Combination of Nurr1 agonist with at least one of aldosterone antagonist, insulin modulator and sulfonylurea

Abstract

The present invention provides (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) sulfonylureas and at least one additional ingredient selected from The present invention provides a combination comprising: a) a compound selected from the group consisting of hydroxybenzoates, ...

Description

[Technical field]

[0001] The present invention provides a combination suitable for treating one or more of stroke, neurodegenerative disorders, neuroinflammation, neuroinflammatory disorders, and treating and / or preventing ischemia and / or reperfusion injury in various vital organs, including the brain and the heart. More specifically, the combination of the present invention comprises a Nurr1 agonist.

[0002] Further aspects of the invention relate to pharmaceutical products and compositions containing said combinations and methods of treatment using same. [Background technology]

[0003] Stroke is a significant cause of severe long-term disability and the third leading cause of death in the United States. Stroke is caused by lack of blood flow in the brain (ischemic stroke) or bleeding in the brain (hemorrhagic stroke), both conditions leading to brain cell death. Ischemic stroke accounts for more than 88% of all strokes, making it the most common type of cerebrovascular injury. Cerebral ischemia causes the death of neurons, leading to permanent sensory-motor impairments. Stroke is associated with memory loss and depression, as well as causing significant physical disability.

[0004] According to the World Health Organization, stroke is the second most important cause of death worldwide, accounting for approximately 6 million deaths in 2016. The high burden of stroke worldwide suggests that primary prevention strategies are not widely implemented or are not sufficiently effective. Guidelines are available for the management of acute ischemic stroke (Powers WJ, et al. Stroke. 2019; 50: e344- e418). Interestingly, the guidelines conclude that currently, no pharmacological or non-pharmacological treatments with putative neuroprotective effects have shown efficacy in improving outcomes after ischemic stroke, and therefore, other neuroprotective agents are not recommended. Guidelines also exist for the management of hemorrhagic stroke, but these guidelines do not recommend any therapy to manage the neurodegenerative consequences of hemorrhagic stroke other than rehabilitation (Hemphill JC 3rd, et al. Stroke. 2015; 46: 2032-2060).

[0005] The above data clearly indicate that there is currently a lack of effective pharmacological treatments for ischemic or hemorrhagic stroke, and that neuroprotective treatments for patients with stroke are necessary. Effective treatment of stroke-related reperfusion injury may provide neuroprotection. However, so far, attempts to develop effective neuroprotective treatments for stroke patients based on reducing reperfusion injury have been unsuccessful (Savitz SI, et al. Stroke. 2017; 48: 3413-3419, Patel RAG, et al. Prog Cardiovasc Dis. 2017; 59: 542-548). Previous research in the field of cardioprotection and reperfusion injury has revealed the surprising discovery that combination therapies not indicated for the treatment of cardiovascular disorders may provide significant synergistic effects in protecting against myocardial reperfusion injury when used at lower dose levels than those indicated for these other conditions (WO 2017 / 077378; U.S. Pat. No. 10,172,914; Genesis Pharma SA). Previous work by the applicant has shown that combination therapies using sulfonylureas and a second active ingredient have potential therapeutic applications in the treatment of ischemia and / or reperfusion injury, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for use in providing cardioprotection against cardiotoxic drugs, or for use in providing neuroprotection against neurotoxic drugs (WO 2021 / 005147; Genesis Pharma SA). In particular, research by the applicant has demonstrated that a combination of glibenclamide with exenatide and / or potassium canrenoate can reduce the extent of cerebral infarction and / or improve neurological severity scores and / or improve motor skills.

[0006] Therapies that exhibit neuroprotective effects are also expected to be useful in the treatment of neurodegenerative disorders, which are due to the progressive loss of neuronal structure or function, ultimately leading to neuronal death. Neurodegenerative disorders include diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and vascular dementia, which are currently incurable. Neuroinflammatory pathways are also understood to play an important role in neurodegenerative diseases (Chen et al. 2016; Liddelow et al, 2017).

[0007] Vascular dementia is a dementia caused by problems with the blood supply to the brain, typically a series of minor strokes, leading to worsening cognitive decline that occurs in stages. The term refers to a syndrome consisting of a complex interaction of cerebrovascular disease and risk factors, leading to changes in brain structure due to strokes and lesions, and consequently to changes in cognition. Currently, there are no medications specifically approved for the prevention or treatment of vascular dementia. Currently approved therapies for Alzheimer's disease provide only modest benefits (Atri A. Med Clin North Am. 2019; 103: 263-293) and lack solid evidence of their efficacy. Although multiple pharmacological treatments are available to manage motor and non-motor symptoms of Parkinson's disease, they are essentially symptomatic treatments that ultimately induce dyskinesias, while none of these treatments provide neuroprotection (Chaudhuri KR, et al. Parkinsonism Relat Disord. 2016; 33 (Suppl 1): S2-S8). Currently, there are only two approved drugs (riluzole and edaravone) that slow the progression of amyotrophic lateral sclerosis, albeit modestly, and there are no approved treatments for Huntington's disease. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2017 / 077378 Brochure [Patent Document 2] U.S. Patent No. 10,172,914 [Patent Document 3] International Publication No. 2021 / 005147 Brochure [Non-patent literature]

[0009] [Non-Patent Document 1] Powers WJ, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association / American Stroke Association. Stroke. 2018; 49: e46-e99; updated 2019; 50: e344- e418 [Non-Patent Document 2] Hemphill JC 3rd, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association / American Stroke Association. Stroke. 2015; 46: 2032-2060 [Non-Patent Document 3] Savitz SI, et al. Reconsidering Neuroprotection in the Reperfusion Era. Stroke. 2017; 48: 3413-3419 [Non-Patent Document 4] Patel RAG, et al. Neuroprotection in the Treatment of Acute Ischemic Stroke. Prog Cardiovasc Dis. 2017; 59: 542-548 [Non-Patent Document 5] Chen et al. Role of neuroinflammation in neurodegenerative diseases (Review), Molecular Medicine Reports 13: 3391-3396, 2016 [Non-Patent Document 6] Liddelow et al, Nature, 2017, Jan 26; 541(7638): 481-487 [Non-Patent Document 7] Atri A. The Alzheimer's Disease Clinical Spectrum: Diagnosis and Management. Med Clin North Am. 2019; 103: 263-293 [Non-Patent Document 8] Chaudhuri KR, et al. Unmet needs in Parkinson's disease: New horizons in a changing landscape. Parkinsonism Relat Disord. 2016; 33 (Suppl 1): S2-S8 Summary of the Invention [Problem to be solved by the invention]

[0010] Thus, there is a clear need for additional and better treatments that provide neuroprotection and / or that can inhibit neuroinflammation, particularly in the context of the treatment of stroke and neurodegenerative diseases. [Means for solving the problem]

[0011] Description of the Invention The present invention provides combinations which are suitable for use in the prevention or treatment of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction, or for use in providing cardioprotection against cardiotoxic drugs, or for use in providing neuroprotection.

[0012] Advantageously, the combinations and other aspects of the invention claimed in this application provide treatments that are more effective and provide superior clinical outcomes compared to therapies using a single active pharmaceutical agent. In particular, the presence of a Nurr1 agonist provides an additional and different mechanism of action that is believed to be particularly relevant to neurodegeneration compared to the combinations described in WO 2017 / 077378 and WO 2021 / 005147. Furthermore, in certain embodiments, the combinations claimed herein allow the use of lower dosages of the components than those taught in the literature.

[0013] The first aspect of the present invention is (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a combination comprising:

[0014] A second aspect of the invention relates to a pharmaceutical composition comprising a combination as described above and a pharma- ceutically acceptable carrier, diluent or excipient.

[0015] A third aspect of the present invention is (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a pharmaceutical product comprising:

[0016] A fourth aspect of the invention relates to a combination or pharmaceutical composition or pharmaceutical product as described above for use in the treatment and / or prevention of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction or for use in providing cardioprotection against cardiotoxic drugs or for use in providing neuroprotection.

[0017] A fifth aspect of the present invention provides a method for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, comprising administering to a subject in need thereof (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a method comprising administering simultaneously, sequentially or separately

[0018] A sixth aspect of the present invention relates to a method for the treatment and / or prevention of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, comprising: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from Regarding the use of.

[0019] A seventh aspect of the present invention relates to a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to the use of a combination comprising DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The preferred embodiments described below are applicable to any of the above aspects of the invention, where appropriate.

[0021] As used herein, structural analogs, also known as chemical analogs, are compounds that are similar to the structure of another compound, but have a different structure with respect to certain components. Structural analogs may differ in one or more atoms, functional groups, or substructures, which are replaced by other atoms, groups, or substructures. Structural analogs can be imagined, at least in theory, to be formed from other compounds. Structural analogs are often isoelectronic.

[0022] As used herein, a functional analog is a chemical compound that has similar physical, chemical, biochemical, or pharmacological properties as another compound. A functional analog is not necessarily a structural analog that has a similar chemical structure.

[0023] Nurr1 agonists The combinations, pharmaceutical compositions and pharmaceutical products described herein comprise a Nurr1 agonist in combination with at least one second active agent.

[0024] The Nurr1 receptor, also known as nuclear receptor 4A2 (NR4A2; nuclear receptor subfamily 4 group A member 2), is a protein encoded by the NR4A2 gene in humans. NR4A2 is a member of the nuclear receptor family of intracellular transcription factors and plays a key role in maintaining the brain's dopaminergic system (Sacchetti P, et al 2006). Mutations in this gene are associated with disorders related to dopaminergic dysfunction, including Parkinson's disease and schizophrenia. Nurr1 is also understood to play a role in neuroinflammatory pathways associated with certain neurodegenerative disorders, such as ALS and Alzheimer's disease (Valsecchi et al. Dis. Model Mech. 2020;13(5):dmm043513; Jeon et al. Aging Dis., 2020;11(3):705-724).

[0025] In the CNS, inflammation can be generated by activated microglia and other proinflammatory factors such as bacterial lipopolysaccharide (LPS). LPS induces the expression of inflammatory genes by binding to toll-like receptors (TLRs) and promoting signal-dependent transcription factors. NR4A2 has been shown to protect dopaminergic neurons from LPS-induced inflammation by reducing the expression of inflammatory genes in microglia and astrocytes. When short hairpins against NR4A2 are expressed in microglia and astrocytes, these cells produce inflammatory mediators such as TNFα, NO synthase, and IL-1β, supporting the conclusion that reduction of NR4A2 promotes inflammation and leads to cell death of dopaminergic neurons. NR4A2 interacts with the transcription factor complex NF-κB-p65 on inflammatory gene promoters. However, whether NR4A2 can participate in these interactions depends on other factors. These interactions require NR4A2 SUMOylation and phosphorylation of its co-regulator glycogen synthase kinase 3. SUMOylated NR4A2 recruits CoREST, a complex of several proteins that organize chromatin-modifying enzymes. The NR4A2 / CoREST complex inhibits the transcription of inflammatory genes (Saijo K, et al; 2009).

[0026] Nurr1 agonists have been shown to improve behavioral deficits in animal models of Parkinson's disease (Kim et al. 2015). Postmortem studies have shown that Nurr1 expression is reduced in both aged and Parkinson's Disease (PD) postmortem brains (Chu Y et al. 2002, Chu Y, et al. 2006). Furthermore, functional mutations / polymorphisms in Nurr1 have been identified in rare cases of familial late-onset PD (Le WD, et al. 2003). In addition, Nurr1 heterozygous null mice behave like animal models of PD, as both rotarod performance and locomotor activity are severely reduced in association with reduced dopamine (DA) levels in the striatum and reduced numbers of A9 DA neurons (Jiang C, et al. 2005). Taken together, these findings strongly suggest that impaired Nurr1 function / expression is associated with neurodegeneration of DA neurons and that its activation may ameliorate PD pathogenesis (Glass CK et al. 2010).

[0027] ★ Kim et al. (ibid.) successfully identified Nurr1 agonists sharing the same chemical scaffold, 4-amino-7-chloroquinoline, suggesting important structure-activity relationships. Notably, amodiaquine and chloroquine were found to stimulate the transcriptional function of Nurr1 through physical interaction with the ligand binding domain (LBD) of Nurr1. Notably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in a 6-hydroxydopamine-lesioned rat PD model, without detectable signs of dyskinesia-like behavior. These findings provide proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-of-action-based neuroprotective strategy for PD.

[0028] Suitable Nurr1 agonists can be identified using known assays (see, for example, as described in Kim 2015). In one preferred embodiment, the Nurr1 agonist in the combination of the invention is selected from amodiaquine, chloroquine, hydroxychloroquine and glafenine, and pharma- ceutically acceptable salts thereof: [ka]

[0029] Amodiaquine In one particularly preferred embodiment, the Nurr1 agonist in the combination of the present invention is amodiaquine, or a pharma- ceutically acceptable salt thereof. In one preferred embodiment, the Nurr1 agonist is amodiaquine hydrochloride. More preferably, the Nurr1 agonist is amodiaquine.

[0030] Amodiaquine is the compound 4-[(7-chloroquinolin-4-yl)amino]-2[(diethylamino)methyl]-phenol with the structure shown above. Amodiaquine is an alternative first-line drug for uncomplicated malaria and has been shown to induce vasorelaxation in the rat superior mesenteric artery (Oluwatosin et al. 2010). Studies have also shown that amodiaquine reduces inflammatory events and neurological deficits in a mouse model of intracerebral haemorrhage (ICH) (Kinoshita et al. 2019).

[0031] In particular, Kinoshita demonstrated that Nurr1 (NR4A2) was prominently expressed in microglia / macrophages and astrocytes in the perihematomal area of ​​the striatum of mice after ICH. Daily administration of amodiaquine (40 mg / kg, ip) starting 3 h after ICH induction reduced perihematomal activation of microglia / macrophages and astrocytes. Amodiaquine also suppressed ICH-induced mRNA expression of IL-1β, CCL2, and CXCL2 and improved motor dysfunction in mice, suggesting that Nurr1 may serve as a novel target for ICH therapy.

[0032] Advantageously, the dosage of amodiaquine used in the present combination is significantly lower than that reported in the literature (e.g., Kinoshita et al. 2019).

[0033] Sulfonylurea In certain embodiments, the combination or pharmaceutical product or pharmaceutical composition of the invention comprises a sulfonylurea.

[0034] Sulfonylureas are a class of oral hypoglycemic drugs primarily used in the management of type 2 diabetes and certain forms of monogenic diabetes. Sulfonylureas lower blood glucose levels by stimulating insulin secretion from the beta cells of the pancreas. Their main target is the ATP-sensitive potassium (K ATP ) channel (Proks P, et al. Diabetes. 2002; 51 (Suppl 3): S368-76; Gribble FM, Reimann F. Diabetologia. 2003; 46: 875-891).

[0035] Consistent with their introduction into the clinic, sulfonylureas are traditionally classified into two generations, differing primarily in their properties, allowing for less frequent dosing of second-generation drugs (Sola D, et al. Arch Med Sci. 2015; 11: 840-8): The first generation include chlorpropamide, tolbutamide, acetohexamide, carbutamide, glycilamide, tolhexamide, metahexamide, and tolazamide; however, they are no longer used in clinical practice. Second generation includes glibenclamide (glyburide), glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide. Modified / extended release formulations exist for some second generation sulfonylureas (gliclazide, glipizide).

[0036] Preferably, the sulfonylurea in the combination of the present invention is a second generation sulfonylurea. Current guidelines recommend the use of second generation sulfonylurea as a second-line therapy in combination with metformin when metformin alone is inadequately controlled, and second generation sulfonylurea may also be used in triple combination therapy when adequate glycemic control is not achieved with the two-drug combination (Garber AJ, et al. Endocr Pract. 2019; 25: 69-100, Inzucchi SE, et al. Diabetes Care. 2015; 38: 140-9). The decision to use a sulfonylurea should take into account the patient's characteristics and potential adverse events associated with the sulfonylurea (Cordiner RLM, Pearson ER. Diabetes Obes Metab. 2019; 21: 761-771).

[0037] In one particularly preferred embodiment, the sulfonylurea is a Sur-1 receptor antagonist. Suitable Sur-1 receptor antagonists can be identified using known assays.

[0038] In one particularly preferred embodiment, the sulfonylurea is a SUR1-TRPM4 channel antagonist. Suitable SUR1-TRPM4 channel antagonists can be identified using known assays.

[0039] The invention also encompasses structural or functional analogs of sulfonylureas, particularly those modified to extend the half-life of the drug, such as conjugates of sulfonylureas.

[0040] In one preferred embodiment, the sulfonylurea is selected from glibenclamide (glyburide), glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide.

[0041] In one highly preferred embodiment, the sulfonylurea is selected from glibenclamide and its structural and functional analogs.

[0042] Preferably, the sulfonylurea is selected from the acylhydrazone, sulfonamide and sulfonylthiourea derivatives of glibenclamide, glimepiride, glipizide and gliclazide.

[0043] In one preferred embodiment, the sulfonylurea has the structure shown below: [ka] and glimepiride, which has the formula:

[0044] In one preferred embodiment, the sulfonylurea has the structure shown below: [ka] and gliclazide, which has the formula:

[0045] In one preferred embodiment, the sulfonylurea has the structure shown below: [ka] and glipizide, which has the formula:

[0046] In one particularly preferred embodiment, the sulfonylurea is glibenclamide.

[0047] The systematic (IUPAC) name of glibenclamide is 5-chloro-N-[2-[4-(cyclohexylcarbamoyl-sulfamoyl)phenyl]ethyl]-2-methoxybenzamide (chemical formula C 23 H 28 ClNOS) and has a molecular weight of 494; it has the following chemical structure: [ka] has.

[0048] The present invention also encompasses structural and functional analogs of glibenclamide, particularly those modified to extend the half-life of the drug, such as conjugates of glibenclamide.

[0049] Glibenclamide (also known as glyburide) is a sulfonylurea receptor-1 (Sur-1) antagonist used as a hypoglycemic agent to treat diabetes. Glibenclamide has been explored as a treatment to reduce edema after brain injuries such as ischemic stroke, traumatic brain injury, and subarachnoid hemorrhage, but results to date have been inconsistent (Wilkinson CM, et al. PLoS One. 2019; 14: e0215952, Xu F, et al. Brain Behav. 2019; 9(4): e01254, King ZA, et al. Drug Des Devel Ther. 2018; 12: 2539-2552). We investigated the role of glibenclamide as part of a combination therapy aimed at reducing reperfusion injury and potentially providing a neuroprotective effect.

[0050] Glibenclamide is available generically and is sold under many trade names, including Gliben-J, Daonil, Diabeta, Euglucon, Gilemal, Glidanil, Glybovin, Glynase, Maninil, Micronase, and Semi-Daonil, in doses of 1.25, 2.5, and 5 mg. Glibenclamide is used orally for the treatment of type 2 diabetes mellitus, either as a tablet formulation (for adults) or as an oral suspension (for children). The defined daily dose (DDD) of glibenclamide for the treatment of type 2 diabetes is 7 mg for the micronized formulation, which is more bioavailable, and 10 mg for the conventional formulation. The defined daily dose (DDD) is the expected average daily maintenance dose of the drug used for its primary indication in adults, as defined according to the WHO Collaborating Centre for Drug Statistics Methodology. The DDD is a unit of measurement and does not necessarily reflect the recommended or prescribed daily dose. Treatment doses for individual patients and patient groups are based on individual characteristics (such as age, weight, ethnic differences, type and severity of disease) and pharmacokinetic considerations, and therefore often differ from the DDD. The DDD values ​​for glibenclamide are obtained from the WHO Collaborating Centre for Drug Statistics Methodology (see https: / / www.whocc.no / atc_ddd_index / ?code=A10BB01&showdescription=yes). The usual starting dose of glibenclamide (micronized formulation) as initial therapy is 2.5-5 mg per day, and the usual maintenance dose ranges from 1.25-20 mg per day, which may be given as a single or divided dose with breakfast or the first main meal (according to the FDA label for Micronase® glyburide tablets). This corresponds to a maintenance dose of about 18 μg / kg to about 285 μg / kg in a 70 kg adult.

