaxalone.

24. The method according to claim 22, wherein the neuroactive steroid is alfadolone or alfadolone acetate.

25. The method according to any one of claims 1-14 and 20-24, wherein the neuroactive steroid is administered intravenously, orally, subcutaneously, intramuscularly or intranasally.

26. The method according to any one of claims 1-14 and 20-25, wherein the neuroactive steroid is administered in a modified-release formulation, is titrated up to a dose that causes a burst suppression in an electroencephalogram, or is titrated up to a dose that causes a bispectral index of 0.

27. The method according to any one of claims 1-14 and 20-26, wherein the neuroactive steroid is administered in an amount in the range of from about 0.05 mg to about 250 mg per kg body weight of the subject, or an amount that causes sedation of the subject.

28. The method according to claim 27, wherein the neuroactive steroid is administered in an amount that does not cause anaesthesia of the subject.

29. The method according to any one of claims 1-14 and 20-28, wherein the method further comprises administering one or more other therapeutic agents selected from the group consisting of an analgesic, sedative, anaesthetic, antiviral, N-methyl-D- aspartate (NMDA) receptor antagonist, antidiuretic hormone, fluid therapy, inotrope, antiarrhythmic agent, vasodilator, calcium channel antagonist, therapy for delayed ischemic deficit from nitric oxide excess, therapy for tetrahydrobiopterin deficiency, sedating neuroprotective agent, therapy for lactic acidosis or ketosis, and Toll-like receptor antagonist.

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