[0051] Several studies in animal models have demonstrated a protective role for glibenclamide in inflammation-associated injury, including reducing deleterious neuroinflammation and improving behavioral outcomes after central nervous system injury (Zhang G, et al. Mediators Inflamm. 2017; 2017: 3578702) or ischemic and hemorrhagic stroke (Caffes N, et al. Int J Mol Sci. 2015; 16: 4973-84). In a rat model of traumatic brain injury, glibenclamide was administered intraperitoneally as a loading dose of 10 μg / kg followed by an infusion of 200 ng / h for 7 days (Patel AD, et al. J Neuropathol Exp Neurol. 2010; 69: 1177-90); whereas in a mouse model of traumatic brain injury, the dose of glibenclamide was 10 μg for 3 days after a controlled cortical impact injury (Xu ZM, et al. J Neurotrauma. 2017; 34: 925-933). In a rodent model of cerebral ischemia and reperfusion injury, glibenclamide was shown to be effective at a dose of 1 mg / kg administered 10 min before reperfusion (Abdallah DM, et al. Brain Res. 2011; 1385: 257-62). In rodent models of subarachnoid hemorrhage, glibenclamide was shown to be effective when administered intraperitoneally at a loading dose of 10 μg / kg followed by an infusion of 200 ng / h for 24 h (Simard, JM, et al. Journal of Cerebral Blood Flow and Metabolism. 2009; 29; 317-330) or 1 week (Tosun C, et al. Stroke. 2013; 44: 3522-8). Glibenclamide administered as a continuous infusion (75 ng / h) reduced cerebral edema, infarct volume, and mortality by 50%, and the reduction in infarct volume was associated with cortical sparing 7 days after middle cerebral artery occlusion in a thromboembolic model of stroke in rats (Simard JM, et al. Nat Med. 2006; 12: 433-40).Glibenclamide administered at a dose of 10 μg either before or 2 h after experimental intracerebral hemorrhage in mice was shown to reduce brain edema, BBB disruption, and neurological deficits (Xu F, et al. Brain Behav. 2019; 9: e01254), and similar findings were obtained in another study (Jiang B, et al. Transl Stroke Res. 2017; 8: 183-193), but a widely used dose of glibenclamide shown to be effective in other studies (10 μg / kg loading dose followed by 200 ng / h for up to 7 days) was not shown to be effective when intracerebral hemorrhage was produced by intrastriatal injection of collagenase (Wilkinson CM, et al. PLoS One. 2019; 14(5): e0215952).

[0052] Glibenclamide has also been shown to exert beneficial effects in stroke patients in several clinical trials. The Glyburide Advantage in Malignant Edema and Stroke (GAMES) clinical trial, in which glyburide was administered intravenously as a bolus intravenous injection of 0.13 mg in the first 2 minutes (RP-1127), followed by an infusion of 0.16 mg / hour for the first 6 hours, then 0.11 mg / hour for the remaining 66 hours, revealed promising findings regarding brain swelling (midline shift), MMP-9, functional outcomes, and mortality (King ZA, et al. Drug Des Devel Ther. 2018; 12: 2539-2552). An exploratory study of oral glibenclamide in patients with acute hemispheric infarction showed that treatment was safe, but did not substantially improve 6-month functional outcomes, although there was a slight trend toward less cerebral edema and less severe disability and death with treatment (Huang K, et al. Acta Neurol Scand. 2019 May 29). A retrospective analysis of data on sulfonylurea-naïve diabetic patients in the days following acute ischemic stroke found a strong association between sulfonylurea treatment and improved survival, increased functional independence, lower NIH Stroke Scale scores, and less hemorrhagic transformation (Kunte H, et al. Ann Neurol. 2012; 72: 799-806).

[0053] The above preclinical and clinical findings may be related to the upregulation of SUR1-TRPM4 channels after brain injury such as ischemia (Woo SK, et al. J Biol Chem. 2013; 288: 3655-67, Mehta RI et al. J Neuropathol Exp Neurol. 2015; 74: 835-49).

[0054] Neuroprotective effects in animal models of ischemia and reperfusion injury have also been reported for other sulfonylureas, such as gliclazide (Tan F, et al. Brain Res. 2014;1560: 83-90), and protective effects in animal models of ischemia and reperfusion injury in other tissues, such as myocardium, for glimepiride (Nishida H et al. J Pharmacol Sci. 2009; 109: 251-6).

[0055] Some other drugs have insulinotropic effects such as sulfonylureas; examples include glinides (such as repaglinide, nateglinide, and mitiglinide). In addition, other compounds such as resveratrol bind to sulfonylurea receptors (Hambrock A, et al. J Biol Chem. 2007; 282: 3347-56) and have been shown to have neuroprotective effects in stroke and traumatic CNS injury (Lopez MS, et al. Neurochem Int. 2015; 89: 75-82).

[0056] Research by applicants, and that is described in more detail in the accompanying Examples, has shown that administering a sulfonylurea (e.g., glibenclamide) in combination with amodiaquine and an aldosterone antagonist (e.g., potassium canrenoate) provides clinically beneficial effects even when the sulfonylurea is administered only in very low doses.

[0057] Insulin Modulators In certain embodiments, the combination, or pharmaceutical composition or pharmaceutical product of the invention comprises an insulin modulator.

[0058] As used herein, the term "insulin modulator" refers to an agent that can directly or indirectly increase or decrease the activity of insulin, which in turn can increase or decrease insulin-mediated physiological responses.

[0059] In one embodiment, the insulin modulator is selected from a GLP-1 agonist, a DPP-4 inhibitor, a PPAR agonist, insulin, and analogs thereof.

[0060] Examples of GLP-1 agonists include exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) and pharma- ceutically acceptable salts thereof.

[0061] Examples of DPP-4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, and omarigliptin (MK-3102), and pharma- ceutical acceptable salts thereof.

[0062] Examples of PPAR agonists include clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, saroglitazar, aleglitazar, muraglitazar and tesaglitazar, and pharma- ceutically acceptable salts thereof.

[0063] Examples of insulin analogues include insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin degludec, insulin glargine, and pharma- ceutically acceptable salts thereof.

[0064] Thus, in one embodiment, the insulin modulator is selected from exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide, dulaglutide (LY2189265), sitagliptin, vildagliptin, saxagliptin, linagliptin anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, omarigliptin (MK-3102), clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, saroglitazar, aleglitazar, muraglitazar, tesaglitazar, insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin degludec, insulin glargine, and pharma- ceutically acceptable salts thereof.

[0065] In one embodiment, the insulin modulator is a GLP-1 agonist selected from exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide, dulaglutide (LY2189265) and pharma- ceutically acceptable salts thereof. Preferably, the GLP-1 agonist is exenatide.

[0066] Exenatide In one particularly preferred embodiment, the insulin modulator is selected from exenatide and its structural and functional analogs, and pharma- ceutically acceptable salts thereof.

[0067] In one preferred embodiment, exenatide is in the form of a pharma- ceutically acceptable salt, more preferably exenatide acetate.In another preferred embodiment, exenatide is in free base form.

[0068] As used herein, the term "exenatide" refers to a 39-mer peptide of the following sequence: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Ar g-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

[0069] Exenatide (synonymous exendin-4) was originally isolated from the saliva of the Gila monster Heloderma suspectum in 1992. It is an insulinotropic agent with glucoregulatory effects similar to those of the human peptide glucagon-like peptide-1 (GLP-1).

[0070] Exenatide mimics human glucagon-like peptide 1 (GLP-1), an intestinal incretin hormone released in response to nutrient intake (Goke R, et al. J. Biol. Chem., 1993, 268: 19650-19655). It exerts insulinotropic and insulinomimetic properties via the GLP-1 receptor. GLP-1 receptors are widely expressed in many organs, including the heart and vascular endothelium (Bullock BP, et al. Endocrinology. 1996, 137: 2968-2978; Nystrom T, et al. Am J Physiol Endocrinol Metab, 2004, 287: E1209- E1215). Currently, exenatide is approved as an antidiabetic drug for the treatment of patients with type 2 diabetes. The recommended dose for this indication is initially 5 micrograms (µg) twice daily, increased to 10 µg twice daily after 1 month based on clinical response.

[0071] GLP-1 is ineffective as a therapeutic agent because it has a very short circulating half-life (<2 min) due to rapid degradation by dipeptidyl peptidase-4. Exenatide is 50% homologous to GLP-1 but lacks the dipeptidyl peptidase-4 cleavage site, resulting in a half-life of 2.4 hours in humans.

[0072] Exenatide enhances glucose-dependent insulin secretion by pancreatic beta cells, inhibits inappropriately elevated glucagon secretion, and delays gastric emptying. Exenatide is highly potent, with a minimal effective concentration in humans of 50 pg / mL (12 pM). Current treatment with exenatide involves twice-daily injections (Byetta®). A sustained-release formulation (Bydureon®) is also approved for weekly injections.

[0073] As used herein, a functional analog of exenatide refers to a compound that has a similar structure but differs therefrom in certain aspects (e.g., one or more atoms, functional groups, amino acid residues, or substructures may differ and be replaced by others). Functional analogs exhibit similar pharmacological properties and may be structurally related.

[0074] In one embodiment, a structural or functional analog of exenatide is a form of exenatide that has been modified to extend its half-life, for example, a conjugate of exenatide.

[0075] In one preferred embodiment, the structural or functional analog of exenatide is PEGylated exenatide.For example, in one preferred embodiment, the structural or functional analog is exenatide mono-PEGylated with 40kDa PEG.PEGylated exenatide can be prepared by methods known in the art.For example, PEGylated forms of exenatide are described in WO2013 / 059323 (Prolynx LLC), the contents of which are incorporated herein by reference.Exenatide can also be conjugated to other molecules, such as proteins.

[0076] In one particularly preferred embodiment, the structural or functional analog of exenatide is in a sustained release form, for example, sold under the trade name Bydureon®. In another preferred embodiment, the structural or functional analog of exenatide is in the form of a multi-layered nanoparticle for sustained delivery, for example, as described in (Kim JY, et al, Biomaterials, 2013; 34: 8444-9), the contents of which are incorporated herein by reference.

[0077] In another particularly preferred embodiment, exenatide is in an injectable form, such as that sold under the trade name Byetta®.

[0078] Functional analogues of exenatide include GLP receptor agonists. Suitable functional analogues of exenatide include lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265).

[0079] In one embodiment, functional analogs of exenatide include modified exenatide in which one or more amino acid residues have been replaced with another amino acid residue, and / or one or more amino acid residues have been deleted, and / or one or more amino acid residues have been added and / or inserted.

[0080] In one embodiment, a functional exenatide analog contains fewer than 10 amino acid modifications (substitutions, deletions, additions (including insertions) and any combination thereof) compared to exenatide, or fewer than 9, 8, 7, 6, 5, 4, 3, or 2 modifications compared to exenatide.

[0081] In one embodiment, the functional exenatide analog contains 10 amino acid modifications (substitutions, deletions, additions (including insertions) and any combination thereof) compared to exenatide, or 9, 8, 7, 6, 5, 4, 3, 2 or 1 modification compared to exenatide.

[0082] Structural and functional analogs of exenatide also include salts, isomers, enantiomers, solvates, polymorphs, prodrugs, and metabolites thereof.

[0083] Aldosterone antagonists In certain embodiments, the combination, or pharmaceutical composition or pharmaceutical product of the invention comprises an aldosterone antagonist.

[0084] Acute myocardial infarction and the subsequent hemodynamic changes lead to complex neurohormonal activation. The renin-angiotensin-aldosterone pathway is one basis of such neurohormonal activation. Aldosterone, which is at its highest level in the post-acute myocardial infarction condition, has been reported to promote a wide range of adverse cardiovascular effects, including acute endothelial dysfunction, inhibition of NO activity, increased endothelial oxidative stress, increased vascular tone, inhibition of tissue recapture of catecholamines, rapid development of vascular smooth muscle cell and cardiomyocyte necrosis, intravascular collagen deposition, myocardial hypertrophy, and fibrosis (Struthers, Am Heart J, 2002, 144: S2-S7; Zannad F, Radauceanu, Heart Fail Rev, 2005, 10: 71-78). Moreover, it has been found to predict poor outcome (Beygui et al, Circulation. 2006, 114: 2604-2610). Aldosterone antagonists, or antimineralcorticoids, are diuretics that antagonize the action of aldosterone at the mineralocorticoid receptor. This group of drugs is often used in the management of chronic heart failure. Members of this class are also used in the management of hyperaldosteronism (including Conn's syndrome) and hirsutism in women (due to additive antiandrogenic effects). Most antimineralcorticoids are steroidal spirolactones.

[0085] Mineralocorticoid receptor antagonism inhibits sodium absorption in the collecting ducts of the nephrons of the kidney. This interferes with sodium / potassium exchange, reduces urinary potassium excretion, and weakly increases water excretion (diuresis). In congestive heart failure, aldosterone antagonists are used in addition to other drugs for their additive diuretic effect, which reduces edema and cardiac workload.

[0086] Current guidelines recommend the use of mineralocorticoid receptor antagonists in patients with heart failure after myocardial infarction, based on the results of the EPHESUS trial.

[0087] Several studies in animal models of acute myocardial infarction and in the clinic have shown the benefit of aldosterone blockade in preventing reperfusion injury and improving cardiac function in STEMI patients. The literature has shown that mineralocorticoid receptor antagonists may have beneficial effects on the cerebrovascular system and during stroke (Dinh QN, et al. Neural Regen Res. 2016; 11:1230-1).

[0088] Examples of aldosterone antagonists for use in the combinations of the present invention include spironolactone (the first and most widely used member of this class), eplerenone (much more selective for the target than spironolactone, but somewhat less potent and effective), canrenone and potassium canrenoate, finerenone (non-steroidal, more potent and selective than eplerenone or spironolactone) and prorenone. Some drugs also have anti-mineralcorticoid effects secondary to their primary mechanism of action. Examples include progesterone, drospirenone, gestodene, and benidipine.

[0089] In one particularly preferred embodiment, the aldosterone antagonist is potassium canrenoate.

[0090] The present invention also encompasses structural and functional analogs of aldosterone antagonists, particularly those modified to extend the half-life of the drug, such as conjugates of aldosterone antagonists.

[0091] Potassium canrenoate Canrenoate potassium, also known as the potassium salt of canrenoic acid, is an aldosterone antagonist of the spirolactone group. Like spironolactone, canrenoate potassium is a prodrug that is metabolized in the body to canrenone. Canrenoate potassium is usually administered intravenously in doses ranging from 200 mg / day to 600 mg / day for the treatment of hyperaldosteronism or hypokalemia.

[0092] Potassium canrenoate has the systematic (IUPAC) name potassium 3-[(8R,9S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]propanoate, formula C 22 H 29 KO4, having the following chemical structure: [ka] has.

[0093] combination In one aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0094] The preferred embodiments described below apply mutatis mutandis to other aspects of the invention, including methods, uses, products and compositions.

[0095] In one embodiment the insulin modulator is defined according to any of the above embodiments of an insulin modulator.

[0096] In one embodiment, the aldosterone antagonist is defined according to any of the above embodiments of an aldosterone antagonist.

[0097] In one embodiment the sulfonylurea is defined according to any of the above embodiments of the sulfonylurea.

[0098] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with aldosterone antagonists; at least one of the following components: an insulin modulator, and a sulfonylurea; The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0099] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, glyclopyramide, chlorpropamide, tolbutamide, acetohexamide, carbutamide, glyciclamide, tolhexamide, metahexamide, and tolazamide; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0100] In another embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, glyclopyramide, chlorpropamide, tolbutamide, acetohexamide, carbutamide, glyciclamide, tolhexamide, metahexamide, and tolazamide; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0101] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0102] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; At least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide, and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising, consisting essentially of, or consisting of:

[0103] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0104] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Potassium canrenoate, at least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, glyclopyramide, chlorpropamide, tolbutamide, acetohexamide, carbutamide, glyccyclamide, tolhexamide, metahexamide, and tolazamide; The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0105] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Potassium canrenoate, At least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0106] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; Glibenclamide and or a combination including these.

[0107] In one embodiment, the present invention provides With amodiaquine; Canrenoate potassium and; Glibenclamide and The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0108] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising:

[0109] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and The present invention relates to a combination comprising:

[0110] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof; At least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof; The present invention relates to a combination comprising:

[0111] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; or a combination including these.

[0112] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof; Glibenclamide and The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0113] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0114] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and; Glibenclamide and The present invention relates to a combination of, consisting of, consisting essentially of, or comprising:

[0115] In one aspect of the invention, for each of the above embodiments, the combination consists of a Nurr1 agonist (e.g., amodiaquine or a pharma- ceutically acceptable salt thereof) and a sulfonylurea and / or an aldosterone antagonist and / or an insulin modulator, i.e., these are the only active agents present. In another (alternative) aspect, the combination may further comprise one or more additional active agents, as described below.

[0116] In each of the above embodiments, in addition to the active agent, the combination may further include one or more pharma- ceutically acceptable diluents, carriers, or excipients.

[0117] As used herein, the term "consisting essentially of" means that certain additional components may be present, i.e., components that do not materially affect the essential characteristics of the combination or composition.

[0118] In one preferred embodiment, there is no other pharmacoactive agent in the combination, pharmaceutical composition or pharmaceutical product according to the present invention, i.e. the only pharmacoactive agent present is the Nurr1 agonist and at least one additional component selected from: an aldosterone antagonist; an insulin modulator; and a sulfonylurea.However, the combination may optionally further comprise other inactive components, such as one or more pharmacologic acceptable diluents, carriers or excipients.

[0119] Thus, in one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) sulfonylureas; and at least one additional ingredient selected from: (c) a pharma- ceutically acceptable diluent, excipient, or carrier; and The present invention relates to a pharmaceutical product or composition comprising:

[0120] Preferred embodiments apply mutatis mutandis with respect to the first aspect, e.g. with respect to active substance selection and substitution.

[0121] The effect of drug combination is inherently unpredictable, and in many cases, one drug tends to partially or completely inhibit the effect of the other.The present invention demonstrates that the combination comprising Nurr1 agonist (e.g., amodiaquine) and at least one additional active ingredient selected from sulfonylureas (e.g., glibenclamide), insulin modulators (e.g., exenatide) and aldosterone antagonists (e.g., potassium canrenoate) does not cause serious or dramatic adverse interactions between the two drugs when administered simultaneously, separately, or sequentially.The unexpected lack of such antagonistic interactions is important for the clinical use of the combination.

[0122] Furthermore, preferred combinations according to the present invention surprisingly exhibit an enhancement of the effects of the individual components such that the optimal doses of the drugs are lower than those recommended for the approved indications of these drugs and / or are also lower than those reported in the literature.

[0123] In one embodiment, a combination of active agents of the present invention provides enhanced efficacy compared to each drug administered alone.

[0124] Thus, in a preferred embodiment, the combination is synergistic, ie, at least two of the active agents interact in a synergistic (ie, more than additive) manner.

[0125] By way of illustration, studies by the applicant have shown that the preferred doses of glibenclamide in the context of the combination claimed herein are significantly lower than those previously reported in the literature for hypoglycemia (e.g., diabetes mellitus). In fact, the preferred doses of glibenclamide used in the combination claimed herein are approximately 20-285 times lower than the recommended maintenance doses of glibenclamide (micronized formulations) for the treatment of diabetes mellitus (for the micronized formulations of glibenclamide, the recommended daily maintenance dose is 1.25-20 mg, which corresponds to 18 μg / kg-285 μg / kg for a 70 kg adult, in contrast to the preferred doses of glibenclamide as low as 1 μg / kg body weight required in the combination treatment claimed herein). Advantageously, the use of glibenclamide at these preferred low doses avoids effects on blood glucose levels that could otherwise lead to adverse side effects. Studies by the applicant have also shown that the clinically effective dose of glibenclamide as a double or triple combination according to the present invention with low doses of exenatide and / or potassium canrenoate is also significantly lower than the doses of glibenclamide shown to be neuroprotective in published clinical studies (0.16 or 0.11 mg / hour continuous infusion, i.e. 3.84 mg or 2.64 mg per day) (see King ZA et al.).

[0126] Moreover, in another embodiment, the combination of active agents of the present invention produces unexpected synergistic effects, as demonstrated by a rat model of transient middle cerebral artery occlusion.

[0127] Combinations of two or more drugs can result in different types of drug interactions. A drug interaction is said to be additive if the combined effect of the two drugs is equal to the sum of the effects of each drug given alone. A drug interaction is said to be synergistic if the combined effect of the two drugs exceeds the effect of each drug given alone (Goodman and Gilmans "The Pharmacological Basis of Therapeutics", 12th Edition).

[0128] Combination therapy is an important treatment modality in many disease environments, including cardiovascular disease, cancer and infectious diseases.Recent scientific advances have increased understanding of the pathophysiological processes underlying these and other complex diseases.This increased understanding has further spurred the development of new therapeutic approaches that use drug combinations that target multiple therapeutic targets to improve therapeutic response, minimize resistance development, or minimize adverse events.In environments where combination therapy provides significant therapeutic benefits, there is growing interest in developing new combinations of two or more drugs.

[0129] Advantageously, a synergistic combination allows for lower doses of each component to be present, thereby reducing the toxicity of the therapy while producing and / or maintaining the same or an improved therapeutic effect. Thus, in particularly preferred embodiments, each component of the combination is present in a sub-therapeutic amount. The term "sub-therapeutically effective amount" refers to an amount lower than the amount typically required to produce a therapeutic effect for treatment with each agent alone.

[0130] In one embodiment, the invention relates to a synergistic combination comprising or consisting of a Nurr1 agonist or a pharma- ceutically acceptable salt thereof and an insulin modulator, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0131] In one embodiment the invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof and an insulin modulator, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0132] In one embodiment, the present invention relates to a synergistic combination comprising or consisting of a Nurr1 agonist or a pharma- ceutically acceptable salt thereof and a sulfonylurea, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0133] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof and a sulfonylurea, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0134] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of a Nurr1 agonist, a sulfonylurea, and an aldosterone antagonist, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0135] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, a sulfonylurea, and an aldosterone antagonist, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0136] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of a Nurr1 agonist, an insulin modulator, and an aldosterone antagonist, and may further comprise one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0137] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, an insulin modulator, and an aldosterone antagonist, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0138] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of a Nurr1 agonist, an insulin modulator, a sulfonylurea, and an aldosterone antagonist, and may further comprise one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0139] In another embodiment, the present invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, an insulin modulator, a sulfonylurea, and an aldosterone antagonist, and optionally further comprising one or more pharma- ceutically acceptable diluents, excipients and / or carriers.

[0140] In one embodiment the insulin modulator is defined according to any of the above embodiments of an insulin modulator.

[0141] In one embodiment, the aldosterone antagonist is defined according to any of the above embodiments of an aldosterone antagonist.

[0142] In one embodiment the sulfonylurea is defined according to any of the above embodiments of the sulfonylurea.

[0143] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, a sulfonylurea, and at least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone, and prorenone, or, where applicable, a pharma- ceutically acceptable salt thereof.

[0144] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and The present invention relates to a synergistic combination comprising or consisting of:

[0145] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; with at least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide; Exenatide or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and The present invention relates to a synergistic combination comprising or consisting of:

[0146] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; at least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof; At least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide The present invention relates to a synergistic combination comprising or consisting of:

[0147] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; at least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or a pharma- ceutically acceptable salt thereof; Exenatide or a pharma- ceutically acceptable salt thereof The present invention relates to a synergistic combination comprising or consisting of:

[0148] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and; with at least one of exenatide, lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265) or a pharma- ceutically acceptable salt thereof; The present invention relates to a synergistic combination comprising or consisting of:

[0149] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Canrenoate potassium and; At least one of glibenclamide, glibornuride, gliclazide, glipizide, glimepiride, gliquidone, glisoxepide, and glyclopyramide The present invention relates to a synergistic combination comprising or consisting of:

[0150] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; at least one of potassium canrenoate, canrenone, spironolactone, eplerenone, finerenone and prorenone, or a pharma- ceutically acceptable salt thereof; Glibenclamide and The present invention relates to a synergistic combination comprising or consisting of:

[0151] In one embodiment, the present invention provides amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a synergistic combination comprising or consisting of:

[0152] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine, or a pharma- ceutically acceptable salt thereof, and exenatide, or a pharma- ceutically acceptable salt thereof.

[0153] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, exenatide or a pharma- ceutically acceptable salt thereof, and potassium canrenoate.

[0154] In one embodiment, the present invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, potassium canrenoate, and glibeclamide.

[0155] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine, or a pharma- ceutically acceptable salt thereof, exenatide, or a pharma- ceutically acceptable salt thereof, and glibenclamide.

[0156] In one embodiment, the invention relates to a synergistic combination comprising or consisting of amodiaquine or a pharma- ceutically acceptable salt thereof, potassium canrenoate, glibeclamide, and exenatide or a pharma- ceutically acceptable salt thereof.

[0157] Additional Active Pharmaceutical Ingredients In one embodiment, the above combinations, pharmaceutical compositions and pharmaceutical products comprise at least one further active pharmaceutical ingredient (API).

[0158] In one embodiment, the combination described above may further comprise at least one additional API selected from beta blockers, renin-angiotensin inhibitors, statins (HMG-CoA reductase inhibitors), inhibitors of platelet activation or aggregation, phosphodiesterase-3 inhibitors, calcium sensitizers, antioxidants, and anti-inflammatory agents.

[0159] Examples of beta blockers include propranolol, metoprolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, and timolol.

[0160] Renin-angiotensin inhibitors include angiotensin converting enzyme inhibitors, angiotensin AT1 receptor inhibitors and renin inhibitors.

[0161] Examples of angiotensin-converting enzyme inhibitors include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, and fosinopril.

[0162] Examples of angiotensin AT1 receptor antagonists include losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan and telmisartan.

[0163] Examples of renin inhibitors include remikiren and aliskiren.

[0164] Examples of calcium sensitizers include levosimendan and its analogs.

[0165] Examples of statins include atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.

[0166] Examples of platelet activation or aggregation inhibitors include prostacyclin (epoprostenol) and its structural and functional analogs (e.g., treprostinil, iloprost), irreversible cyclooxygenase inhibitors (e.g., aspirin, triflusal), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel, prasugrel, ticagrelor, ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor-1 (PAR-1) antagonists (e.g., vorapaxar), glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide, tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors, including thromboxane synthase inhibitors and thromboxane receptor antagonists (e.g., terutroban).

[0167] Examples of phosphodiesterase-3 (PDE-3) inhibitors include amrinone, milrinone, and analogs thereof.

[0168] Examples of antioxidants include ascorbic acid, lipoic acid, glutathione, melatonin and resveratrol.

[0169] Examples of anti-inflammatory agents include COX-2 inhibitors (eg, celecoxib), glucocorticoids (eg, hydrocortisone), and non-steroidal anti-inflammatory drugs (eg, ibuprofen).

[0170] In one embodiment, the combination comprises at least one further API selected from propranolol, metoprolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, telmisartan, remikiren, aliskiren, melatonin, and resveratrol.

[0171] In another embodiment, the above combination comprises at least one additional API selected from carvedilol, metoprolol, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, telmisartan, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, remikiren, aliskiren, melatonin, and resveratrol.

[0172] In another embodiment, the above combination comprises at least one additional API selected from carvedilol, metoprolol, melatonin, and resveratrol.

[0173] Pharmaceutically acceptable salts The active pharmaceutical agents of the present invention can be present as pharma- ceutically acceptable salts.

[0174] Pharmaceutically acceptable salts of the agents of the present invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in (Berge et al., J Pharm Sci, 66, 1-19(1977)). Salts are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids (for example HCl, HBr); with strong organic carboxylic acids, for example alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (for example by halogens), for example acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; with hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; with amino acids, for example aspartic acid or glutamic acid; with benzoic acid; or with organic sulfonic acids, for example (C1-C4)-alkylsulfonic acids or arylsulfonic acids which are unsubstituted or substituted (for example by halogens), for example methanesulfonic acid or p-toluenesulfonic acid.

[0175] Enantiomers / Tautomers The present invention also includes, where appropriate, all enantiomers and tautomers of the active pharmaceutical agents. Those skilled in the art will recognize compounds that have optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0176] Stereoisomers and geometric isomers Some of the active pharmaceutical agents of the present invention may exist as stereoisomers and / or geometric isomers, e.g., they may have one or more asymmetric centers and / or geometric centers, and therefore may exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of these inhibitors, as well as mixtures thereof. The terms used in the claims encompass these forms, so long as they retain the appropriate functional activity (although not necessarily to the same degree).

[0177] The present invention also includes all suitable isotopic variations of the active pharmaceutical agent or its pharma- ceutically acceptable salt. An isotopic variation of the agent or its pharma- ceutically acceptable salt of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that usually found in nature. Examples of isotopes that can be incorporated into the agent and its pharma- ceutical acceptable salt include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the agent and its pharma- ceutical acceptable salt, such as those incorporating radioactive isotopes such as 3H or 14C, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, substitution with isotopes such as deuterium, i.e., 2H, can impart certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopic variations of the agents of the present invention and pharma- ceutically acceptable salts thereof of the present invention can generally be prepared by conventional procedures using the appropriate isotopic variations of suitable reagents.

[0178] solvate The present invention also includes solvated forms of the active pharmaceutical agents of the invention and the terms used in the claims encompass these forms.

[0179] polymorph The present invention further relates to the active pharmaceutical agents of the present invention in various crystalline, polymorphic and (an)hydrated forms. It is well established within the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slight variations in the purification and / or isolation methods from solvents used in the synthetic preparation of such compounds.

[0180] Pharmaceutical Compositions In another aspect, the present invention relates to a pharmaceutical composition comprising a combination according to the invention as described above, and a pharma- ceutically acceptable carrier, diluent or excipient.

[0181] Although the compounds of the invention (including their pharma- ceutically acceptable salts) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy. The pharmaceutical compositions may be for human or non-human animal use, in human and veterinary medicine, respectively.

[0182] Examples of such excipients suitable for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), edited by A Wade and PJ Weller.

[0183] Carriers or diluents acceptable for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985). The carrier, or each of the carriers, if more than one carrier is present, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol, and water.

[0184] The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. Exemplary routes of administration include parenteral (e.g., intravenous, intramuscular, intradermal, intraperitoneal, or subcutaneous), oral, inhalation, transdermal (topical), intraocular, iontophoretic, and transmucosal administration.

[0185] The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), buffer(s), flavoring agent(s), surfactant(s), thickening agent(s), preservative(s) (including antioxidants), and the like, as well as substances included for rendering the formulation isotonic with the blood of the intended recipient.

[0186] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose and polyethylene glycol.

[0187] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0188] Preservatives, stabilizers, dyes, and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used.

[0189] Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and pulmonary administration, e.g., by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0190] In one embodiment, the pharmaceutical composition is for oral administration. Pharmaceutical formulations suitable for oral administration in which the carrier is a solid are most preferably provided as unit dose formulations such as boluses, capsules or tablets, each containing a predetermined amount of the active compound. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersing agent. Molded tablets may be made by molding the active compound with an inert liquid diluent. Tablets may be optionally coated, or if uncoated, may be optionally scored. Capsules may be prepared by filling the active compound, alone or in admixture with one or more accessory ingredients, into a capsule shell and then sealing in the usual manner. Cachets are similar to capsules, in which the active compound is sealed in a rice paper envelope with accessory ingredients. The active compound may also be formulated as dispersible granules, which may be suspended in water or sprinkled on food before administration, for example. Granules may be packaged, for example, in a sachet.Formulations suitable for oral administration where the carrier is a liquid may be presented as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0191] Formulations for oral administration include controlled release dosage forms, such as tablets in which the active compound is incorporated into a suitable release-controlling matrix or coated with a suitable release-controlling film. Such formulations may be particularly advantageous for prophylactic use.

[0192] The pharmaceutical preparation suitable for rectal administration, in which the carrier is solid, is most preferably provided as a unit dose suppository.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by mixing the active compound with a softened or melted carrier, followed by cooling and shaping in a mold.The pharmaceutical preparation suitable for parenteral administration includes a sterile solution or suspension of the active compound in an aqueous or oily vehicle.

[0193] The injectable formulations can be adapted for bolus injection or continuous infusion. Such formulations are conveniently provided in unit-dose or multi-dose containers that are sealed until needed for use after the formulation is introduced. Alternatively, the active compound can be in powder form that is reconstituted with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0194] The active compound may also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or by implantation, for example subcutaneously or intramuscularly.The depot preparation may include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins.Such long-acting preparations are particularly convenient for prophylactic use.

[0195] Formulations suitable for pulmonary administration via the buccal cavity are provided such that particles containing the active compound, desirably having a diameter in the range of 0.5 to 7 microns, are delivered into the recipient's bronchial tree.

[0196] As one possibility, such formulations can be provided either in the form of finely divided powder, which can be conveniently provided in a puncturable capsule, such as gelatin, for use in an inhalation device, or as a self-propelling formulation, which may contain active compound, suitable liquid or gaseous propellants, and other components such as surfactants and / or solid diluents.Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide.Self-propelling formulations, in which active compound is dispensed in the form of droplets of solution or suspension, may also be used.

[0197] Such autopropellant formulations are similar to those known in the art and may be prepared by established procedures. Suitably, the autopropellant formulations are provided in a container equipped with a manually operable or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of the metered type that delivers a fixed volume, e.g., 25 to 100 microliters, per actuation thereof.

[0198] As a further possibility, the active compound may be in the form of a solution or suspension for use in an atomizer or nebulizer, which utilizes accelerated air or ultrasonic agitation to produce a fine mist of droplets for inhalation.

[0199] In another embodiment, the pharmaceutical composition is for nasal administration. Formulations suitable for nasal administration include formulations generally similar to those described above for pulmonary administration. Such formulations, when prepared, should desirably have a particle diameter in the range of 10-200 microns to allow retention in the nasal cavity; this can be achieved, if necessary, by the use of powders of appropriate particle size or by the selection of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range of 20-500 microns, administered by rapid inhalation through the nasal passages from a container held at close range to the nose, and nasal drops containing the active compound in a 0.2-5% w / v aqueous or oily solution or suspension.

[0200] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Furthermore, such pharma-ceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, such as saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, inert gases, and the like.

[0201] Suitable formulations for topical preparations may be provided, for example, as gels, creams, or ointments. Such formulations may be applied to the wound or ulcer, for example, by either spreading it directly on the surface of the wound or ulcer, or by placing it on a suitable support, such as a bandage, gauze, mesh, etc., which can be applied to or over the area to be treated.

[0202] Liquid or powder formulations can also be provided that can be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer, or the formulation can be sprayed or sprinkled onto a carrier such as a bandage, gauze, mesh, etc., and then applied to the area to be treated.

[0203] According to a further aspect of the invention there is provided a process for preparing a pharmaceutical composition as described above which comprises bringing into association an active compound with a carrier, for example by mixing.

[0204] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. The present invention extends to a process for preparing a pharmaceutical composition which comprises combining or combining a compound described herein with a pharma- ceutical or veterinarily acceptable carrier or vehicle.

[0205] In one embodiment, the pharmaceutical composition is for parenteral administration (e.g., intravenous, intraarterial, intrathecal, intramuscular, intradermal, intraperitoneal or subcutaneous). Preferably, the composition is prepared from a sterile or sterilizable solution.

[0206] In another embodiment, the pharmaceutical composition is for intravenous, intramuscular, or subcutaneous administration.

[0207] In another embodiment, the pharmaceutical composition is for intravenous administration.

[0208] Solutions or suspensions used for parenteral, intradermal or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer, such as acetates, citrates, or phosphates, and an agent for adjusting isotonicity, such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0209] Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor™, or phosphate buffered saline (PBS). In all cases, compositions for parenteral administration must be sterile and should be fluid to the extent that easy injection with a syringe is possible. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0210] Sterile injectable solutions can be prepared by incorporating the required amount of active compound into a suitable solvent with one or a combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersions are prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other necessary components from the above-listed ones.For the preparation of sterile powder for the preparation of sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, which can produce a powder of active ingredient and any additional desired ingredients from the solution that has been previously sterile-filtered.The present invention also includes liposomal and nanoparticle preparations containing active agents.Such preparations, together with the methods for their preparation, are well known to those skilled in the art.

[0211] Pharmaceutical Products In another aspect, the present invention provides a method for producing a composition comprising: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a pharmaceutical product comprising or consisting of:

[0212] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with aldosterone antagonists; at least one of the following components: an insulin modulator, and a sulfonylurea; The present invention relates to a pharmaceutical product comprising:

[0213] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with aldosterone antagonists; at least one of the following components: an insulin modulator, and a sulfonylurea; The present invention relates to a pharmaceutical product consisting of or consisting essentially of:

[0214] In another aspect, the present invention provides a method for producing a composition comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to a pharmaceutical product comprising:

[0215] In another aspect, the present invention provides a method for producing a composition comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analog thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product consisting of or consisting essentially of:

[0216] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product comprising:

[0217] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product consisting of or consisting essentially of:

[0218] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product comprising:

[0219] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product consisting of or consisting essentially of:

[0220] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to a pharmaceutical product comprising:

[0221] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to a pharmaceutical product consisting of or consisting essentially of:

[0222] In one preferred embodiment, each component of the pharmaceutical product is for separate administration.

[0223] In one preferred embodiment, the components are combined in a single formulation.

[0224] In one embodiment, the pharmaceutical product is a kit of parts containing all the supplies needed for the course of treatment (eg, a vial of drug, a vial of diluent, a syringe, and a needle).

[0225] The components of the kit and pharmaceutical product are as described above. In a preferred embodiment, each component of the kit or pharmaceutical product is admixed with one or more pharma- ceutically acceptable diluents, excipients, and / or carriers.

[0226] In one embodiment, the kit includes a separate container for each active agent, which may be an ampule, a disposable syringe, or a multiple dose vial.

[0227] In another embodiment, the kit comprises a container that contains a combined preparation of each active agent.

[0228] The kit may further comprise instructions for treating and / or preventing reperfusion injury.

[0229] therapeutic use The present invention further relates to the above combinations, pharmaceutical products or compositions for use in the treatment of various therapeutic disorders, as detailed below, and related methods of treatment.

[0230] One aspect of the invention relates to a combination or pharmaceutical composition or pharmaceutical product as described herein for use in the treatment and / or prevention of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction or for use in providing cardioprotection against cardiotoxic drugs or for use in providing neuroprotection.

[0231] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of stroke.

[0232] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of the neurodegenerative consequences of stroke.

[0233] A stroke is when insufficient blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. As a result, parts of the brain do not function properly. Signs and symptoms of a stroke include an inability to move or feel one side of the body, problems understanding or speaking, feeling like the world is spinning, and loss of vision on one side, among others. Ischemic strokes are usually caused by a blockage in a blood vessel. Ischemic stroke treatment involves surgery to open (reperfuse) the arteries to the brain in patients where narrowing is the problem. If detected within 3-4 1 / 2 hours, ischemic strokes can sometimes be treated with medicines that can break up blood clots. In 2013, stroke was the second leading cause of death after coronary artery disease, accounting for 6.4 million deaths (12% of the total).

[0234] Ischemic stroke and acute myocardial infarction require urgent reperfusion to improve functional outcomes (Patel and Saver, 2013, Stroke, 44: 94-98). Intravenous tissue-type plasminogen activator has long been the only reperfusion therapy with proven clinical benefit in patients with acute ischemic stroke. As in acute myocardial infarction, endovascular methods to restore reperfusion in acute ischemic stroke expose patients to increased ischemia / reperfusion injury, which may counter the benefits of recanalization by promoting hemorrhagic transformation and severe vasogenic edema, both considered markers of reperfusion injury (Bai and Lyden. 2015; Int J Stroke, 10: 143-152). Experimental evidence indicates that cerebral ischemic reperfusion injury (as can myocardial reperfusion injury) can be attenuated by ischemic preconditioning and postconditioning. Glibenclamide has been shown to enhance the therapeutic benefits of early hypothermia after severe stroke in rats (Zhu S, et al. Aging Dis. 2018; 9: 685-695). In addition, in a clinically relevant rat model of stroke (middle cerebral artery occlusion), reperfusion was initiated at 4.5 hours, with simultaneous administration of recombinant tissue plasminogen activator, followed by administration of glibenclamide (10 μg / kg IP loading dose plus constant subcutaneous infusion at 200 ng / hour) starting at 4.5 hours or 10 hours after the onset of ischemia; glibenclamide significantly reduced hemispheric swelling at 24 hours and 48 hours of death and improved Garcia score at 48 hours, suggesting that the treatment period of glibenclamide extends to 10 hours after the onset of ischemia. This finding is consistent with the observations of retrospective clinical studies suggesting that the use of sulfonylureas is beneficial in the context of rt-PA-assisted recanalization / reperfusion after acute ischemic stroke (Simard, JM, et al. Ann. NY Acad. Sci. 2012; 1268: 95-107).

[0235] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of intracerebral hemorrhage (ICH).

[0236] In one preferred embodiment, the stroke is a hemorrhagic stroke.

[0237] In another preferred embodiment, the stroke is an ischemic stroke. Ischemic stroke is one of the most common clinical indications of reperfusion injury.

[0238] The applicant's study using a rat model of transient middle cerebral artery occlusion showed that treatment with the combination according to the present invention improved neurological scores and significantly reduced infarct size when administered 20 minutes before perfusion and twice daily for 7 days thereafter compared to treatment with vehicle control (see Example 2). Furthermore, the beneficial effects associated with treatment are observed over a long period of time. For example, when treated immediately after perfusion and twice daily for 28 days thereafter, the triple combination therapy significantly improved neurological scores and improved performance in the stepping test and forelimb placing test compared to vehicle control. Treatment with the combination according to the present invention also significantly improved anxiety in the elevated plus maze test during the second week of the study. Furthermore, after 28 days, improved cognitive function was observed in the object recognition cognitive test, and a significant reduction in infarct size was observed (see Example 3).

[0239] Therefore, long-term treatment with the combination of the present invention at a low dose provides a new therapeutic approach to the treatment of stroke and other chronic disorders compared to currently approved short-term treatments available. Since lesion formation does not stop after stroke but continues after circulation resumes, long-term low-dose administration of the combination of the present invention is therapeutically advantageous. At the same time, long-term low-dose administration can minimize the side effects typically associated with conventional short-term high-dose treatments. Treatment of stroke with the combination of the present invention is understood to be a two-step process. The first step involves minimizing the deleterious effects of reperfusion injury, and the second step takes into account the immune response after stroke, thereby improving recovery of brain function.

[0240] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of neuroinflammation or a neuroinflammatory disorder.

[0241] Neuroinflammation is defined as inflammation of neural tissue and can be triggered by a variety of different stimuli. Neuroinflammation is widely considered to be a chronic inflammation, as opposed to acute inflammation in the central nervous system (Streit WJ et al, July 2004, Journal of Neuroinflammation; 1(1): 14). Chronic inflammation involves persistent activation of glial cells and recruitment of other immune cells to the brain. Common triggers of chronic neuroinflammation include toxic metabolites, autoimmunity, aging, microbes, viruses, traumatic brain injury, spinal cord injury, air pollution, and passive smoking.

[0242] Microglia are the innate immune cells of the central nervous system (Gendelman HE, December 2002, Journal of Neurovirology; 8 (6): 474-9), actively surveying their environment and undergoing profound changes in cellular morphology in response to neuronal injury (Garden GA, October 2013, Neurotherapeutics. 10 (4): 782-8). Astrocytes are glial cells involved in the maintenance / support of neurons and constitute an important component of the blood-brain barrier. Astrocytes are abundant in the CNS and, in addition to performing a variety of other homeostatic functions, provide trophic support to neurons, promote synapse formation and function, and prune synapses by phagocytosis. Following injury to the brain, such as traumatic brain injury, astrocytes can be activated in response to signals released by damaged neurons or activated microglia (Mayer CL et al, Headache. 53 (9): 1523-30; Ebert SE et al, Eur J Neurol 2019. doi:10.1111 / ene.13971). Upon activation, astrocytes can release various growth factors and undergo morphological changes.

[0243] Astrocytes are understood to play both protective and detrimental roles. Liddelow et al (Nature, 2017, Jan 26; 541(7638): 481-487) distinguished two different types of reactive astrocytes, termed "A1" and "A2", respectively. Reactive astrocytes induced by ischemia (termed A2 astrocytes) are understood to promote CNS recovery and repair, whereas astrocytes induced by activated microglia in neuroinflammation (termed A1 reactive astrocytes) lose normal astrocyte function and become neurotoxic.

[0244] Liddelow et al. disclosed that neurotoxic astrocytes play a key role in the pathological response of the CNS to neuroinflammation, acute CNS injury, and many neurodegenerative diseases. After brain injury or certain diseases, astrocytes undergo a dramatic transformation called "reactive astrocytosis," upregulating many genes to form a glial scar. A1-reactive astrocytes are induced by activated microglia, lose most of their normal astrocyte functions, acquire new neurotoxic functions, and rapidly kill neurons and mature differentiated oligodendrocytes. Liddelow demonstrated that A1 is rapidly formed in vivo after CNS injury and contributes to neuronal death after acute CNS injury. Liddelow further demonstrated that inhibition of A1-reactive astrocyte formation after acute CNS injury can prevent the death of axotomized neurons.

[0245] The applicant's histopathological study showed that treatment with the triple combination of amodiaquine / canrenoate potassium / glibenclamide resulted in a statistically significant reduction in NG2 oligodendrocyte precursor cells compared to control vehicle. This reduction in activated microglial cells is consistent with a reduction in harmful A1 reactive astrocytes. Further studies by the applicant showed that treatment with the triple combination according to the present invention reduced GFAP markers (representing reactive astrocytes) and also reduced Iba-1 (microglial cells) compared to control vehicle, also consistent with a reduction in A1 reactive astrocytes. The study also showed an increase in neurogenesis as measured by doublecortin staining. Further details of these experiments are described in the attached examples (see in particular Example 3).

[0246] Taken together, these studies show that the combination according to the present invention affects neuroinflammatory pathways. Without wishing to be bound by theory, the combination claimed in this application may act to protect cells from neurotoxicity (e.g., caused by the accumulation of toxic substances or the prevention of their removal) and / or support repair mechanisms. In light of the mechanistic pathways described in Liddelow (Nature 2017), the above histopathological results indicate that the combination described herein has therapeutic application in the treatment of various neuroinflammatory disorders and / or diseases with neuroinflammatory components.

[0247] Neuroinflammation is also known to play a role in neurodegenerative disorders (Chen et al. 2016). Recent data have identified the role of inflammatory processes, and particularly proinflammatory cytokines, as closely linked to multiple neurodegenerative pathways. In particular, A1-reactive astrocytes are known to be present in many neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, ALS, and MS (Liddelow et al, Nature, 2017). The cellular and molecular mechanisms of neuroinflammation are likely to be the same in aging, metabolic diseases, hypertension, diabetes, depression, and dementia, or after brain injury such as stroke. Although multiple mechanisms likely contribute to the pathogenesis and progression of neurodegeneration in Alzheimer's Disease (AD), the pathogenic role of neuroinflammation is now well recognized and accepted (Onyango et al, 2021). A study by Kinoshita et al. showed that amodiaquine, a Nurr1 agonist, reduced inflammatory events and neurological deficits in a mouse model of intracerebral hemorrhage (Kinoshita et al. 2019). More specifically, the study showed that daily administration of amodiaquine (40 mg / kg, ip) starting 3 hours after ICH induction reduced perihematomal activation of microglia / macrophages and astrocytes. Amodiaquine also suppressed ICH-induced mRNA expression of IL-1β, CCL2, and CXCL2, and improved motor dysfunction in mice. Administration of amodiaquine not only attenuated the inflammatory response associated with glial cell activation, but also improved neurological outcomes after ICH.

[0248] In one preferred embodiment, the neuroinflammatory disorder is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis, and neuromyelitis optica (NMO).

[0249] In a preferred embodiment, the neuroinflammation is associated with traumatic brain injury, spinal cord injury, aging, schizophrenia, depression, migraine, epilepsy, neuropathic pain, Down's syndrome, autism, premature birth, glaucoma, or viral infection.

[0250] Neuroinflammation plays an important role in migraine pathophysiology, and neuroinflammatory pathways, particularly those involving inflammasome proteins, are promising candidates for therapeutic targets (Kurson et al. 2021).

[0251] In one preferred embodiment, the neuroinflammation is associated with aging, which is characterized by a progressive increase in neuroinflammation, which contributes to the cognitive impairment associated with aging and age-related neurodegenerative diseases such as Alzheimer's disease.

[0252] In one embodiment, the combination or pharmaceutical composition or pharmaceutical product described herein is for use in treating aging-related diseases (commonly referred to as age-related diseases or "ARDs"). Essentially, aging-related diseases are complications resulting from aging, and are distinct from the aging process itself. Examples of aging-related diseases are atherosclerosis and cardiovascular diseases, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease. The incidence of all these diseases increases exponentially with age.

[0253] ARD is most often seen with increasing frequency with the progression of senescence, a phenomenon characterized by the arrest of cell division. Senescence is a cellular program that stably arrests damaged or old cells and avoids replication. Senescent cells undergo profound phenotypic changes, including not only proliferation arrest but also chromatin reorganization, increased β-galactosidase activity (termed senescence-associated β-galactosidase or SA-β-Gal), and secretion of multiple factors, primarily proinflammatory, collectively referred to as the senescence-associated secretory phenotype (SASP). Senescent cells accumulate during the aging process and are associated with many diseases, including cancer, fibrosis, and many age-related pathologies. Recent evidence suggests that senescent cells are detrimental in multiple pathologies and that their removal may provide many benefits, improving multiple pathologies and extending healthspan and lifespan.

[0254] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of a neurodegenerative disease, preferably selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), and vascular dementia.

[0255] In one preferred embodiment, the neurodegenerative disorder is Parkinson's disease.

[0256] In one preferred embodiment, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS).

[0257] In one preferred embodiment, the neurodegenerative disorder is vascular dementia.The study of the effect of the combination according to the present invention in a rat model of vascular dementia is described in more detail in the accompanying examples (see Example 1).

[0258] In one preferred embodiment, the neurodegenerative disorder is Alzheimer's disease.

[0259] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in providing neuroprotection, even more preferably for use in providing neuroprotection against neurotoxic drugs.

[0260] As used herein, the term "neuroprotection" refers to protecting neural entities, including the brain, for example, by preventing, reducing or delaying brain damage that can lead to neuronal death and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease or vascular dementia.

[0261] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in providing neuroprotection in stroke.

[0262] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in providing neuroprotection in neurodegenerative disorders.

[0263] In one embodiment, the combination or pharmaceutical composition or pharmaceutical product described herein is for use in providing neuroprotection to a subject against the neurotoxic effects of drugs. Examples of neurotoxic drugs are described by Gouzoulis-Mayfrank and Daumann (Dialogues Clin Neurosci. 2009; 11(3): 305-17). Neurotoxic drugs include drugs of abuse (e.g., 3,4-methylenedioxymethamphetamine, methamphetamine, and amphetamine), pesticides (e.g., organophosphate pesticides), certain chemotherapeutics (e.g., platinum), and dopamine.

[0264] In one embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in providing cardioprotection to a subject against the cardiotoxic effects of a drug (e.g., anthracyclines). Examples of cardiotoxic drugs are described in Bovelli et al (Annal of Oncology 21 (Supplement 5): v277-v282, 2010).

[0265] As used herein, the term "cardioprotection" refers to protecting the heart, for example, by preventing, reducing, or delaying myocardial injury. Cardiotoxic drugs include drugs associated with cardiac failure, drugs associated with ischemia or thromboembolism, drugs associated with hypertension, drugs associated with other toxic effects, such as tamponade and endomyocardial fibrosis, hemorrhagic myocarditis, bradyarrhythmia, Raynaud's phenomenon, autonomic neuropathy, QT prolongation or polymorphic ventricular tachycardia, or pulmonary fibrosis. Examples of cardiotoxic drugs include anthracyclines / anthraquinolones, cyclophosphamide, trastuzumab and other monoclonal antibody-based tyrosine kinase inhibitors, antimetabolites (fluorouracil, capecitabine), microtubule inhibitors (paclitaxel, docetaxel), cisplatin, thalidomide, bevacizumab, sunitinib, sorafenib, busulfan, paclitaxel, vinblastine, bleomycin, vincristine, arsenic trioxide, bleomycin, and methotrexate.

[0266] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of ischemia and / or reperfusion injury.

[0267] As used herein, the term "reperfusion injury" refers to damage to tissues caused when blood supply returns to the tissue after a period of ischemia. The lack of oxygen and nutrients from the blood creates a condition in which the return of circulation leads to inflammation, mitochondrial dysfunction and oxidative damage through the induction of oxidative stress, rather than the restoration of normal function. Reperfusion injury can occur after either naturally occurring events, such as arterial occlusion, or planned events, such as some surgical interventions. Myocardial reperfusion injury can occur, for example, after myocardial infarction or as a result of heart transplantation. Cerebral reperfusion injury can occur, for example, after ischemic stroke or as a result of neonatal asphyxia.

[0268] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of reperfusion injury in stroke.

[0269] In a more preferred embodiment, the ischemia and / or reperfusion injury is cerebral, cardiac, pulmonary, renal ischemia and / or reperfusion injury, preferably cerebral ischemia, cerebral reperfusion injury or stroke.

[0270] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of reperfusion injury in the brain, heart, lungs, kidneys or other organs / tissues susceptible to reperfusion injury.

[0271] In one embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of ischemia in the brain, heart, lungs, kidneys or other organs / tissues susceptible to ischemia.

[0272] In one embodiment, the ischemia and / or reperfusion injury is cerebral ischemia and / or reperfusion injury, preferably cerebral ischemia and / or cerebral reperfusion injury.

[0273] In one embodiment, the ischemia and / or reperfusion injury is cardiac ischemia and / or reperfusion injury, preferably myocardial ischemia and / or myocardial reperfusion injury.

[0274] In another embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of cerebral reperfusion injury, preferably cerebral reperfusion injury.

[0275] In another embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of cardiac ischemia, preferably myocardial ischemia.

[0276] In one particularly preferred embodiment, the combination or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment and / or prevention of acute myocardial infarction, which is one of the most common clinical indications of reperfusion injury.

[0277] In one embodiment, the combination or pharmaceutical composition or pharmaceutical product described herein is for use in treating a subject with cardiogenic shock. Cardiogenic shock is a life-threatening medical condition resulting from insufficient blood circulation due to primary failure of the effective function of the ventricles of the heart. This condition occurs in 2-10% of patients hospitalized for myocardial infarction and is the leading cause of death among these patients (Holmes et al, 1995, J Am Coll Cardiol, 26: 668-674). More specifically, cardiogenic shock is the result of a complex process initiated by cardiac pump failure, involving failure of oxygen delivery, systemic ATP deficiency and multiple organ dysfunction (Okuda, 2006, Shock, 25: 557-70). As this is a type of circulatory shock, tissue perfusion is insufficient to meet the demand for oxygen and nutrients. This condition is accompanied by increasingly more widespread cell death from oxygen deprivation (hypoxia) and nutrient deprivation (e.g. hypoglycemia). This condition can therefore lead to cardiac arrest (or circulatory arrest), which is the sudden cessation of cardiac pumping function (as well as respiratory arrest and loss of consciousness). Cardiogenic shock is defined by sustained hypotension with tissue hypoperfusion despite adequate left ventricular filling pressure. Signs of tissue hypoperfusion include low urine production (less than 30 mL / hr), cold extremities, and altered level of consciousness. Several large trials have shown that coronary revascularization is the most important strategy to improve patient survival (Hochman et al, 1999, N Engl J Med, 341: 625-634). However, patients who develop cardiogenic shock despite rapid revascularization have a poor prognosis, likely due to reperfusion injury and related to the resulting infarct size. Indeed, hypothermia has been shown to provide tissue protection in myocardial ischemia, and preclinical studies have shown beneficial results in reducing infarct size in experimentally induced myocardial infarction (Dae et al, 2002, Am J Physiol Heart Circ Physiol, 282: H1584-1591).Thus, in a porcine model, mild therapeutic hypothermia reduced acute mortality and improved hemodynamic parameters in cardiogenic shock (Gotberg et al, 2010, Resuscitation, 81: 1190-96).

[0278] In one embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in treating a subject having cardiac arrest. Cardiac arrest is the sudden cessation of effective blood flow due to failure of effective contraction of the heart. The most common cause of cardiac arrest is coronary artery disease. Treatment of cardiac arrest is immediate cardiopulmonary resuscitation (CPR) and, if a shockable rhythm is present, defibrillation. In the United States, out-of-hospital cardiac arrest occurs in approximately 13 per 10,000 people per year (326,000 cases). In-hospital cardiac arrest occurs in an additional 209,000 people (Kronick et al, Circulation, 2015, 132: S397-S413). In addition to providing high-quality cardiopulmonary resuscitation, optimizing the management of post-resuscitation syndrome is critical to improving long-term outcomes in cardiac arrest patients. In this syndrome ("postresuscitation syndrome"), there are three main areas of focus: (1) post-cardiac arrest brain injury; (2) post-cardiac arrest myocardial dysfunction and reperfusion injury; and (3) the whole-body ischemia-reperfusion response. It is now clear that post-resuscitation care can affect the long-term survival of survivors as well as myocardial and neurological recovery and function (Kern, 2015, Circ J, 79: 1156-1163).

[0279] In one embodiment, the subject is at risk for (or susceptible to) vaso-occlusive injury or cardiac ischemia-reperfusion injury.

[0280] In one embodiment, the combination or pharmaceutical composition or pharmaceutical product described herein is administered to a donor subject and / or a recipient subject before and / or during and / or after heart transplantation.For example, in some embodiments, the combination can be administered to a first subject from which a heart organ is removed for transplantation into a second subject. Additionally or alternatively, in some embodiments, the combination is administered to the extracted heart organ before introduction into the second subject. Additionally or alternatively, in some embodiments, the combination therapy is administered to a second subject before, during and / or after heart transplantation.

[0281] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is for use in the treatment or prevention of neonatal asphyxia.

[0282] Neonatal asphyxia (or perinatal asphyxia) is a medical condition resulting from a lack of oxygen to a newborn, usually to the brain, during the birth process that lasts long enough to cause physical damage. The most common cause of neonatal asphyxia is a drop in maternal blood pressure during labor or other interruption to blood flow to the infant's brain, for example due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation.

[0283] Neonatal asphyxia can cause hypoxic damage to most of the infant's organs (heart, lungs, liver, digestive tract, kidneys), but brain damage is the most severe and is probably the least likely to heal immediately or completely. In more severe cases, the infant survives, but the damage to the brain manifests as either mental disabilities, such as developmental delay or intellectual disability, or physical disabilities, such as spasticity. Infants suffering from severe perinatal asphyxia are usually poorly colored (cyanotic), poorly perfused, poorly responsive, have poor muscle tone, and poor respiratory effort. Excessive asphyxia can cause cardiac arrest and death. Neonatal asphyxia occurs in 2-10 per 1000 newborns born at term, and more frequently in preterm newborns. The WHO estimates that birth asphyxia causes 4 million newborn deaths each year, representing 38% of deaths in children under the age of five.

[0284] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is formulated for intravenous administration.

[0285] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is formulated for subcutaneous administration.

[0286] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is formulated for oral administration.

[0287] In one preferred embodiment, the combination, or pharmaceutical composition or pharmaceutical product described herein is formulated for nasal administration.

[0288] Another aspect relates to the use of a compound according to the invention in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection. (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from Regarding the use of.

[0289] In one preferred embodiment of the invention, in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof Regarding the use of.

[0290] Another preferred embodiment of the present invention is the use of a compound of formula (I) in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Regarding the use of.

[0291] Another preferred embodiment of the invention is a combination of amodiaquine, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Regarding the use of.

[0292] Another preferred embodiment of the present invention is the use of a compound of formula (I) in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof Regarding the use of.

[0293] Another preferred embodiment of the present invention is the use of a compound of formula (I) in the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof Regarding the use of.

[0294] Another aspect relates to a method of treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, comprising administering to a subject in need thereof: (a) a first component that is a Nurr1 agonist; (b)(i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to a method comprising administering simultaneously, sequentially or separately

[0295] The preferred embodiments of the invention described above apply mutatis mutandis.

[0296] In one embodiment, the subject is a mammal, more preferably a human.

[0297] In one preferred embodiment, the method comprises administering to a subject in need thereof: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof simultaneously, sequentially or separately.

[0298] In one preferred embodiment, the method comprises administering to a subject in need thereof: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; simultaneously, sequentially or separately.

[0299] In one preferred embodiment, the method comprises administering to a subject in need thereof: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof simultaneously, sequentially or separately.

[0300] In one preferred embodiment, the method comprises administering to a subject in need thereof: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof simultaneously, sequentially or separately.

[0301] In one preferred embodiment, the method comprises administering to a subject in need thereof: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof simultaneously, sequentially or separately.

[0302] Administration The pharmaceutical composition of the present invention can be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.Preferably, the formulation is an oral administration formulation.The formulation may conveniently be provided in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or in the form of a multiple or subunit of a unit dose.By way of example, the formulation may be in the form of tablets and sustained release capsules, and may be prepared by any method well known in the art of pharmacy.

[0303] Formulations for oral administration in the present invention may be provided as discrete units such as capsules, gels, drops, cachets, pills or tablets, each containing a predetermined amount of the active agent; as powders or granules; as a solution, emulsion or suspension of the active agent in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, etc. Preferably, these compositions contain 1-250 mg, more preferably 10-100 mg, of active ingredient per dose.

[0304] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles, such as common excipients, such as binders, such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc wax, oils and colloidal silica. Flavoring agents, such as peppermint, wintergreen oil, cherry flavoring, and the like, can also be used. It may be desirable to add coloring agents to make the dosage form easily identifiable. Tablets can also be coated by methods well known in the art.

[0305] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as a powder or granules, which may be mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be optionally coated or scored and may be formulated to provide slow or controlled release of the active agent.

[0306] Other formulations suitable for oral administration include lozenges, which usually contain the active agent in a flavored base such as sucrose and acacia or tragacanth; troches, which contain the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes, which contain the active agent in a suitable liquid carrier.

[0307] Other administration forms include solutions or emulsions which can be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly and are prepared from sterile or sterilizable solutions. Injectable forms typically contain 10-1000 mg, preferably 10-250 mg, of active ingredient per dose.

[0308] Pharmaceutical compositions of the present invention may also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution or dusting powder.

[0309] An alternative means of transdermal administration is by the use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated in an ointment consisting of a white wax or white soft paraffin base, together with such stabilizers and preservatives as may be required, at a concentration of 1 to 10% by weight.

[0310] The pharma- ceutical active ingredients of the combination can be administered separately or in a combined formulation. Preferably, the pharma- ceutical active ingredients are administered separately.

[0311] Each component may be administered by the same or a different route as the other components.

[0312] In another preferred embodiment, the components of the combination are administered by the same route.

[0313] In another preferred embodiment, the components of the combination are administered by more than one route, for example, in one preferred embodiment, the insulin modulator is administered subcutaneously and the other components of the combination are administered orally.

[0314] In one preferred embodiment, the components are administered parenterally (eg, intravenously, intramuscularly, intradermally, intraperitoneally, or subcutaneously).

[0315] In one preferred embodiment, the components are administered intravenously, intramuscularly, or subcutaneously. More preferably, the components are administered intravenously.

[0316] In another preferred embodiment, the components are administered orally.

[0317] In one preferred embodiment, the components are administered subcutaneously.

[0318] In another preferred embodiment, the components are administered intranasally.

[0319] In one preferred embodiment, the components are administered once daily.

[0320] In another preferred embodiment, the ingredients are administered twice daily.

[0321] In one preferred embodiment, the components are administered by multiple routes at different stages of treatment.

[0322] In one preferred embodiment, the components are administered in a first administration phase and at least a second administration phase.

[0323] In the first administration step, the components of the combination can be administered by the same or different routes of administration.

[0324] In the second administration step, the components of the combination can be administered by the same or a different route of administration.

[0325] In one preferred embodiment, during the first administration step, the component is administered parenterally, more preferably intravenously.Typically, the first administration step is performed in a clinical setting, such as a hospital or clinic.

[0326] During the second administration step, the components of the combination can be administered by the same or a different route as the first administration step.

[0327] In one preferred embodiment, during the second administration step, the components of the combination are administered by a different route than the first administration step, e.g., orally, nasally or subcutaneously, more preferably orally. This second administration step may be referred to as a chronic administration step and may last for an extended period of time, e.g., days, weeks or months.

[0328] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered parenterally and the components of the at least one second administration step being administered orally.

[0329] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered intravenously and the components of the at least one second administration step being administered orally.

[0330] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered parenterally and the components of the at least one second administration step being administered intranasally.

[0331] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered intravenously and the components of the at least one second administration step being administered intranasally.

[0332] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered parenterally and the components of the at least one second administration step being administered subcutaneously.

[0333] In one preferred embodiment, the components are administered in a first administration step and at least one second administration step, the components of the first administration step being administered intravenously and the components of the at least one second administration step being administered subcutaneously.

[0334] In one preferred embodiment, the components of the combination are administered by different routes in the second administration step, for example, in one preferred embodiment, the insulin modulator is administered subcutaneously and the other components of the combination are administered orally.

[0335] In one preferred embodiment, the first administration step involves administering one dose or a combination of two doses per day for a period of about 1 to about 7 days, more preferably about 2 to about 7 days.

[0336] In one preferred embodiment, during the first administration step: Nurr1 agonists are administered at a dose of 0.05–0.5 mg / kg; The insulin modulator is administered at a dosage of 0.01-0.1 μg / kg; Aldosterone antagonists are administered at a dose of 0.1-1 mg / kg; Sulfonylureas are administered at a dose of 0.5 to 5 μg / kg.

[0337] Preferably, in the first administration step, the above-mentioned doses of Nurr1 agonist, insulin modulator, aldosterone antagonist and sulfonylurea are administered once or twice per day for a period of about 1 to about 7 days, more preferably for a period of about 2 to about 7 days.

[0338] In one preferred embodiment, the second administration step involves administering one or two doses per day for a period of about 7 to about 90 days after completion of the first administration step.

[0339] In one preferred embodiment, the second administration step begins immediately after the end of the first administration step. For example, in one preferred embodiment, the first administration step ends on one day and the second administration step begins on the next day.

[0340] In another preferred embodiment, the first and second administration steps are separated by a period during which none of the components of the combination of the invention are administered, i.e. there is a delay between the first and second administration steps. For example, this period (or delay) may be at least 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.

[0341] In one preferred embodiment, the invention comprises a first administration phase comprising a first dose of the combination at one or two doses per day for a period of about 1 to about 7 days, more preferably 2 to about 7 days, followed by a second administration phase comprising a second dose of the combination at one or two doses per day for a period of 7 to 90 days. Preferably, the first and second doses are different.

[0342] Preferably, the second dosage is less than the first dosage, i.e., the second administration phase can be considered as a "long-term" administration phase. As used herein, "first dosage" and "second dosage" refer in each case to the dosage of each component of the combination. Without wishing to be bound by theory, administering a higher dosage during the first administration phase may be advantageous in reducing the deleterious effects of reperfusion injury, while administering a lower dosage during the second administration phase, for example, for a longer period of time, may potentially be beneficial to the immune response after stroke, thereby improving recovery of brain function.

[0343] In another preferred embodiment, the second administration step comprises a second dosage of one or two combination doses per day administered for at least 30 days after the end of the first administration step. In another preferred embodiment, the second administration step comprises a second dosage of one or two combination doses per day administered for at least 60 days after the end of the first administration step. In another preferred embodiment, the second administration step comprises a second dosage of one or two combination doses per day administered for at least 90 days after the end of the first administration step.

[0344] In one preferred embodiment, during the second administration step: Nurr1 agonists are administered at a dose of 0.05–0.5 mg / kg; The insulin modulator is administered at a dosage of 0.01-0.1 μg / kg; Aldosterone antagonists are administered at a dose of 0.1-1 mg / kg; Sulfonylureas are administered at a dose of 0.5 to 5 μg / kg.

[0345] Preferably, in the second administration step, the above doses of Nurr1 agonist, insulin modulator, aldosterone antagonist and sulfonylurea are administered once or twice per day for a period of 7 to 90 days after completion of the first administration step.

[0346] In one preferred embodiment, the method comprises administering the components to said subject simultaneously.

[0347] In one preferred embodiment, each of the pharma- ceutical active ingredients of the combination, pharmaceutical product or pharmaceutical composition is administered separately.

[0348] The components of the combination of the invention may be for simultaneous, sequential or separate administration (as part of a dosing regimen).

[0349] Amodiaquine, exenatide or a structural or functional analogue thereof or a pharma- ceutically acceptable salt thereof, potassium canrenoate or a structural or functional analogue thereof, and glibenclamide or a structural or functional analogue thereof or a pharma- ceutically acceptable salt thereof may be for simultaneous, sequential, or separate administration (as part of a dosing regimen).

[0350] As used herein, "concurrently" is used to mean that two agents are administered simultaneously.

[0351] As used herein, "sequentially" is used to mean that the active agents are not administered simultaneously, but one is administered after the other.Thus, "sequential" administration may allow one agent to be administered within 5 minutes, 10 minutes, or about a few hours after the other, as long as the circulating half-life of the agent administered first is such that one agent and the other are both present simultaneously in therapeutically effective amounts.The time delay between the administration of these components varies depending on the exact nature of these components, the interaction between them, and their respective half-lives.

[0352] In contrast to "sequentially," "separately" is used herein to mean that there is a significant gap between the administration of one agent and the other, i.e., the agent administered first may no longer be present in the bloodstream in therapeutically effective amounts when the second agent is administered.

[0353] In one embodiment, the components are administered simultaneously.

[0354] In one embodiment, the components are administered sequentially or separately.

[0355] In the case of a combination of two components, the two components may be administered simultaneously or separately in any order.

[0356] For combinations of three components, all three components can be administered simultaneously, or any two components can be administered simultaneously and the third component can be administered separately or sequentially, or all three components can be administered separately or sequentially in any order.

[0357] For combinations of four components, all four components can be administered simultaneously, or two or three components can be administered simultaneously and the remaining components administered separately or sequentially, or all four components can be administered separately or sequentially in any order.

[0358] In one embodiment, each component is administered in a therapeutically effective amount with respect to the individual component.

[0359] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount that results in prevention or reduction of ischemia and / or reperfusion injury or one or more symptoms associated with ischemia and / or reperfusion injury.

[0360] In the context of therapeutic or prophylactic use, the amount of the composition administered to a subject depends on the type and severity of the disease, as well as on the individual's characteristics, such as general health, age, sex, weight, and tolerance to drugs. It also depends on the severity and type of the disease. Those skilled in the art can determine the appropriate dosage depending on these and other factors. The composition can also be administered in combination with one or more additional therapeutic agents.

[0361] In one embodiment, each component is administered in a sub-therapeutically effective amount with respect to the individual component.

[0362] In one embodiment, the component is administered prior to reperfusion of the subject.

[0363] In one embodiment, the component is administered during reperfusion of the subject.

[0364] In one embodiment, the component is administered after reperfusion of the subject.

[0365] In one embodiment, the moiety is administered before and / or during and / or after reperfusion of the subject.

[0366] In some embodiments, one or more of the components are administered sequentially before, during, and after reperfusion of the subject, with the remaining components being administered before or after reperfusion.

[0367] In some embodiments, the subject is administered the components sequentially before, during, and after reperfusion of the subject.

[0368] In some embodiments, additional administration of one or more components may occur after reperfusion, preferably at least twice, more preferably 2-100 times, or may be in the form of a continuous infusion.

[0369] In some embodiments of the method, the subject is administered the component as a bolus dose prior to reperfusion.

[0370] In some embodiments of the method, the subject is administered the component as a bolus dose during reperfusion.

[0371] In some embodiments of the method, the subject is administered the component as a bolus dose after reperfusion.

[0372] As used herein, "reperfusion" is the restoration of blood flow to any organ or tissue in which blood flow has been reduced or blocked. For example, blood flow can be restored to any organ or tissue affected by ischemia or hypoxia. Restoration of blood flow (reperfusion) can occur by any method known to those of skill in the art. For example, reperfusion of ischemic cardiac tissue can result from revascularization.

[0373] In one embodiment, reperfusion is achieved by a revascularization procedure selected from the group consisting of percutaneous coronary angioplasty, balloon angioplasty, insertion of a bypass graft, insertion of a stent, directional coronary atherectomy, treatment with one or more thrombolytic agents, and removal of an obstruction.

[0374] In one embodiment, the one or more thrombolytic agents are selected from the group consisting of tissue plasminogen activator; urokinase; pro-urokinase; streptokinase; acylated forms of plasminogen; acylated forms of plasmin; and acylated streptokinase-plasminogen complex.

[0375] Dosage Those skilled in the art can easily determine the appropriate dose of one of the compositions to be administered to a subject without undue experimentation.Typically, a doctor will determine the actual dosage that will be most suitable for an individual patient, which depends on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the specific condition, and the individual ongoing therapy.The dosages disclosed herein are examples of the average case.Of course, there may be individual cases where higher or lower dosage ranges are advantageous, and such cases are within the scope of the present invention.

[0376] In one highly preferred embodiment of the invention, the dose of the Nurr1 agonist (e.g., amodiaquine) in the combination is generally lower than the dose typically used in monotherapy in the context of its currently approved therapy and / or lower than the common doses reported in the reperfusion injury literature.

[0377] In one highly preferred embodiment of the invention, the dose of the insulin modulator (e.g., exenatide) in the combination is generally lower than the dose typically used in monotherapy in the context of its currently approved therapy and / or lower than the common doses reported in the reperfusion injury literature.

[0378] In one highly preferred embodiment of the invention, the dose of the aldosterone antagonist (e.g., potassium canrenoate) in the combination is generally lower than the dose typically used in monotherapy in the context of its currently approved therapy and / or lower than the common doses reported in the reperfusion injury literature.

[0379] In one highly preferred embodiment of the invention, the dose of the sulfonylurea (e.g., glibenclamide) in the combination is generally lower than the dose typically used in monotherapy in the context of its currently approved therapy and / or lower than the common doses reported in the reperfusion injury literature.

[0380] Each component of the claimed combination may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or in the form of a multiple or subunit of a unit dose. The dosages described herein are applicable to each of the above medical uses.

[0381] In one preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.01 to about 20 mg / kg of the subject's body weight, preferably about 0.1 to about 10 mg / kg, more preferably about 0.1 to about 5 mg / kg, and even more preferably about 0.1 to about 1 mg / kg. In another preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 1 to about 10 mg / kg or about 1 to about 5 mg / kg. In one preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 2 mg / kg or about 7 mg / kg. In one particularly preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.1 to about 0.5 mg / kg, more preferably about 0.1 to about 0.25 mg / kg. Advantageously, the dosage of amodiaquine suitable for use in the present combination is significantly lower than that reported in the literature, e.g., 40 mg / kg in the context of treating intracerebral hemorrhage (Kinoshita et al. 2019) and 20 mg / kg in the context of enhancing cognitive function by increasing hippocampal neurogenesis in adults (Kim et al. 2016).

[0382] In one highly preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dosage of about 0.5 mg / kg. In one highly preferred embodiment, amodiaquine or a pharma- ceutically acceptable salt thereof is administered at a dosage of about 0.1 mg / kg or about 0.15 mg / kg.

[0383] When used in the combinations claimed herein, the insulin modulator (e.g., exenatide) is preferably administered at a dose of about 0.001 to about 1.5 μg / kg, more preferably about 0.005 to about 0.15 μg / kg. In one preferred embodiment, the insulin modulator (e.g., exenatide) is preferably administered at a dose of about 0.01 to about 1.5 μg / kg, more preferably about 0.05 to about 1.5 μg / kg. As used herein, the dosage of the insulin modulator is in μg / kg body weight (μg=micrograms).

[0384] In one preferred embodiment, the insulin modulator (e.g., exenatide) is administered at a dose of preferably about 0.01 to about 0.5 μg / kg, more preferably about 0.02 to about 0.5 μg / kg, or about 0.03 to about 0.5 μg / kg, or about 0.04 to about 0.5 μg / kg, or about 0.05 to about 0.5 μg / kg, or about 0.05 to about 0.2 μg / kg, or about 0.05 to about 0.15 μg / kg.

[0385] In one preferred embodiment, the insulin modulator (e.g., exenatide) is administered at a dose of preferably about 0.01 to about 0.1 μg / kg, more preferably about 0.02 to about 0.08 μg / kg, or about 0.03 to about 0.07 μg / kg, or about 0.04 to about 0.06 μg / kg, or at a dose of about 0.05 μg / kg.

[0386] When used in the combinations claimed herein, the aldosterone antagonist (e.g., potassium canrenoate) is preferably administered at a dose of about 0.03 to about 10 mg / kg, or about 0.1 to about 10 mg / kg, or about 0.3 to about 5 mg / kg, or about 1 to about 10 mg / kg, or about 1 to about 5 mg / kg, or about 1 to about 3 mg / kg. As used herein, the dosage of the aldosterone antagonist is in mg / kg body weight.

[0387] In one preferred embodiment, the aldosterone antagonist (e.g., potassium canrenoate) is preferably administered at a dose of about 0.1 to about 3 mg / kg, or about 0.2 to about 2 mg / kg, or about 0.3 to about 1.5 mg / kg, or about 0.3 to about 1 mg / kg.

[0388] In one preferred embodiment, the aldosterone antagonist (e.g., potassium canrenoate) is administered at a dose of preferably about 0.1 to about 0.5 mg / kg, or about 0.2 to about 0.5 mg / kg, more preferably about 0.2 to about 0.4 mg / kg, and even more preferably about 0.3 to about 0.4 mg / kg.

[0389] When used in the combinations claimed herein, the sulfonylurea (e.g., glibenclamide) is preferably administered at a dose of about 0.001 to about 30 μg / kg, more preferably about 0.01 to about 5 μg / kg, and even more preferably about 0.01 to about 2 μg / kg. As used herein, the dosage of the sulfonylurea is in μg / kg body weight.

[0390] In one preferred embodiment, the sulfonylurea (e.g., glibenclamide) is preferably administered at a dose of about 0.5 to about 20 μg / kg, or about 0.5 to about 15 μg / kg, or about 0.5 to about 10 μg / kg, or about 1 to about 10 μg / kg.

[0391] In one preferred embodiment, the sulfonylurea (e.g., glibenclamide) is preferably administered at a dose of about 0.5 to about 8 μg / kg, or about 0.5 to about 7 μg / kg, or about 0.5 to about 6 μg / kg, or about 0.5 to about 5 μg / kg. In one preferred embodiment, the sulfonylurea (e.g., glibenclamide) is preferably administered at a dose of about 0.5 to about 3 μg / kg, or about 0.5 to about 2 μg / kg, or about 0.5 to about 1.5 μg / kg, or about 0.8 to about 1.2 μg / kg, or about 1 μg / kg.

[0392] In one highly preferred embodiment, the combination is a fixed dose combination comprising a predetermined dosage of each pharmacoactive ingredient, which allows, for example, the dosage amounts described above, e.g., about 0.001 to about 1.5 μg / kg of exenatide, about 0.001 to about 30 μg / kg of glibenclamide, about 0.03 to about 10 mg / kg of potassium canrenoate, and about 0.01 to about 20 mg / kg of amodiaquine to be administered to a subject.

[0393] Preferably, the fixed dose combination comprises a predetermined dose of each pharmacologic active ingredient to enable the following doses to be administered to a subject.

[0394] In one highly preferred embodiment, the combination is a fixed dose combination comprising from about 0.01 to about 0.5 μg / kg of exenatide and from about 0.01 to about 20 mg / kg of amodiaquine.

[0395] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.01 to about 0.1 μg / kg of exenatide and about 0.1 to about 10 mg / kg of amodiaquine.

[0396] In one highly preferred embodiment, the combination is a fixed dose combination comprising from about 0.01 to about 0.1 μg / kg of exenatide and 0.1 to about 5 mg / kg of amodiaquine.

[0397] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.01 to about 0.1 μg / kg of exenatide and about 0.1 to about 1 mg / kg of amodiaquine, more preferably about 0.1 to about 0.5 mg / kg of amodiaquine.

[0398] In one highly preferred embodiment, the combination is a fixed dose combination comprising a predetermined dosage of each component, for example, from about 0.03 to about 10 mg / kg potassium canrenoate, from about 0.001 to about 30 μg / kg glibenclamide, and from about 0.01 to about 20 mg / kg amodiaquine.

[0399] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 3 mg / kg potassium canrenoate, about 0.5 to about 20 μg / kg glibenclamide, and about 0.1 to about 10 mg / kg amodiaquine.

[0400] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.5 to about 8 μg / kg glibenclamide, and about 0.1 to about 5 mg / kg amodiaquine.

[0401] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.5 to about 1.5 μg / kg glibenclamide, and 0.1 to about 1 mg / kg amodiaquine, more preferably about 0.1 to about 0.5 mg / kg amodiaquine.

[0402] In one highly preferred embodiment, the combination is a fixed dose combination comprising a predetermined dosage of each component, for example, from about 0.03 to about 10 mg / kg potassium canrenoate, from about 0.005 to about 0.15 μg / kg exenatide, and from about 0.01 to about 20 mg / kg amodiaquine.

[0403] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 3 mg / kg potassium canrenoate, about 0.01 to about 0.5 μg / kg exenatide, and about 0.1 to about 10 mg / kg amodiaquine.

[0404] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.01 to about 0.1 μg / kg exenatide, and about 0.1 to about 5 mg / kg amodiaquine.

[0405] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.01 to about 0.1 μg / kg exenatide, and about 0.1 to about 1 mg / kg amodiaquine, more preferably about 0.1 to about 0.5 mg / kg amodiaquine.

[0406] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.03 to about 10 mg / kg potassium canrenoate, about 0.01 to about 0.5 μg / kg exenatide, about 0.001 to about 30 μg / kg glibenclamide, and 0.01 to about 20 mg / kg amodiaquine.

[0407] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 3 mg / kg potassium canrenoate, about 0.01 to about 0.1 μg / kg exenatide, about 0.5 to about 20 μg / kg glibenclamide, and 0.1 to about 10 mg / kg amodiaquine.

[0408] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.01 to about 0.1 μg / kg exenatide, about 0.5 to about 8 μg / kg glibenclamide, and 0.1 to about 5 mg / kg amodiaquine.

[0409] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.1 to about 0.5 mg / kg potassium canrenoate, about 0.01 to about 0.1 μg / kg exenatide, about 0.5 to about 1.5 μg / kg glibenclamide, and 0.1 to about 1 mg / kg amodiaquine, more preferably about 0.1 to about 0.5 mg / kg amodiaquine.

[0410] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.05 μg / kg exenatide, 1 μg / kg glibenclamide, and about 0.5 mg / kg amodiaquine.

[0411] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.33 mg / kg potassium canrenoate, about 1 μg / kg glibenclamide, and about 0.5 mg / kg amodiaquine.

[0412] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.05 μg / kg exenatide, about 0.33 mg / kg potassium canrenoate, about 1 μg / kg glibenclamide, and about 0.5 mg / kg amodiaquine.

[0413] In one highly preferred embodiment, the combination is a fixed dose combination comprising about 0.05 μg / kg of exenatide and about 0.5 mg / kg of amodiaquine.

[0414] Non-therapeutic use In another aspect, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: (a) a first component that is a Nurr1 agonist; (b) Below: (i) Aldosterone antagonists; (ii) an insulin modulator; and (iii) Sulfonylurea and at least one additional ingredient selected from The present invention relates to the use of a combination comprising or consisting of:

[0415] In one preferred embodiment, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to the use of a combination comprising or consisting of:

[0416] In another preferred embodiment, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Glibenclamide, or a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; The present invention relates to the use of a combination comprising or consisting of:

[0417] In another preferred embodiment, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to the use of a combination comprising or consisting of:

[0418] In another preferred embodiment, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analogue thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to the use of a combination comprising or consisting of:

[0419] In another preferred embodiment, the present invention provides a method for treating and / or preventing ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: amodiaquine, or a pharma- ceutically acceptable salt thereof; Exenatide, a structural or functional analogue thereof, or a pharma- ceutically acceptable salt thereof The present invention relates to the use of a combination comprising or consisting of:

[0420] Ex vivo (removed from the body) organs may be susceptible to reperfusion injury due to lack of blood flow. Therefore, the combination of the present invention can be used to prevent reperfusion injury in removed organs. Preferably, the organ is the heart, liver or kidney, more preferably the heart.

[0421] In some embodiments, the removed organ is placed in a standard buffer solution, such as a solution commonly used in the art, containing the combination of the present invention. For example, the removed heart can be placed in a cardioplegic solution containing amodiaquine and one or more of exenatide, potassium canrenoate, and glibenclamide. The concentrations of amodiaquine, exenatide, potassium canrenoate, and glibenclamide useful in standard buffer solutions can be easily determined by those skilled in the art. Such concentrations may be, for example, about 0.1 nM to about 10 μM, preferably about 1 nM to about 10 μM.

[0422] The present invention will now be further described with reference to the accompanying non-limiting examples and the following figures: [Brief description of the drawings]

[0423] [Figure 1] Latency to find the hidden platform (in seconds, mean ± SEM) in three trials T1, T2, and T3 at weeks 4 and 8 in each test. See Example 1. Statistical analysis - **p<0.01 by two-way ANOVA followed by Bonferroni post hoc comparison (3M vs. 1M). Group 1M: vehicle-treated control; Group 2M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + glibenclamide 1 μg / kg; Group 3M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + glibenclamide 1 μg / kg + amodiaquine 20 mg / kg; Group 4M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + amodiaquine 20 mg / kg; Group 5M: sham operation. [Diagram 2]Distance swam to reach the hidden platform (in cm; mean ± SEM of three trials T1, T2, and T3 at weeks 4 and 8 in each test). See Example 1. Statistical analysis - *p<0.05 by two-way ANOVA followed by Bonferroni post hoc comparison (3M vs. 1M). Group 1M: vehicle-treated control; Group 2M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + glibenclamide 1 μg / kg; Group 3M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + glibenclamide 1 μg / kg + amodiaquine 20 mg / kg; Group 4M: exenatide 0.05 μg / kg + potassium canrenoate 0.33 mg / kg + amodiaquine 20 mg / kg; Group 5M: sham operation. [Diagram 3] Hippocampal CA1 and CA3 cell damage at the end of the study. See Example 1. Group 1M: Vehicle-treated control; Group 2M: Exenatide 0.05 μg / kg + Potassium canrenoate 0.33 mg / kg + Glibenclamide 1 μg / kg; Group 3M: Exenatide 0.05 μg / kg + Potassium canrenoate 0.33 mg / kg + Glibenclamide 1 μg / kg + Amodiaquine 20 mg / kg; Group 4M: Exenatide 0.05 μg / kg + Potassium canrenoate 0.33 mg / kg + Amodiaquine 20 mg / kg; Group 5M: Sham-operated. [Figure 4] Neurological scores throughout the study (amodiaquine monotherapy) (Part I). See Example 2. AM20 = amodiaquine 20 mg / kg; AM7 = amodiaquine 7 mg / kg; AM2 = amodiaquine 2 mg / kg; AM0.5 = amodiaquine 0.5 mg / kg. Before surgery, all animals behaved normally. Two-way ANOVA followed by Bonferroni post-hoc comparisons found statistically significant differences between group 1M (vehicle) and drug-treated groups 2M amodiaquine (20 mg / kg), 3M amodiaquine (7 mg / kg) and 5M amodiaquine (0.5 mg / kg) on ​​days 1 and 8. Figures show mean values ​​± SEM; ** indicates p<0.01, *** indicates p<0.001. [Diagram 5]Neurological scores throughout the study (combination therapy) (Part II). See Example 2. AM = amodiaquine; PC = potassium canrenoate; Gli = glibenclamide; Ex = exenatide. Before surgery, all animals behaved normally. Statistically significant differences were found between group 1M (vehicle) and drug-treated groups 6M, 7M, 8M, 9M and 11M on day 1, and among all treatment groups on day 8. Figures show mean values ​​± SEM; * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001 using two-way ANOVA statistical analysis followed by Bonferroni post-hoc comparisons. [Figure 6] Cerebral infarct size (%) at end of study (amodiaquine monotherapy) (Part I). See Example 2. AM20 = amodiaquine 20 mg / kg; AM7 = amodiaquine 7 mg / kg; AM2 = amodiaquine 2 mg / kg; AM0.5 = amodiaquine 0.5 mg / kg. Statistically significant differences in infarct size were found between group 1M (vehicle) and drug treatment groups 2M amodiaquine (20 mg / kg), 3M amodiaquine (7 mg / kg) and 5M amodiaquine (0.5 mg / kg). Figures show mean values ​​± SEM; * indicates p<0.05 and *** indicates p<0.001 using one-way ANOVA statistical analysis followed by Bonferroni multiple comparison test. [Figure 7] Cerebral infarct size (%) at end of treatment (combination therapy) (Part II). See Example 2. AM = amodiaquine; PC = potassium canrenoate; Gli = glibenclamide; Ex = exenatide. Statistically significant differences in infarct size were found between group 1M (vehicle) and drug-treated groups 6M, 8M, 9M and 11M. Figures show mean values ​​± SEM; * indicates p<0.05 and *** indicates p<0.001 using one-way ANOVA statistical analysis followed by Bonferroni multiple comparison test. [Figure 8] Summary of NSS scores and infarct sizes on day 8 for groups 2M-11M expressed as percentage of control values. See Example 2. [Figure 9]The neurological severity scores of selected combinations in the rat model of chronic stroke study described in Example 3 are shown (geometric mean ± SD). Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 10] The results of the stepping test of selected combinations in the rat model of chronic stroke research described in Example 3 are shown (geometric mean ± SD). Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 11] The results of the forelimb placement test of selected combinations in the rat model of chronic stroke research described in Example 3 are shown (geometric mean ± SD). Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 12]The results of the object recognition test of selected combinations in the rat model of chronic stroke research described in Example 3 are shown (geometric mean ± SD). Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 13] The results of the elevated plus maze test of selected combinations in rat model of chronic stroke research described in Example 3 are shown (geometric mean ± SD). Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 14] Figure 2 shows the percentage of infarct size at 28 days for selected combinations in the rat model of chronic stroke study described in Example 3. Group 2M: vehicle treatment; Group 3M: potassium canrenoate + amodiaquine + glibenclamide; Group 4M: exenatide + amodiaquine + glibenclamide; Group 5M: exenatide + potassium canrenoate + amodiaquine; Group 6M: exenatide + potassium canrenoate + glibenclamide; Doses: amodiaquine (0.5mg / kg); exenatide (0.05μg / kg); potassium canrenoate (0.33mg / kg); glibenclamide (1μg / kg). [Figure 15] 1 shows the NSS effect of selected combinations versus control (%) from Examples 2 and 3 (days 8 and 28). [Figure 16] Figure 1 shows the infarct size effect of selected combinations relative to control (%) from Examples 2 and 3 (days 8 and 28). [Figure 17] Apoptosis (TUNEL staining) in the α-penumbra, striatum and dorsal hippocampus regions at the end of the study on day 28 for selected combinations in the rat model of chronic stroke study described in Example 3 is shown (mean ± SEM). Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: amodiaquine (0.5 mg / kg); Exenatide (0.05 μg / kg); Canrenoate potassium (0.33 mg / kg); Glibenclamide (1 μg / kg). [Figure 18] Olig-2 mature oligodendrocytes for selected combinations in rat model of chronic stroke study described in Example 3-Percentage of activated cells at the end of the study on day 28 (mean ± SEM). Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: amodiaquine (0.5mg / kg); Exenatide (0.05μg / kg); Canrenoate potassium (0.33mg / kg); Glibenclamide (1μg / kg). [Figure 19] NG2 oligodendrocyte precursor cells-percentage of cells at the end of the study on day 28 (mean ± SEM) for selected combinations in rat model of chronic stroke study described in Example 3. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: amodiaquine (0.5mg / kg); Exenatide (0.05μg / kg); Canrenoate potassium (0.33mg / kg); Glibenclamide (1μg / kg). [Figure 20]1 shows the NeuN damage (mean ± SEM) at the end of the study on day 28 for selected combinations in the rat model of chronic stroke study described in Example 3. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: amodiaquine (0.5 mg / kg); Exenatide (0.05 μg / kg); Canrenoate potassium (0.33 mg / kg); Glibenclamide (1 μg / kg). [Figure 21] GFAP histology results (mean ± SEM) at the end of study on day 28 for selected combinations in rat model of chronic stroke study described in Example 3 are shown. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: Amodiaquine (0.5mg / kg); Exenatide (0.05μg / kg); Canrenoate potassium (0.33mg / kg); Glibenclamide (1μg / kg). [Figure 22] Iba-1 histological results (mean ± SEM) at the end of the study on day 28 for selected combinations in the rat model of chronic stroke study described in Example 3. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: amodiaquine (0.5 mg / kg); Exenatide (0.05 μg / kg); Canrenoate potassium (0.33 mg / kg); Glibenclamide (1 μg / kg). [Diagram 23]Figure 2 shows the percentage of activated cells stained with doublecortin (mean ± SEM) at 4 weeks, 28 days for selected combinations in the rat model of chronic stroke study described in Example 3. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: Amodiaquine (0.5mg / kg); Exenatide (0.05μg / kg); Canrenoate potassium (0.33mg / kg); Glibenclamide (1μg / kg). [Figure 24] 1 shows MBP myelin damage (mean ± SEM) at the end of the study for selected combinations in the rat model of chronic stroke study described in Example 3. Group 1M: Sham; Group 2M: Vehicle treatment; Group 3M: Canrenoate potassium + amodiaquine + glibenclamide; Group 4M: Exenatide + amodiaquine + glibenclamide; Group 5M: Exenatide + Canrenoate potassium + amodiaquine; Group 6M: Exenatide + Canrenoate potassium + glibenclamide; Doses: Amodiaquine (0.5 mg / kg); Exenatide (0.05 μg / kg); Canrenoate potassium (0.33 mg / kg); Glibenclamide (1 μg / kg). [Example]

[0424] This invention is further illustrated by the following examples, which should not be construed as limiting in any way. Example 1

[0425] Study of amodiaquine combinations in a rat model of vascular dementia Research purpose The aim of this study was to evaluate the neuroprotective effects of amodiaquine and its various combinations given intravenously, twice daily for 3 weeks, 24 hours after permanent ligation of both common carotid arteries, using a Wistar rat vascular dementia model.

[0426] material Exenatide acetate was obtained from Bachem AG, Switzerland. Potassium canrenoate was obtained from Pfizer, Switzerland. Glibenclamide was obtained from Tocris Bioscience. Amodiaquine was obtained from Sigma. The vehicle was saline obtained from Biological Industries.

[0427] Study Design and Timeline This study sought to evaluate the neuroprotective effects of different combinations administered intravenously at low doses twice daily for 3 weeks in a Wistar rat model of vascular dementia. The study (sponsored by the applicant) was carried out at Pharmaseed Ltd (Ness-Ziona, Israel) in 6 cycles, each cycle including 12-15 rats. Test compounds were administered twice daily for 3 weeks, 24 hours after common carotid artery ligation. On day 1, both common carotid arteries were permanently ligated. Morris water maze tests were performed before common carotid artery ligation as baseline training, and at weeks 4 and 8 thereafter. At the end of the study, at the end of the 8th week after common carotid artery occlusion (CCAO), after completion of the MWM test, rats were subjected to transcardial perfusion with 2.5% buffered PFA, and brains were harvested, fixed in the same solution, and stored at 4°C. Histological analysis was performed according to plan:

[0428] The experimental design and study timeline are presented in Tables 1 and 2, respectively. [Table 1] [Table 2]

[0429] animal Male Wistar rats were used in the study and weighed between 196 and 320 g at the start of the study.

[0430] animal control Breeding Animal handling was performed in accordance with the guidelines of the National Institutes of Health (NIH) and the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were housed in 42.5 × 26.5 × 18.5 cm polyethylene cages (maximum 3 rats / cage) equipped with stainless steel top grills to facilitate access to pelleted food and drinking water in plastic bottles; bedding: steam-sterilized clean rice husk (Envigo, Sani-chips Cat. No. 7090C). Bedding material was changed along with the cages at least twice a week.

[0431] feed Animals were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Cat. No. 2018SC) ad libitum. Animals had ad libitum access to autoclaved, acidified drinking water (pH 2.5–3.5) obtained from a municipal source.

[0432] environmental conditions Animals were housed under standard laboratory conditions with an adequate fresh air supply (minimum 15 air changes / h) and filtered air (HEPA F6 / 6). Animals were kept in a temperature-controlled environment with a temperature range of 18-24°C and a relative humidity range of 30-70% with a 12-h light and 12-h dark cycle.

[0433] Randomization Animals were randomly assigned to cages according to Pharmaseed's SOP#027 "Random allocation of animals."

[0434] Treatment and Evaluation Surgical procedure: ligation of two common carotid arteries On the day of surgery, anesthesia was induced with 4% isoflurane in a mixture of 70% N2O and 30% O2 on a heating pad and maintained with 1.5–2% isoflurane. 0.1 mg / kg buprenorphine was injected subcutaneously. Two common carotid artery occlusions were performed according to the method described by Hyun Joon Lee et al (Citicoline Protects Against Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion, J Clin Neurol. 2009; 5(1):33-38). Both common carotid arteries (CCA, Common Carotid Arteries) were exposed by a midline cervical incision and carefully cut free of surrounding nerves and fascia. Both arteries were double ligated with 4-0 silk sutures 8–10 mm below the visible area of ​​the external carotid artery. The surgical wound was closed and the animals were returned to their cages and allowed to recover from anesthesia. Analgesic treatment was resumed by the end of the day and twice daily for the next 4 days.

[0435] Administration of the Combination Twenty-four hours after arterial ligation, treatment was initiated by intravenous (IV) injection of all mixtures except amodiaquine, which was administered intraperitoneally at 20 mg / kg. Treatment was administered twice daily for three consecutive weeks.

[0436] Morris water maze test The Morris water maze (MWM) test was performed to evaluate cognitive impairment after common carotid artery ligation. The test was performed according to Pharmaseed's SOP 100 (Morris Water Maze Testing V6) and related publications (e.g., Brandeis R, Brandys Y and Yehuda S, "The use of the Morris Water Maze in the study of memory and learning", Int J Neurosci. 1989; 48(1-2):29-69).

[0437] Pre-operative training Animals were trained and conditioned in Morris water maze for 1 week according to Pharmaseed's SOP100 and scientific publications (see, for example, Brandeis R et al.). Before MWM, rat cages were moved from the animal house to the behavioral testing room for about 1 hour of acclimation. The training results on the last day were considered as baseline data for comparison. The MWM test had the following exclusion criteria: failure to escape to the platform in 90 seconds (the third day of training).

[0438] After common carotid artery ligation test Before the MWM, the rats were transferred from the animal house to the behavioral testing room and allowed to acclimate for approximately 1 hour. The MWM test was performed at 4 and 8 weeks after common carotid artery ligation.

[0439] end Eight weeks after common carotid artery occlusion (CCAO) and after completion of the MWM test, rats were sacrificed. All rats were subjected to transcardial perfusion with 2.5% buffered PFA, and the brains were harvested, fixed in the same solution, and stored at 4°C.

[0440] Histological analysis Tissue preparation and trimming (affected hemisphere), precise sectioning of striatum (corpus callosum) dorsal hippocampus, and optic tract per brain X3. Paraffin block preparation H&E and TUNEL staining, IHC: doublecortin for neuronal regeneration in the subventricular zone of the brain. MBP, myelin in white matter, Iba-1 for microglia, GFAP for reactive astrocytes. Olig-2 for mature oligodendrocytes, NG2 for young oligodendrocytes. Slide evaluation analysis; cell bodies counting in the CA1 and CA3 regions of the hippocampus - 3 sections per brain, 3 fields per section. Morphometric analysis of neuronal death numbers in hippocampal regions, and additional MBP, Olig-2 and NG2 morphometrics were performed in the optic tract, striatum and dorsal hippocampal regions. Photographs of histology slides were acquired.

[0441] result Morris water maze test The Morris Water Maze (MWM) test was performed to evaluate vascular dementia-associated cognitive impairment after ischemic hippocampal damage, expressed as learning and memory impairment. As expected, a significant decline in cognitive function was observed in all groups compared to the sham-operated group 5M during the 4th week of testing after both CCAOs.

[0442] The results of the MWM trial in the five study arms can be summarized as follows: a) During a brief introduction to the maze before surgery, rats from the five groups behaved similarly. b) Rats that received sham surgery only (group 5M) performed better in the cognitive test and reached the hidden platform faster than all rats that received vascular dementia surgery, indicating the effectiveness of the ischemic treatment. c) During maze acquisition (more sensitive learning function), triple combination treatment rats (2M and 4M groups) and quadruple combination treatment rats (3M group) outperformed vehicle treatment rats (1M group). This was shown mainly in the first and second trials of task learning in the fourth week (marked as T1 and T2 in Figure 1). Thereafter, no improvement over the vehicle group was observed in the eighth week test. d) A significant ischemic effect was also shown in the distance the animals swam to reach the platform (see Figure 2). The different treatments showed a similar pattern, with Group 3M showing a statistical difference compared to Group 1M (*p<0.05 in trial 2 at week 4).

[0443] Histology Results: The triple combination (group 2M) significantly reduced the number of apoptotic cells in the hippocampus as measured by Tunnel staining. Group (4M) slightly reduced the number of apoptotic cells, but less than group 2M (*p<0.05). The number of pyknotic cells in the CA1 and CA3 hippocampal regions was assessed. CA1 cells are known to be sensitive to various toxic substances, while CA3 cells are primarily sensitive to reduced oxygenation, and their damage has been shown to correlate with cognitive dysfunction. (T Kadar, M Silbermann, R Brandeis and A Levy, Age-related structural changes in the rat hippocampus: correlation with working memory deficiency, Brain Res 1990;512(1):113-120;T Kadar, I Arbel, M Silbermann and A Levy, Morphological hippocampal changes during normal aging and their relation to cognitive deterioration, J Neural Transm Suppl. 1994;44:133-143;B Shukitt-Hale, T Kadar, BE Marlowe, MJ Stillman, RL Galli, A Levy, JA Devine, HR Lieberman, Morphological alterations in the hippocampus following hypobaric hypoxia, Hum Exp Toxicol. 1996;15(4):312-319).

[0444] As shown in Figure 3, the average number of pyknotic cells in CA1 was relatively low, with no statistically significant difference between any of the treatments compared to the vehicle control. The pyknotic damage in CA3 was extensive, as shown by the vehicle treatment group 1M. In this parameter, the quadruple combination 3M and the triple combination 4M showed better and more significant results compared to the vehicle treatment than the original 2M. No statistically significant differences were found in Iba-1, GFAP, Olig-2, NG2, myelin density, and doublecortin cells in all brain regions between all animal groups.

[0445] Observations and Conclusions Chronic cerebral hypoperfusion induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats has been shown to cause significant white matter damage, learning and memory impairment, and hippocampal neuronal damage. Therefore, BCCAO in rats provided a useful model for understanding the pathophysiology of chronic cerebrovascular hypoperfusion and screening drugs with potential therapeutic value for vascular dementia. Moreover, this model is also relevant to Alzheimer's disease, because Alzheimer's disease is also accompanied by a slowly progressive reduction in cerebral blood flow.

[0446] This study was carried out to determine whether the proposed treatment could improve cognitive impairment caused by chronic cerebral hypoperfusion and reduce brain neuronal damage mainly in the CA-1 and CA-3 regions of the hippocampus as well as lesions in white matter regions. The combination was initially administered intravenously 24 hours after the surgical procedure and then twice daily for 3 weeks. As expected, cognitive impairment was observed 4 weeks after CCCA treatment. Rats that received only sham surgery (5M group) performed better in cognitive tests and reached the hidden platform faster than all rats that received vascular dementia surgery, indicating the effectiveness of the ischemia treatment. During maze acquisition (more sensitive learning function), the triple combination treated rats (2M and 4M groups) as well as the quadruple combination treated rats (3M) performed better than the vehicle treated rats (1M group). The treatment was started 24 hours after surgery and then twice daily for 3 weeks, which protected against hippocampal cell damage. The new triple combination (4M) also reduced the number of apoptotic cells. Advantageously, the combinations containing amodiaquine (groups 3M and 4M) show improved activity against nuclear pyknosis and hippocampal cell death. Example 2

[0447] Efficacy study of amodiaquine combinations in a rat model of transient middle cerebral artery occlusion the purpose The objectives of this study were a) to evaluate the neuroprotective effects of amodiaquine at four doses compared to vehicle control, and b) to evaluate the efficacy of combinations of amodiaquine with two other test items (exenatide and canrenoate) compared to their individual performance and compared to vehicle control. One combination also included glibenclamide.

[0448] To understand the pathophysiology of cerebral ischemia and to identify therapeutic strategies to minimize the severity of ischemic damage, several animal models have been used to study cerebral ischemia. Focal ischemia leads to localized cerebral infarction, usually caused by transient middle cerebral artery occlusion (t-MCAO) in rats, which is increasingly accepted as a model of hemispheric infarction in humans. After MCAO, cortical and striatal infarction with temporal and spatial evolution occurs within the vascular territory supplied by the middle cerebral artery.

[0449] material Exenatide acetate was obtained from Bachem AG, Switzerland. Potassium canrenoate was obtained from Pfizer, Switzerland. Glibenclamide was obtained from Tocris Bioscience. Amodiaquine was obtained from Sigma. The vehicle was saline obtained from Biological Industries.

[0450] animal Male Sprague Dawley (SD) rats were used in the study and weighed 300-410 g at the start of the study.

[0451] animal control Breeding Animal care was performed in accordance with the guidelines of the National Institutes of Health (NIH) and the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were housed in 42.5 × 26.5 × 18.5 cm polyethylene cages (3 animals / cage) with stainless steel top grills that facilitated the feeding of pelleted food and drinking water in plastic bottles; bedding: steam-sterilized clean rice husk (Envigo, Sani-chip, Cat. No.: 7090C), and bedding material was changed along with the cage at least twice a week.

[0452] feed Animals were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Envigo, Cat. No. 2018SC) ad libitum. Animals had ad libitum access to standard tap drinking water obtained from a municipal source and treated according to Pharmaseed's SOP No. 214: "Water system". Animal diets arrived with a certificate of analysis and water was autoclaved prior to use.

[0453] environmental conditions Animals were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Cat. No. 2018SC) ad libitum. Animals had ad libitum access to autoclaved, acidified drinking water (pH 2.5–3.5) obtained from a municipal source.

[0454] Randomization Upon arrival, animals were assigned to cages according to Pharmaseed's SOP#027 "Random allocation of animals."

[0455] Experimental design and conditions Pain relief methods The MCAO procedure was performed under anesthesia with 4% isoflurane in a mixture of 70% N2O and 30% O2, and maintained with 1.5-2% isoflurane. Meloxicam at 2 mg / kg was administered subcutaneously (SC) before and after surgery, once daily for the next 4 days, and thereafter only if there were signs of pain or discomfort.

[0456] Continuation of the experimental period Seven days after the end of acclimation, the first administration day was assigned as “Day 1” and the end was “Day 8.”

[0457] Study Design and Timeline This study, sponsored by the applicant, was carried out at Pharmaseed Ltd, Ness-Ziona, Israel.

[0458] Part I: This part of the study was designed to evaluate the neuroprotective effect of amodiaquine administered orally in four doses, given twice daily, 20 minutes before reperfusion, compared to vehicle control.

[0459] Part II: Test items (exenatide, canrenoate, and glibenclamide) were evaluated in combination with amodiaquine and compared to vehicle control. The first two were also compared to their performance alone. The study was performed in cycles, with at least 9 rats in each cycle. Test compounds were administered 20 min before reperfusion and then twice daily. On day 1, stroke was induced by t-MCAO procedure. Neurological scores (NSS) were performed before surgery, 24 h and 7 days after t-MCAO. At the end of the study, brains were harvested, sliced ​​into five 2 mm thick coronal sections, and stained with TTC to measure infarct size. The experimental design and timeline of the two parts of the study are presented below.

[0460] research design Part I: Monotherapy study design Dosage regimen: 20 minutes before the start of reperfusion and twice daily thereafter (every 12 hours). [Table 3]

[0461] Part II: Combination therapy study design Dosage regimen: 20 minutes before the start of reperfusion and twice daily thereafter (every 12 hours). [Table 4] [Table 5]

[0462] Treatment and Evaluation Surgical procedure Transient middle cerebral artery occlusion (t-MCAO) was performed according to the method described by R. Schmid-Elsaesser et al. (Stroke; 1998; 29(10): 2162-70). The right common carotid artery (CCA) was exposed through a midline cervical incision and carefully dissected free of surrounding nerves and fascia - from the bifurcation to the base of the skull. The occipital artery branches of the external carotid artery (ECA) were isolated, dissected and coagulated. The ECA was dissected further distally and coagulated just before the bifurcation, along with the terminal lingual and maxillary artery branches. The internal carotid artery (ICA) was isolated and carefully separated from the adjacent vagus nerve, and the pterygopalatine artery was ligated near its origin with a 5-0 nylon suture. A 4-0 silk suture was then tied loosely around the mobilized ECA stump and a 4 cm long 4-0 monofilament nylon suture (the suture tip was blunted using a flame and the suture was coated with polylysine prior to insertion) was inserted through the proximal ECA into the ICA and from there into the Circle of Willis to effectively occlude the MCA. The surgical wound was closed and the animals were returned to their cages and allowed to recover from anesthesia. One and a half hours after occlusion, the rats were re-anesthetized and the monofilament was removed to allow for reperfusion. The surgical wound was closed and the rats were returned to their cages. After surgery, the animals were placed on a heating pad until they recovered from anesthesia. All animals received 2 mg / kg meloxicam subcutaneously daily for the next 2 days before and after surgery. The animals were observed frequently on the day of t-MCAO surgery and at least once a day thereafter.

[0463] Administration of the Combination Treatment was initiated via IP administration of test compound 20 minutes prior to reperfusion and then at the end of the same day, and continued twice daily for six consecutive days.

[0464] Modified Neurological Score (mNSS) Animals were subjected to the NSS test before surgery as a baseline, 24 hours and 7 days after MCAO surgery (Schabitz WR, Berger C., Kollmar R., Seitz M., Tanay E., Kiessling M., Schwab S., Sommer C. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke. 2004 ;35(4):992-997).

[0465] end Eight days after MCAO surgery, animals were sacrificed by CO2 exposure. Brains were collected, sliced ​​into five 2 mm thick sections, stained with TTC, and subjected to histological evaluation for infarct volume determination. After infarct volume evaluation, slices were stored in PFA for future histological analysis.

[0466] result Neuroscore assessment during the study Several clinical observations recorded after surgery were common after stroke induction and appeared in all groups. The neurological score (NSS) included a series of clinical neurological tests (composite of motor, sensory, reflex and balance tests) used to evaluate the effect of amodiaquine monotherapy and its combination with exenatide, glibenclamide, and potassium canrenoate. The neurological score was graded on a scale of 0 to 18 (with a normal score of 0 and a maximum deficit score of 18). Before surgery, all animals showed normal behavior with a score of 0. A sharp decline in neurological function (increased NSS) was recorded in all rat groups 24 hours after t-MCAO. A similar statistically significant NSS improvement was observed in groups 2M, 3M, and 5M compared to the vehicle-treated group (see Figure 4). This improvement was already apparent during the first test on day 2 and continued until day 8. The combination of amodiaquine with exenatide, glibenclamide and potassium canrenoate also resulted in significant NSS improvements in the treatment groups compared to vehicle-treated controls from the first test on day 2 through day 8 (see FIG. 5).

[0467] Infarct size Infarct size was measured by image analysis using the ImageJ program. As shown in Figures 6 and 7, the cerebral infarct size in vehicle-treated t-MCAO animals was 38% of the total hemisphere volume. Cerebral infarct size was reduced in animals treated with amodiaquine compared to vehicle-treated controls, but mostly in animals treated with high doses. The combination of amodiaquine with exenatide, glibenclamide and potassium canrenoate also resulted in a significant, almost two-fold reduction in infarct size compared to vehicle-treated controls. Less pronounced reductions in infarct volume were observed in animals treated with potassium canrenoate and amodiaquine + exenatide administered 20 min before reperfusion.

[0468] T-tests were performed obtained on infarct size data to determine statistical significance between treatment groups. Group 6M performed significantly better than Group 10M (***p<0.001), Group 5M (**p<0.01), and Group 8M (*p<0.05). Group 11M performed significantly better than Group 10 (**p<0.01), and Groups 5M and 7M (*p<0.05). Group 10M performed significantly better than Group 8M (*p<0.05).

[0469] The performance of each group, expressed as a percentage of the control value, is summarized in FIG.

[0470] Observations and Conclusions In the first part of the study, the dose-response efficacy of amodiaquine was evaluated at four doses compared to vehicle control using a rat t-MCAO stroke model. In the second part, three other active agents (exenatide, canrenoate, and glibenclamide) were evaluated in combination with amodiaquine compared to vehicle control, with the first two also compared to their performance alone. In the first part of the study, clear differences were demonstrated between the groups treated with amodiaquine when compared to the vehicle control group of animals, mainly at the high doses tested. More pronounced effects were observed with combination therapy.

[0471] The main observations can be summarized as follows: None of the treatments had any effect on the weight, health, or mortality of the animals. Amodiaquine monotherapy at different doses significantly improved post-stroke neurological scores in a dose-dependent manner compared with vehicle treatment. Amodiaquine combination therapy also significantly improved neurological scores compared with vehicle treatment. Amodiaquine monotherapy at different doses significantly reduced infarct size compared with vehicle treatment. Amodiaquine combination therapy also significantly reduced infarct size compared with vehicle treatment. Two triple combinations, "amodiaquine + canrenoate + glibenclamide" and "amodiaquine + canrenoate + exenatide" are particularly preferred. The double combination "amodiaquine + exenatide" also showed good results.

[0472] Considering these findings, it can be concluded that under the conditions of the present study, treatment with amodiaquine monotherapy and amodiaquine combination therapy, administered twice daily, 20 min before and after reperfusion, obviously improved sensorimotor function and reduced infarct size in a transient t-MCAO model in rats. Example 3

[0473] Efficacy study in a rat model of transient middle cerebral artery occlusion during 28 days of continuous treatment the purpose The objective of this study was to evaluate the efficacy of amodiaquine, exenatide, canrenoate, and their combinations, as well as one combination containing glibenclamide, in improving functional recovery 28 days after induction of stroke in rats.

[0474] material Exenatide acetate was obtained from Bachem AG, Switzerland. Potassium canrenoate was obtained from Pfizer, Switzerland. Glibenclamide was obtained from Tocris Bioscience. Amodiaquine was obtained from Sigma. The vehicle was saline obtained from Biological Industries.

[0475] animal Male Sprague-Dawley (SD) rats were used in the study, weighing 295-330 g at the start of the study.

[0476] animal control Breeding Animal handling was performed in accordance with the guidelines of the National Institutes of Health (NIH) and the Association for Accreditation of Laboratory Animal Care (AAALAC). Animals were housed in 42.5 x 26.5 x 18.5 cm polyethylene cages (3 animals / cage) with stainless steel top grills that were easy to access for pelleted food and drinking water in plastic bottles; bedding: steam-sterilized clean rice husk (Envigo, Sani-chip, Cat. No.: 7090C), and bedding material was changed along with the cage at least twice a week.

[0477] feed Animals were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Envigo, Cat. No. 2018SC) ad libitum. Animals had free access to standard tap drinking water obtained from a municipal source and treated according to Pharmaseed's SOP No. 214: "Water system". Animal diets arrived with a certificate of analysis and water was autoclaved prior to use.

[0478] environmental conditions Animals were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Cat. No. 2018SC) ad libitum. Animals had ad libitum access to autoclaved, acidified drinking water (pH 2.5–3.5) obtained from a municipal source.

[0479] Randomization Upon arrival, animals were assigned to cages according to Pharmaseed's SOP#027 "Random allocation of animals."

[0480] Experimental design and conditions Pain relief methods The MCAO procedure was performed under anesthesia with 4% isoflurane in a mixture of 70% N2O and 30% O2, and maintained with 1.5-2% isoflurane. Meloxicam, 2 mg / kg, was administered subcutaneously (SC) before and after surgery, and once daily for the next 4 days. Buprenorphine, 0.01 mg / kg, was administered after surgery and at the end of the working day, and thereafter only if there were signs of pain and discomfort.

[0481] Continuation of the experimental period The first administration date was assigned as "Day 1," and the end date was "Day 29," 28 days after surgery.

[0482] Study Design and Timeline Test items-amodiaquine, canrenoate, glibenclamide, and exenatide were evaluated in various combinations and compared to vehicle control treated or sham operated rats. The study was performed in cycles, with 10 rats in each cycle. Test compounds were administered immediately after reperfusion and twice daily thereafter. Stroke was induced on day 1 by t-MCAO procedure. Neurological scores (NSS) were performed pre-surgery as baseline, 24 hours after t-MCAO, and weekly thereafter. Animals with a score of 10 or greater were included in the study. Baseline evaluations were performed for the stepping test, the forelimb placing test, and then at weeks 2 and 4 of the study. The elevated plus maze test was performed at weeks 2 and 4 of the study, and the object recognition test at week 4. At the end of the study, the animals were anesthetized and subjected to transcardial perfusion with 0.9% saline followed by 2.5% buffered PFA. Brains were harvested, fixed in the same fixative and stored at 4° C. Brain samples were embedded in paraffin, sectioned and stained with H&E and other stains for histological markers as previously detailed. The experimental design and timeline are presented below:

[0483] Study Design: This study, sponsored by the applicant, was conducted at Pharmaseed Ltd, Ness-Ziona, Israel. [Table 6]

[0484] Research timeline: [Table 7]

[0485] Treatment and Evaluation Surgical procedure-t-MCAO Transient middle cerebral artery occlusion (t-MCAO) was performed according to the method described by R. Schmid-Elsaesser et al. The right common carotid artery (CCA) was exposed by a midline cervical incision and carefully cut free of surrounding nerves and fascia - from the bifurcation to the base of the skull. The occipital artery branches of the external carotid artery (ECA) were isolated, dissected and coagulated. The ECA was dissected further distally and coagulated just before the bifurcation, along with the terminal lingual and maxillary artery branches. The internal carotid artery (ICA) was isolated and carefully separated from the adjacent vagus nerve, and the pterygopalatine artery was ligated near its origin with a 5-0 nylon suture. A 4-0 silk suture was then tied loosely around the mobilized ECA stump and a 4 cm length of 4-0 monofilament nylon suture (the suture tip was blunted using a flame and the suture was coated with polylysine prior to insertion) was inserted through the proximal ECA into the ICA and from there into the Circle of Willis, effectively occluding the MCA. The surgical wound was closed and the animals were returned to their cages and allowed to recover from anesthesia. One and a half hours after occlusion, the rats were re-anesthetized and the monofilament was removed to allow for reperfusion. The surgical wound was closed and the rats were returned to their cages.

[0486] After surgery, animals were placed on a heating pad until they recovered from anesthesia. All animals received 2 mg / kg meloxicam subcutaneously daily before and after surgery for the next 2 days. The animals were observed frequently on the day of t-MCAO surgery and at least once a day thereafter.

[0487] Test item administration Treatment was initiated immediately after reperfusion and then later the same day via IP administration of test compound at a dose volume of 1 mL / kg, and continued twice daily thereafter for 4 consecutive weeks.

[0488] Animals were subjected to NSS testing 24 hours prior to surgery as a baseline, and then weekly for 4 weeks.

[0489] Forelimb placing test The Forelimb Placement Test (FPT) was performed before MCAO surgery (for baseline), at 2 and 4 weeks. The animal was held close to the table top and the rat's ability to place its forelimbs on the table surface in response to whisker, visual, tactile, or proprioceptive stimulation was scored. Separate subscores were obtained for each mode of sensory input and added together to obtain a total score. Forelimb Placement Test scores range from 0 = normal to 12 = maximal impairment. Typically, scores recover slowly and steadily over the first month after stroke.

[0490] Footstep test Animals were tested for forelimb akinesia in the Stepping Test (ST) according to Pharmaseed's SOP#111 ("Stepping Test for Rat"). ST was performed before, 2 weeks and 4 weeks after MCAO surgery. Animals were held immobile by their hind limbs with one hand and immobile and immobile the unsupervised forelimb with the other hand, with the unrestrained forepaw touching the table. Animals were moved laterally along the table surface (85 cm in approximately 5 seconds) and the number of coordinated steps in the forehand & backhand direction of both forelimbs was counted.

[0491] Elevated Plus Maze Test (Pharmaseed SOP#120) Animals were tested for anxiety levels in the elevated plus maze test at weeks 2 and 4. Normal behavior of rats in the elevated plus maze involves exploratory activity, with rats spending equal amounts of time in the open and closed arms of the maze. Monitoring of behavior in this task (i.e., visiting open and closed arms) reflects the conflict between rodents' preference for protected areas (e.g., closed arms) and their innate motivation to explore novel environments.

[0492] Object Recognition Test (Pharmaseed SOP#116) Animals were tested at week 4 in a novel object recognition task for recognition memory testing. Rats were guided to a novel object versus a familiar object. The number of visits and time spent near either the novel or familiar object were recorded. Under normal conditions, novel objects are visited more frequently and for longer periods of time than familiar objects.

[0493] end On day 29 after MCAO surgery, animals were anesthetized and subjected to transcardial perfusion with 0.9% saline followed by 2.5% buffered PFA. Brains were harvested, fixed in the same fixative and stored at 4°C. Gross examination of the brain Histological analysis included: ○ Preparation and trimming of tissues from all surviving animals (affected hemisphere), precise cross-sections of stroke lesions at 100 micron intervals X8. Regions of interest: α-penumbra, striatum, and dorsal hippocampus. o Preparation of paraffin blocks. H&E staining and infarct volumes were analyzed for all surviving animals. The following analyses were performed across all three regions of interest: TUNEL-apoptosis method (n=46). ○IHC: Doublecortin and NeuN (for mature neurons) for neuronal regeneration in the ventricles (n=46). Myelin analysis: Digital image analysis was used to analyze IHC for MBP, Olig-2, and NG2 (n=46). Inflammation analysis: Digital image analysis was used to analyze IHC for Iba-1 and GFAP (n=46). Neuronal cell death counts, morphometric analysis of MBP, Olig-2, NG2, GFAP, and Iba-2 (n=46).

[0494] result Neuro-score evaluation during the study The neurological score (NSS) included a series of clinical neurological tests (a composite of motor, sensory, reflex and balance tests) used to evaluate the effects of amodiaquine in combination with exenatide, glibenclamide and potassium canrenoate. Neurological scores were graded on a scale of 0 to 18 (with a normal score of 0 and a maximum deficit score of 18). Before surgery, all animals showed normal behavior with a score of 0. As shown in Figure 9, in all groups of rats that underwent t-MCAO surgery, a sharp decline in neurological function (increased NSS) was observed 24 hours after t-MCAO, which then improved somewhat over time. In group 6M, the improvement finally became statistically significant from the second week.

[0495] Two-way ANOVA followed by Bonferroni post hoc comparisons found statistically significant differences between group 2M (vehicle control) and drug treatment groups: 3M amodiaquine (0.5 mg / kg) + canrenoate (0.33 mg / kg) + glibenclamide (1 μg / kg), 4M amodiaquine (0.5 mg / kg) + exenatide (0.05 μg / kg) + glibenclamide (1 μg / kg), 5M amodiaquine (0.5 mg / kg) + canrenoate (0.33 mg / kg) + exenatide (0.05 μg / kg) on ​​day 2 and weeks 1-4. Group 6M - Exenatide (0.05 μg / kg) + Canrenoic acid (0.33 mg / kg) + Glibenclamide (1 μg / kg) - only started to show statistically significant differences from week 2 onwards. Figures show mean ± SEM; ** indicates p<0.01, *** indicates p<0.001.

[0496] Foot Stepping Test (ST) For forelimb akinesia, animals were tested with the stepping test, a commonly used measure of neuromuscular function as an index of animal motor function. On the day before surgery, all animals were behaving normally and performed similarly to the sham-operated group. As shown in Figure 10, all t-MCAO groups showed statistically significant performance impairments (lower scores) compared to the sham-operated group 1M. Statistically significant improvements in motor function over time (higher scores) were observed in all treated animal groups compared to the vehicle-treated group 2M (p<0.001).

[0497] Forelimb Placing Test (FPT) Somatosensory and sensorimotor impairments were assessed using the forelimb placing test. All animals behaved normally the day before surgery. Functional improvements were observed in all treatment groups compared to the vehicle-treated group, which was statistically significant at p<0.001 (by two-way ANOVA followed by Bonferroni post-hoc comparisons). The results are presented in Figure 11.

[0498] Elevated Plus Maze Test (Pharmaseed SOP#120) The animals were tested for anxiety levels at 2 and 4 weeks in the elevated plus maze test. As shown in Figure 13, all animals spent more time in the closed arms of the maze. Statistically significant differences were found between vehicle-treated group 2M and group 3M treated with amodiaquine + canrenoate + glibenclamide at 2 and 4 weeks. Figures show mean values ​​± SEM; *** indicates p<0.001 by two-way ANOVA followed by Bonferroni post-hoc comparison. No statistically significant differences were found between all other groups during the study.

[0499] Object Recognition Test (Pharmaseed SOP#116) The animals were tested at week 4 in an object recognition test for recognition memory testing. Rats were guided to a novel object versus a familiar object. The time spent near either the novel or familiar object was recorded. Vehicle-treated animals showed impairment compared to sham-operated rats (p<0.05) and spent more time exploring the familiar object. Statistically significant improvements compared to vehicle treatment were found in groups 3M (treated with amodiaquine + canrenoate + glibenclamide combination) and 4M (treated with amodiaquine + exenatide + glibenclamide combination). The results are presented in Figure 12. The figures show the mean ± SEM; * indicates p<0.05 and ** indicates p<0.01 using two-way ANOVA followed by Bonferroni post-hoc comparisons.

[0500] Infarct size Infarct size was measured by image analysis using the ImageJ program. As shown in Figure 14 below, all amodiaquine-containing groups - 3M, 4M, and 5M (but not 6M) - treatments showed statistically significant reductions in cerebral infarct size (more than 2-fold smaller) compared to vehicle-treated controls. Two groups, 3M and 5M, showed statistical improvement over group 6M.

[0501] histology results Apoptosis measured by TUNEL Apoptosis, an important specific parameter for neuroprotection, was measured by TUNEL staining, revealing that all t-MCAO groups presented significantly more apoptotic cells compared to the sham-operated group. The triple combination (group 3M) significantly reduced the apoptotic number of cells compared to the vehicle-treated control (group 2M) (*p<0.05). At this stage, the combination without amodiaquine (group 6M) showed a higher percentage of apoptotic cells than group 3M treatment (**p<0.01). See Figure 17.

[0502] Myelin Basic Protein (MBP) density measured by IHC MBP density represents myelin damage. Control vehicle-treated animals showed a significant decrease in myelin density compared to sham-operated animals. Group 6M, treated without amodiaquine, also showed a significant decrease in myelin density compared to sham-operated animals. However, all combination groups containing amodiaquine were not significantly different from sham-operated animals, suggesting a protective effect of these combinations (see FIG. 24).

[0503] Mean cell numbers of Olig-2 determined by morphometric analysis According to one-way ANOVA, the triple combination group 4M significantly increased Oligo-2 density compared with the triple combination group 3M (group 1M) (*p<0.05). No statistically significant differences were found between the sham-operated group and all other groups (Figure 18).

[0504] NG2 oligodendrocyte precursor cells NG2 oligodendrocyte precursor cells were statistically significantly increased in the vehicle-treated group (Group 2M) compared to the sham-operated group (1M) and were also higher in two of the treatment combinations (4M and 5M) (P<0.05 by t-test). The triple combination groups (3M and 6M) at this stage significantly reduced the area of ​​activated microglia compared to the vehicle control group (Group 2M) by one-way ANOVA (*p<0.05; **p<0.01). For further details, see Figure 19.

[0505] NeuN neurons The vehicle control group (Group 2M) significantly reduced NeuN density compared to the sham control (Group 1M) (*p<0.05). The triple combination group (3M) at this stage also significantly reduced NeuN density compared to the sham operation control (Group 1M) (*p<0.05) by one-way ANOVA. For details, see Figure 20.

[0506] As shown in Figures 21, 22 and 23, the other three parameters assessed by morphometric analysis at the end of the fourth week were GFAP, Ila-1 and doublecortin in the brain regions.

[0507] GFAP Morphometric analysis of Glial Fibrillary Acidic Protein (GFAP), which represents reactive astrocytes, showed a statistically significant increase in GFAP in the vehicle-treated control group 2M compared to the sham-operated groups 1M (p<0.001) and 6M (p<0.01). By one-way ANOVA, the triple combination treatment groups 3M, 4M, and 5M reduced the GFAP marker compared to the vehicle treatment group 2M (p<0.001, p<0.001, and p<0.05, respectively). See Figure 21.

[0508] Iba-1 staining The results of morphometric analysis of Iba-1 staining (representing microglial cells in the ischemic brain) showed the same trend as that shown for GFAP, i.e., group 2M (vehicle treatment) showed the highest values ​​and the triple combination groups (3M, 4M, 5M and sham operation group 1M) showed the lowest values ​​by one-way ANOVA (**p<0.01; ***p<0.001). Group 6M was only statistically significant compared to the sham operation 1M group (p<0.001). See Figure 22.

[0509] Doublecortin staining The results of morphometric analysis of doublecortin staining (representing the neurogenesis process) showed higher values ​​in the triple combination groups of 3M, 4M, and 5M compared to group 2M (vehicle treatment) by t-test (p<0.05), see Figure 23.

[0510] conclusion The results of Example 3 are consistent with previous stroke model studies (placebo group, infarct size, NSS test). A progressive improvement in NSS is observed over time (day 28 vs. day 8). Furthermore, a relatively better improvement in infarct size with the triple combination was observed at day 28 compared to day 8 results, and compared to the control (38%-27% vs. 12%-8% and 15%-10%). Significant improvements are also observed in memory tests.

[0511] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

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Claims

1. (a) a first component that is a Nurr1 agonist; (b)(i) an aldosterone antagonist; (ii) an insulin modulator; and (iii) sulfonylurea and at least one additional ingredient selected from A combination including:

2. 2. The combination of claim 1, wherein the Nurr1 agonist is selected from amodiaquine, chloroquine, hydroxychloroquine and glafenine, and pharmaceutically acceptable salts thereof, more preferably amodiaquine or a pharmaceutically acceptable salt thereof.

3. amodiaquine, or a pharmaceutically acceptable salt thereof; Aldosterone antagonists; 10. The combination of claim 1, comprising at least one of the following components: an insulin modulator, and a sulfonylurea.

4. 2. The combination of claim 1, wherein the aldosterone antagonist is potassium canrenoate or a structural or functional analog thereof.

5. 2. The combination of claim 1, comprising amodiaquine, or a pharmaceutically acceptable salt thereof; an aldosterone antagonist; and an insulin modulator.

6. 6. The combination of claim 5, wherein the insulin modulator is selected from exenatide, its structural and functional analogs, and pharmaceutically acceptable salts thereof.

7. 7. The combination of claim 6, wherein the structural or functional analog of exenatide is selected from lixisenatide, albiglutide, semaglutide, liraglutide, taspoglutide and dulaglutide (LY2189265).

8. amodiaquine, or a pharmaceutically acceptable salt thereof; Aldosterone antagonists; and Sulfonylurea 2. The combination of claim 1, comprising:

9. 9. The combination of claim 8, wherein the sulfonylurea is selected from glibenclamide, its pharmaceutically acceptable salts, and structural and functional analogs thereof.

10. 10. The combination according to claim 9, wherein the structural or functional analogue of glibenclamide is selected from the acylhydrazone, sulfonamide and sulfonylthiourea derivatives of glibenclamide, glimepiride, glipizide and gliclazide, preferably gliclazide.

11. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 2. The combination of claim 1, comprising:

12. amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharmaceutically acceptable salt thereof 2. The combination of claim 1, comprising:

13. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Glibenclamide, a structural or functional analogue thereof, or a pharmaceutically acceptable salt thereof 2. The combination of claim 1, comprising:

14. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; and glibenclamide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof.

2. The combination of claim 1, comprising:

15. amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 2. The combination of claim 1, comprising:

16. 3. The combination of claim 2, comprising the hydrochloride salt of amodiaquine.

17. 10. The combination of claim 1, comprising at least one further active pharmaceutical ingredient (API) selected from beta blockers, renin-angiotensin inhibitors, statins (HMG-CoA reductase inhibitors), inhibitors of platelet activation or aggregation, phosphodiesterase-3 inhibitors, calcium sensitizers, antioxidants, and anti-inflammatory agents.

18. 10. A pharmaceutical composition comprising the combination of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

19. (a) a first component that is a Nurr1 agonist; (b)(i) an aldosterone antagonist; (ii) an insulin modulator; and (iii) sulfonylureas, and at least one additional ingredient selected from Pharmaceutical products including:

20. amodiaquine, or a pharmaceutically acceptable salt thereof; Aldosterone antagonists; 20. The pharmaceutical product of claim 19, comprising at least one of the following ingredients: an insulin modulator, and a sulfonylurea.

21. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 21. The pharmaceutical product of claim 20, comprising:

22. amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; Glibenclamide, a structural or functional analogue thereof, or a pharmaceutically acceptable salt thereof 21. The pharmaceutical product of claim 20, comprising:

23. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Glibenclamide, a structural or functional analogue thereof, or a pharmaceutically acceptable salt thereof 21. The pharmaceutical product of claim 20, comprising:

24. amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; and glibenclamide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical product of claim 20, comprising:

25. amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 21. The pharmaceutical product of claim 20, comprising:

26. 26. A combination according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, or a pharmaceutical product according to any one of claims 19 to 25, for use in the treatment and / or prevention of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock and acute myocardial infarction, or for use in providing cardioprotection against cardiotoxic drugs, or for use in providing neuroprotection.

27. 27. The combination, pharmaceutical composition or pharmaceutical product for use according to claim 26, wherein the ischemia and / or reperfusion injury is cerebral, cardiac, pulmonary or renal ischemia and / or reperfusion injury, preferably cerebral ischemia, cerebral reperfusion injury or stroke.

28. 27. The combination, pharmaceutical composition or pharmaceutical product for use according to claim 26 for use in the treatment or prevention of ischemic stroke.

29. 27. A combination, pharmaceutical composition or pharmaceutical product for use according to claim 26 for use in the treatment or prevention of neuroinflammation or neuroinflammatory disorders.

30. 30. The combination, pharmaceutical composition or pharmaceutical product for use according to claim 29, wherein the neuroinflammatory disorder is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis and neuromyelitis optica (NMO).

31. 30. The combination, pharmaceutical composition or pharmaceutical product for use according to claim 29, wherein the neuroinflammation is associated with traumatic brain injury, spinal cord injury, aging, schizophrenia, depression, migraine, epilepsy, neuropathic pain, Down's syndrome, autism, premature birth, glaucoma, or viral infection.

32. 27. The combination, pharmaceutical composition or pharmaceutical product for use according to claim 26, for use in the treatment or prevention of a neurodegenerative disease, preferably selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), and vascular dementia.

33. 27. A combination, pharmaceutical composition or pharmaceutical product for use according to claim 26 for providing neuroprotection.

34. A combination according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, or a pharmaceutical product according to any one of claims 19 to 25, formulated for intravenous administration.

35. A combination according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, or a pharmaceutical product according to any one of claims 19 to 25, formulated for subcutaneous administration.

36. A combination according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, or a pharmaceutical product according to any one of claims 19 to 25, formulated for oral administration.

37. A combination according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, or a pharmaceutical product according to any one of claims 19 to 25, formulated for nasal administration.

38. For use in the treatment and / or prevention of one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or in cardioprotection against cardiotoxic drugs, or in neuroprotection, (a) a first component that is a Nurr1 agonist; (b)(i) an aldosterone antagonist; (ii) an insulin modulator; and (iii) sulfonylureas, At least one additional ingredient selected from wherein the components are for simultaneous, sequential or separate administration.

39. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, (a) a first component that is a Nurr1 agonist; (b)(i) an aldosterone antagonist; (ii) an insulin modulator; and (iii) sulfonylurea and at least one additional ingredient selected from Use of.

40. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 40. The use of claim 39, comprising the use of

41. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Glibenclamide, a structural or functional analogue thereof, or a pharmaceutically acceptable salt thereof 40. The use of claim 39, comprising the use of

42. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; and glibenclamide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof.

40. The use of claim 39, comprising the use of

43. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharmaceutically acceptable salt thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof 40. The use of claim 39, comprising the use of

44. In the manufacture of a medicament for treating and / or preventing one or more of ischemia and / or reperfusion injury, neuroinflammation, neuroinflammatory disorders, stroke, neurodegenerative diseases, neonatal asphyxia, cardiac arrest, cardiogenic shock, and acute myocardial infarction, or for providing cardioprotection against cardiotoxic drugs, or for providing neuroprotection, amodiaquine, or a pharmaceutically acceptable salt thereof; with potassium canrenoate, or a structural or functional analog thereof; Exenatide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof; and glibenclamide, a structural or functional analog thereof, or a pharmaceutically acceptable salt thereof.

40. The use of claim 39, comprising the use of

45. 1. A combination for use in the treatment and / or prevention of ischemia and / or reperfusion injury in an ex vivo organ prior to or during transplantation, comprising: (a) a first component that is a Nurr1 agonist; (b)(i) an aldosterone antagonist; (ii) an insulin modulator; and (iii) sulfonylureas, and at least one additional ingredient selected from The combination comprising:

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